Project description:PNAS article classification is rooted in long-standing disciplinary divisions that do not necessarily reflect the structure of modern scientific research. We reevaluate that structure using latent pattern models from statistical machine learning, also known as mixed-membership models, that identify semantic structure in co-occurrence of words in the abstracts and references. Our findings suggest that the latent dimensionality of patterns underlying PNAS research articles in the Biological Sciences is only slightly larger than the number of categories currently in use, but it differs substantially in the content of the categories. Further, the number of articles that are listed under multiple categories is only a small fraction of what it should be. These findings together with the sensitivity analyses suggest ways to reconceptualize the organization of papers published in PNAS.
Project description:Herein, we developed an innovative and easily accessible solid-phase synthetic protocol for Peptide Nucleic Acid (PNA) oligomers by systematically investigating the ultrasonication effects in all steps of the PNA synthesis (US-PNAS). When compared with standard protocols, the application of the so-obtained US-PNAS approach succeeded in improving the crude product purities and the isolated yields of different PNA, including small or medium-sized oligomers (5-mer and 9-mer), complex purine-rich sequences (like a 5-mer Guanine homoligomer and the telomeric sequence TEL-13) and longer oligomers (such as the 18-mer anti-IVS2-654 PNA and the 23-mer anti-mRNA 155 PNA). Noteworthy, our ultrasound-assisted strategy is compatible with the commercially available PNA monomers and well-established coupling reagents and only requires the use of an ultrasonic bath, which is a simple equipment generally available in most synthetic laboratories.
Project description:Antisense oligonucleotide (ASO)-based drug development is gaining significant momentum following the recent FDA approval of Eteplirsen (an ASO based on phosphorodiamidate morpholino) and Spinraza (2'-O-methoxyethyl-phosphorothioate) in late 2016. Their attractiveness is mainly due to the backbone modifications which have improved the in vivo characteristics of oligonucleotide drugs. Another class of ASO, based on peptide nucleic acid (PNA) chemistry, is also gaining popularity as a platform for development of gene-specific therapy for various disorders. However, the chemical synthesis of long PNAs, which are more target-specific, remains an ongoing challenge. Most of the reported methodology for the solid-phase synthesis of PNA suffer from poor coupling efficiency which limits production to short PNA sequences of less than 15 residues. Here, we have studied the effect of backbone modifications with Hmb (2-hydroxy-4-methoxybenzyl) and Dmb (2,4-dimethoxybenzyl) to ameliorate difficult couplings and reduce "on-resin" aggregation. We firstly synthesized a library of PNA dimers incorporating either Hmb or Dmb and identified that Hmb is superior to Dmb in terms of its ease of removal. Subsequently, we used Hmb backbone modification to synthesize a 22-mer purine-rich PNA, targeting dystrophin RNA splicing, which could not be synthesized by standard coupling methodology. Hmb backbone modification allowed this difficult PNA to be synthesized as well as to be continued to include a cell-penetrating peptide on the same solid support. This approach provides a novel and straightforward strategy for facile solid-phase synthesis of difficult purine-rich PNA sequences.
Project description:BackgroundCitation data can be used to evaluate the editorial policies and procedures of scientific journals. Here we investigate citation counts for the three different publication tracks of the Proceedings of the National Academy of Sciences of the United States of America (PNAS). This analysis explores the consequences of differences in editor and referee selection, while controlling for the prestige of the journal in which the papers appear.Methodology/principal findingsWe find that papers authored and "Contributed" by NAS members (Track III) are on average cited less often than papers that are "Communicated" for others by NAS members (Track I) or submitted directly via the standard peer review process (Track II). However, we also find that the variance in the citation count of Contributed papers, and to a lesser extent Communicated papers, is larger than for direct submissions. Therefore when examining the 10% most-cited papers from each track, Contributed papers receive the most citations, followed by Communicated papers, while Direct submissions receive the least citations.Conclusion/significanceOur findings suggest that PNAS "Contributed" papers, in which NAS-member authors select their own reviewers, balance an overall lower impact with an increased probability of publishing exceptional papers. This analysis demonstrates that different editorial procedures are associated with different levels of impact, even within the same prominent journal, and raises interesting questions about the most appropriate metrics for judging an editorial policy's success.