Coupling of nitric oxide and release of nitrous oxide from rare-earth-dinitrosyliron complexes

Addition of Lewis acidic [Cp*2M]+ (M = Y, Gd) to the dinitrosyliron complexes (DNICs) [(NacNacAr)Fe(NO)2]− (Ar = mesityl, 2,6-diisopropylphenyl) results in formation of the isonitrosyl-bridged DNICs [(Cp*)2M(μ-ON)2Fe(NacNacAr)]. When Ar = 2,6-diisopropylphenyl, coupling of the NO ligands and release of N2O occur. Two factors contribute to this previously unobserved DNIC reactivity mode. First, the oxophilic rare-earth elements drive the formation of isonitrosyl bonds, forcing the DNIC nitrogen atoms into proximity. Second, the bulky substituents further squeeze the DNIC, which ultimately overcomes the barrier to NO coupling, demonstrating that N2O elimination can occur from a single iron center

Indeterminacy of Reverse Engineering of Gene Regulatory Networks: The Curse of Gene Elasticity

Gene Regulatory Networks (GRNs) have become a major focus of interest in recent years. A number of reverse engineering approaches have been developed to help uncover the regulatory networks giving rise to the observed gene expression profiles. However, this is an overspecified problem due to the fact that more than one genotype (network wiring) can give rise to the same phenotype. We refer to this phenomenon as “gene elasticity.” In this work, we study the effect of this particular problem on the pure, data-driven inference of gene regulatory networks.We simulated a four-gene network in order to produce “data” (protein levels) that we use in lieu of real experimental data. We then optimized the network connections between the four genes with a view to obtain the original network that gave rise to the data. We did this for two different cases: one in which only the network connections were optimized and the other in which both the network connections as well as the kinetic parameters (given as reaction probabilities in our case) were estimated. We observed that multiple genotypes gave rise to very similar protein levels. Statistical experimentation indicates that it is impossible to differentiate between the different networks on the basis of both equilibrium as well as dynamic data.We show explicitly that reverse engineering of GRNs from pure expression data is an indeterminate problem. Our results suggest the unsuitability of an inferential, purely data-driven approach for the reverse engineering transcriptional networks in the case of gene regulatory networks displaying a certain level of complexity

Genomes, structural biology and drug discovery: combating the impacts of mutations in genetic disease and antibiotic resistance

For over four decades structural biology has been used to understand the mechanisms of disease, and structure-guided approaches have demonstrated clearly that they can contribute to many aspects of early drug discovery, both computationally and experimentally. Structure can also inform our understanding of impacts of mutations in human genetic diseases and drug resistance in cancers and infectious diseases. We discuss the ways that structural insights might be useful in both repurposing off-licence drugs and guide the design of new molecules that might be less susceptible to drug resistance in the future.D.B.A. and T.L.B. are supported by the Wellcome Trust Programme Grant [093167/Z/10/Z]. A.P.P. and T.L.B. have been supported by the Gates HIT-TB and the EU MM4TB [Project ID: 260872] programmes. S.E.T. and T.L.B. are supported by Cystic Fibrosis Trust (Registered as a charity in England and Wales (1079049) and in Scotland (SC040196). Tom L. Blundell was awarded the Biochemical Society Award in 2013; this review is based on the work for which he won the Award

BLOOM: A 176B-Parameter Open-Access Multilingual Language Model

Large language models (LLMs) have been shown to be able to perform new tasks based on a few demonstrations or natural language instructions. While these capabilities have led to widespread adoption, most LLMs are developed by resource-rich organizations and are frequently kept from the public. As a step towards democratizing this powerful technology, we present BLOOM, a 176B-parameter open-access language model designed and built thanks to a collaboration of hundreds of researchers. BLOOM is a decoder-only Transformer language model that was trained on the ROOTS corpus, a dataset comprising hundreds of sources in 46 natural and 13 programming languages (59 in total). We find that BLOOM achieves competitive performance on a wide variety of benchmarks, with stronger results after undergoing multitask prompted finetuning. To facilitate future research and applications using LLMs, we publicly release our models and code under the Responsible AI License

