Integrating cryo-OrbiSIMS with computational modelling and metadynamics simulations enhances RNA structure prediction at atomic resolution.

The 3D architecture of RNAs governs their molecular interactions, chemical reactions, and biological functions. However, a large number of RNAs and their protein complexes remain poorly understood due to the limitations of conventional structural biology techniques in deciphering their complex structures and dynamic interactions. To address this limitation, we have benchmarked an integrated approach that combines cryogenic OrbiSIMS, a state-of-the-art solid-state mass spectrometry technique, with computational methods for modelling RNA structures at atomic resolution with enhanced precision.

Uploading Risk: Examining the Social Profile of Young Adults Most Susceptible to Engagement in Risky Social Media Challenges.

The aim of this study was to determine the social profile of individuals who are most at risk of engaging in risky social media challenges (RSMCs). Young adults ( = 331, 56.3 percent female) aged 18-25 years ( = 21.

Narrative Elicitation as Ethnography: Methodological Insights From the Examination of Children's Perspective Marking in Amdo Tibetan.

This paper employs a case study with Amdo Tibetan children to demonstrate the benefits of narrative elicitation for ethnographic language socialization research in under-studied languages. Primarily by examining spontaneous verbal interaction, existing language socialization research has demonstrated how salient grammatical resources shape children's understanding of cultural belief systems pertaining to sociality and the appropriate display of emotion. However, spontaneous data do not always capture children's full linguistic repertoires and competencies, and may therefore present a partial picture of their mastery over particular grammatical systems.

Does teaching an omnibus mand preclude the development of specifying mands?

When problem behavior is controlled by a synthesized reinforcement contingency, a simple omnibus mand that yields access to all reinforcers simultaneously has been shown to effectively replace problem behavior. The question arises as to whether teaching an omnibus mand will preclude the acquisition of specifying mands for each of the combined reinforcers. In this study, after 3 students diagnosed with autism acquired an omnibus mand ("My way, please") that yielded all identified reinforcers simultaneously, specifying mands (e.

The effect of the branched-chain amino acids on the in-vitro activity of bovine intestinal alkaline phosphatase.

Branched-chain amino acids (BCAA) are used as nutritional support for patients with a range of conditions including liver cirrhosis and in-born errors of amino acid metabolism, and they are commonly used "sports" or exercise supplements. The effects of the BCAA on the in-vitro activity of calf intestinal alkaline phosphatase (EC. 3.

A retrospective analysis of biochemical and haematological parameters in patients with eating disorders.

Background: The objective of the study was to determine whether levels of biochemical and haematological parameters in patients with eating disorders (EDs) varied from the general population. Whilst dietary restrictions can lead to nutritional deficiencies, specific abnormalities may be relevant to the diagnosis, pathogenesis and treatment of EDs.

Methods: With ethics approval and informed consent, a retrospective chart audit was conducted of 113 patients with EDs at a general practice in Brisbane, Australia.

Conceiving modernity: discourses on reproduction in a community of Tibetan refugees.

This article examines the trope of reproduction in narratives of Tibetan refugees living in Dharamsala, India. As they make sense of their personal histories, Tibetan refugees invoke a collective story that mirrors human rights literature on Tibet. Women come into contact with this literature through its incorporation into a political discourse expressed by the exile government and health institutions.

Identification of nuclear export inhibitors with potent anticancer activity in vivo.

The export protein CRM1 is required for the nuclear export of a wide variety of cancer-related "cargo" proteins including p53, c-Abl, and FOXO-3A. Leptomycin B (LMB) is a highly specific inhibitor of CRM1 with significant in vitro potency but limited in vivo efficacy due to toxicity. We now report a series of semisynthetic LMB derivatives showing substantially improved therapeutic windows.

Precursor-directed biosynthesis of 6-deoxyerythronolide B analogues is improved by removal of the initial catalytic sites of the polyketide synthase.

Precursor-directed biosynthesis has been shown to be a powerful tool for the production of polyketide analogues that would be difficult or cost prohibitive to produce from medicinal chemistry efforts alone. It has been most extensively demonstrated using a KS1 null mutation (KS1(0)) to block the first round of condensation in the biosynthesis of the erythromycin polyketide synthase (DEBS) for the production of analogues of its aglycone, 6-deoxyerythronolide B (6-dEB). Here we show that removing the DEBS loading domain and first module (mod1Delta), rather than using the KS1(0) system, can lead to an increase in the utilization of some chemical precursors and production of 6-dEB analogues (R-6dEB) in both Streptomyces coelicolor and Saccharopolyspora erythraea.

Chalcomycin biosynthesis gene cluster from Streptomyces bikiniensis: novel features of an unusual ketolide produced through expression of the chm polyketide synthase in Streptomyces fradiae.

Chalcomycin, a 16-membered macrolide antibiotic made by the bacterium Streptomyces bikiniensis, contains a 2,3-trans double bond and the neutral sugar D-chalcose in place of the amino sugar mycaminose found in most other 16-membered macrolides. Degenerate polyketide synthase (PKS)-specific primers were used to amplify DNA fragments from S. bikiniensis with very high identity to a unique ketosynthase domain of the tylosin PKS.

Production of hybrid 16-membered macrolides by expressing combinations of polyketide synthase genes in engineered Streptomyces fradiae hosts.

Combinations of the five polyketide synthase (PKS) genes for biosynthesis of tylosin in Streptomyces fradiae (tylG), spiramycin in Streptomyces ambofaciens (srmG), or chalcomycin in Streptomyces bikiniensis (chmG) were expressed in engineered hosts derived from a tylosin-producing strain of S. fradiae. Surprisingly efficient synthesis of compounds predicted from the expressed hybrid PKS was obtained.

Engineered biosynthesis of 16-membered macrolides that require methoxymalonyl-ACP precursors in Streptomyces fradiae.

Development of host microorganisms for heterologous expression of polyketide synthases (PKS) that possess the intrinsic capacity to overproduce polyketides with a broad spectrum of precursors supports the current demand for new tools to create novel chemical structures by combinatorial engineering of modular and other classes of PKS. Streptomyces fradiae is an ideal host for development of generic polyketide-overproducing strains because it contains three of the most common precursors--malonyl-CoA, methylmalonyl-CoA and ethylmalonyl-CoA--used by modular PKS, and is a host that is amenable to genetic manipulation. We have expanded the utility of an overproducing S.

Elucidating the mechanism of cis double bond formation in epothilone biosynthesis.

The epothilones, originally isolated from the myxobacterium Sorangium cellulosum, are macrocyclic compounds that are synthesized by a modular polyketide synthase, an enzyme complex composed of six large, multifunctional proteins. The penultimate intermediates in epothilone production, and the products of the PKS-catalyzed reactions, are epothilones D and C, which contain a 12,13-cis-double bond. The 12 and 13 positions of epothilones are generated during the fourth elongation step that is governed by module 4.