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Expansion of intronic GGGGCC repeats in the C9orf72 gene causes amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Transcription of the expanded repeats results in the formation of RNA-containing nuclear foci and altered RNA metabolism. In addition, repeat-associated non-AUG (RAN) translation of the expanded GGGGCC-repeat sequence results in the production of highly toxic dipeptide-repeat (DPR) proteins. GGGGCC repeat-containing transcripts form G-quadruplexes, which are associated with formation of RNA foci and RAN translation. Zfp106, an RNA-binding protein essential for motor neuron survival in mice, suppresses neurotoxicity in a Drosophila model of C9orf72 ALS. Here, we show that Zfp106 inhibits formation of RNA foci and significantly reduces RAN translation caused by GGGGCC repeats in cultured mammalian cells, and we demonstrate that Zfp106 coexpression reduces the levels of DPRs in C9orf72 patient-derived cells. Further, we show that Zfp106 binds to RNA G-quadruplexes and causes a conformational change in the G-quadruplex structure formed by GGGGCC repeats. Together, these data demonstrate that Zfp106 suppresses the formation of RNA foci and DPRs caused by GGGGCC repeats and suggest that the G-quadruplex RNA-binding function of Zfp106 contributes to its suppression of GGGGCC repeat-mediated cytotoxicity. [ABSTRACT FROM AUTHOR]

Abstract: Analogous to reversible post‐translational protein modifications, the ability to attach and subsequently remove modifications on proteins would be valuable for protein and biological research. Although bioorthogonal functionalities have been developed to conjugate or cleave protein modifications, they are introduced into proteins on separate residues and often with bulky side chains, limiting their use to one type of control and primarily protein surface. Here we achieved dual control on one residue by genetically encoding S‐propargyl‐cysteine (SprC), which has bioorthogonal alkyne and propargyl groups in a compact structure, permitting usage in protein interior in addition to surface. We demonstrated its incorporation at the dimer interface of glutathione transferase for in vivo crosslinking via thiol–yne click chemistry, and at the active site of human rhinovirus 3C protease for masking and then turning on enzyme activity via Pd‐cleavage of SprC into Cys. In addition, we installed biotin onto EGFP via Sonogashira coupling of SprC and then tracelessly removed it via Pd cleavage. SprC is small in size, commercially available, nontoxic, and allows for bond building and breaking on a single residue. Genetically encoded SprC will be valuable for chemically controlling proteins with an essential Cys and for reversible protein modifications. [ABSTRACT FROM AUTHOR]

Described for the first time is that carbon dioxide (CO2) can be successfully inserted into aryl C−H bonds of the backbone of a metal-organic framework (MOF) to generate free carboxylate groups, which serve as Brønsted acid sites for efficiently catalyzing the methanolysis of epoxides. The work delineates the very first example of utilizing CO2 for heterogeneous C−H activation and carboxylation reactions on MOFs, and opens a new avenue for CO2 chemical transformations under mild reaction conditions. [ABSTRACT FROM AUTHOR]

Foldamers offer an attractive opportunity for the design of novel molecules that mimic the structures and functions of proteins and enzymes including biocatalysis and biomolecular recognition. Herein we report a new class of nonnatural helical sulfono-γ-AApeptide foldamers of varying lengths. The crystal structure of the sulfono-γ-AApeptide monomer S6 illustrates the intrinsic folding propensity of sulfono-γ-AApeptides, which likely originates from the bulkiness of tertiary sulfonamide moiety. The two-dimensional solution NMR spectroscopy data for the longest sequence S1 demonstrates a 10/16 right-handed helical structure. Optical analysis using circular dichroism further supports well- defined helical conformation of sulfono-γ-AApeptides in solution containing as few as five building blocks. Future development of sulfono-γ-AApeptides may lead to new foldamers with discrete functions, enabling expanded application in chemical biology and biomedical sciences. [ABSTRACT FROM AUTHOR]

Herein we report a highly efficient new method for preparing γ-AApeptides capable of theoretically containing any functionality; the method uses a few common N-alloc γ-AApeptide building blocks. More importantly, using the same approach, new classes of peptidomimetics bearing novel backbone scaffolds can also be readily generated. Our results not only demonstrate the versatility of this new synthetic method, but also highlight the possibility that the resulting novel peptidomimetics may find discrete biomedical/biomaterial applications in the future. [ABSTRACT FROM AUTHOR]

Although peptide amphiphiles have been explored as nanomaterialsfor different applications, nanostructures formed by hierarchicalmolecular assembly of sequence-specific peptidomimetics are much lessdeveloped. Such protein-like nanomaterials could enhance the currentapplication of peptide-based amphiphiles by enriching the diversityof nanostructures, increasing in vivostability forbiomedical applications, and facilitating the understanding of biomacromolecularself-assembly. Herein we present a biomimetic γ-AApeptide amphiphilewhich forms nanorods. Our results demonstrate the capability of γ-AApeptideamphiphiles as a potential scaffold for the preparation of biomimeticand bioinspired nanostructures. The programmability and biocompatibilityof γ-AApeptides could lead to novel nanomaterials for a widevariety of applications. [ABSTRACT FROM AUTHOR]