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

A Pd-6 Molecular Cage via Multicomponent Self-Assembly Incorporating Both Neutral and Anionic Linkers

A Pd-6 molecular cage [{(tmen)Pd}(6)(bpy)(3)(tma)2)](NO3)(6) [1; where tmen = N,N,N,N-tetramethylethylene diamine, bpy = 4,4'-bipyridyl,and H(3)tma = trimesic acid] was prepared via the template-free three-component seff-assembly of a cis-blocked palladium(II) acceptorin combination with a tricarboxylate and a dipyridyl donor. Complex 1 represents the first example of a 3D palladium(II) cage of defined shape incorporating anionic and neutral linkers. Guest-induced exclusive formation of this cage was also monitored by an NMR study

Ruthenium-Oxygen Coordination-Driven Self-Assembly of a Ru-8(II) Incomplete Prism: Synthesis, Structure, and Shape-Selective Molecular Recognition Study

Coordination-driven self-assembly of 1,3,5-benzenetricarboxylate (tma; 1) and oxalato-bridged p-cymeneruthenium(II) building block Ru-2(mu-eta(4)-C2O4)(MeOH)(2)(eta(6)-p-cymene)(2)](O3SCF3)(2) (2) affords an unusual octanuclear incomplete prism Ru-8(eta(6)-p-cymene)(8)(tma)(2)(mu-eta(4)-C2O4)(2)(OMe)(4)](O3SCF3)( 2) (3), which exhibits a remarkable shape-selective binding affinity for neutral phenolic compounds via hydrogen-bonding interactions (p-cymene = p-(PrC6H4Me)-Pr-i). Such a binding was confirmed by single-crystal X-ray diffraction analysis using 1,3,5-trihydroxybenzene as an analyte

Modification of Extended Open Frameworks with Fluorescent Tags for Sensing Explosives: Competition between Size Selectivity and Electron Deficiency

Three new electron-rich metal-organic frameworks (MOF-1-MOF-3) have been synthesized by employing ligands bearing aromatic tags. The key role of the chosen aromatic tags is to enhance the -electron density of the luminescent MOFs. Single-crystal X-ray structures have revealed that these MOFs form three-dimensional porous networks with the aromatic tags projecting inwardly into the pores. These highly luminescent electron-rich MOFs have been successfully utilized for the detection of explosive nitroaromatic compounds (NACs) on the basis of fluorescence quenching. Although all of the prepared MOFs can serve as sensors for NACs, MOF-1 and MOF-2 exhibit superior sensitivity towards 4-nitrotoluene (4-NT) and 2,4-dinitrotoluene (DNT) compared to 2,4,6-trinitrotoluene (TNT) and 1,3,5-trinitrobenzene (TNB). MOF-3, on the other hand, shows an order of sensitivity in accordance with the electron deficiencies of the substrates. To understand such anomalous behavior, we have thoroughly analyzed both the steady-state and time-resolved fluorescence quenching associated with these interactions. Determination of static Stern-Volmer constants (K-S) as well as collisional constants (K-C) has revealed that MOF-1 and MOF-2 have higher K-S values with 4-NT than with TNT, whereas for MOF-3 the reverse order is observed. This apparently anomalous phenomenon was well corroborated by theoretical calculations. Moreover, recyclability and sensitivity studies have revealed that these MOFs can be reused several times and that their sensitivities towards TNT solution are at the parts per billion (ppb) level

Self-Assembly of a Pd-6-Molecular Double-Square and a Cu-3-Trigonalbipyramidal Cage via a New Tripodal Flexible Ligand

A new tripodal flexible ligand (L) containing pyrazolyl functionality has been prepared and successfully used to obtain a pd(6) (1) molecular double-square and a cu(3) trigonalbipyramidal cage (2), where complex 1 represents the first example of a double-square obtained using a flexible tripodal ligand