The solid-phase synthesis of γ-AApeptides using a novel submonomeric approach that utilizes an allyl protection is reported. The strategy successfully circumvents the necessity of preparing γ-AApeptide building blocks in order to prepare γ-AApeptide sequences. This method will maximize the potential of developing chemically diverse γ-AApeptide libraries and thereby facilitate the biological applications of γ-AApeptides in the future. [ABSTRACT FROM AUTHOR]

We report the identification of a new class of antimicrobial peptidomimetics-γ-AApeptides with potent and broad-spectrum activity, including clinically-relevant strains that are unresponsive to most antibiotics. They are also not prone to select for drug-resistance. [ABSTRACT FROM AUTHOR]

We report a new class of peptide mimetics, α-AApeptides, that display broad-spectrum activity against both Gram-negative and Gram-positive bacteria and fungi. With non-hemolytic activity, resistance to protease hydrolysis, and easy sequence programmability, α-AApeptides may emerge as a novel class of antibiotics. [ABSTRACT FROM AUTHOR]

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Objective: To assess the reliability of quantitative ultrasound (QUS) in diagnosing and screening osteoporosis in elder women., Methods: We conducted a systematic search of the online databases, including PubMed, Embase, Web of Science, and China National Knowledge, and screened the studies according to the inclusion criteria. We directly extract or calculate the value of true positive (TP), false positive (FP), false negative (FN), and true negative (TN) from eligible studies. We sought to evaluate the diagnostic parameters of QUS, containing the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC)., Results: Twelve studies were included in this study with a total of 2260 women. QUS showed a pooled diagnostic odds ratio of 5.07 (95% CI 3.28-7.84), sensitivity of 0.69 (95% CI 0.65-0.72), specificity of 0.67 (95% CI 0.64-0.69), and an AUC of 0.7523 (Q*=0.6953). There was no obvious heterogeneity and threshold effect according to the Spearman correlation coefficient (P = 0.059). No significant publication bias was found through the Deek's funnel., Conclusion: Our study suggested that the diagnostic value of QUS for osteoporosis in elder women was acceptable, but the accuracy still needed to be improved, QUS can be recommended as a pre-screening tool for osteoporosis to determine whether DXA measurement was needed.

Genetically encoded non-canonical amino acids (ncAAs) with electrophilic moieties are excellent tools to investigate protein-protein interactions (PPIs) both in vitro and in vivo . These ncAAs, including a series of alkyl bromide-based ncAAs, mainly target cysteine residues to form protein-protein cross-links. Although some reactivities towards lysine and tyrosine residues have been reported, a comprehensive understanding of their reactivity towards a broad range of nucleophilic amino acids is lacking. Here we used a recently developed OpenUaa search engine to perform an in-depth analysis of mass spec data generated for Thioredoxin and its direct binding proteins cross-linked with an alkyl bromide-based ncAA, BprY. The analysis showed that, besides cysteine residues, BprY also targeted a broad range of nucleophilic amino acids. We validated this broad reactivity of BprY with Affibody/Z protein complex. We then successfully applied BprY to map a binding interface between SUMO2 and SUMO-interacting motifs (SIMs). BprY was further applied to probe SUMO2 interaction partners. We identified 264 SUMO2 binders, including several validated SUMO2 binders and many new binders. Our data demonstrated that BprY can be effectively used to probe protein-protein interaction interfaces even without cysteine residues, which will greatly expand the power of BprY in studying PPIs., Competing Interests: Author S-TL is employed by the company Glbizzia Biosciences Co., Ltd., Beijing, China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Shu, Asghar, Yang, Li, Wu and Yang.)

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane receptor of the immunoglobulin superfamily that is secreted in a soluble (sTREM2) form. Mutations in TREM2 have been linked to increased risk of Alzheimer's disease (AD). A prominent neuropathological component of AD is deposition of the amyloid-β (Aβ) into plaques, particularly Aβ40 and Aβ42. While the membrane-bound form of TREM2 is known to facilitate uptake of Aβ fibrils and the polarization of microglial processes toward amyloid plaques, the role of its soluble ectodomain, particularly in interactions with monomeric or fibrillar Aβ, has been less clear. Our results demonstrate that sTREM2 does not bind to monomeric Aβ40 and Aβ42, even at a high micromolar concentration, while it does bind to fibrillar Aβ42 and Aβ40 with equal affinities (2.6 ± 0.3 µM and 2.3 ± 0.4 µM). Kinetic analysis shows that sTREM2 inhibits the secondary nucleation step in the fibrillization of Aβ, while having little effect on the primary nucleation pathway. Furthermore, binding of sTREM2 to fibrils markedly enhanced uptake of fibrils into human microglial and neuroglioma derived cell lines. The disease-associated sTREM2 mutant, R47H, displayed little to no effect on fibril nucleation and binding, but it decreased uptake and functional responses markedly. We also probed the structure of the WT sTREM2-Aβ fibril complex using integrative molecular modeling based primarily on the cross-linking mass spectrometry data. The model shows that sTREM2 binds fibrils along one face of the structure, leaving a second, mutation-sensitive site free to mediate cellular binding and uptake., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)