The importance of inherent substrate reactivity for terpene synthase enzymes is discussed, with a focus on recent experimental tests of predictions derived from computations on gas‐phase reactivity ...of carbocations.
I know what I like: The importance of inherent substrate reactivity for terpene synthase enzymes is discussed in this Minireview. Experimental studies are highlighted that support predictions from quantum chemistry that inherent carbocation reactivity is expressed in the presence of terpene synthase enzymes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
This review describes applications of quantum chemical calculations in the field of terpene biosynthesis, with a focus on insights into the mechanisms of terpene-forming carbocation rearrangements ...arising from theoretical studies.
We advocate for the construction of a new detector element at the LHCb experiment, designed to search for displaced decays of beyond Standard Model long-lived particles, taking advantage of a large ...shielded space in the LHCb cavern that is expected to soon become available. We discuss the general features and putative capabilities of such an experiment, as well as its various advantages and complementarities with respect to the existing LHC experiments and proposals such as SHiP and MATHUSLA. For two well-motivated beyond Standard Model benchmark scenarios-Higgs decay to dark photons and B meson decays via a Higgs mixing portal-the reach either complements or exceeds that predicted for other LHC experiments.
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The measured B¯→D(*)lν¯ decay rates for light leptons (l=e, μ) constrain all B¯→D(*) semileptonic form factors, by including both the leading and O(ΛQCD/mc,b) subleading Isgur-Wise functions in the ...heavy quark effective theory. We perform a novel combined fit to the B¯→D(*)lν¯ decay distributions to predict the B¯→D(*)τν¯ rates and determine the Cabibbo-Kobayashi-Maskawa matrix element |Vcb|. Most theoretical and experimental papers have neglected uncertainties in the predictions for form factor ratios at order ΛQCD/mc,b, which we include. We also calculate O(ΛQCD/mc,b) and O(αs) contributions to semileptonic B¯→D(*)ℓν¯ decays for all possible b→c currents. This result has not been available for the tensor current form factors, and for two of those, which are O(ΛQCD/mc,b), the corrections are of the same order as approximations used in the literature. These results allow us to determine with improved precision how new physics may affect the B¯→D(*)τν¯ rates. Our predictions can be systematically improved with more data; they need not rely on lattice QCD results, although these can be incorporated.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and ...bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs.
Conspectus Rh2L4 catalysts have risen in popularity in the world of organic synthesis, being used to accomplish a variety of reactions, including C–H insertion and cyclopropanation, and often doing ...so with high levels of stereocontrol. While the mechanisms and origins of selectivity for such reactions have been examined with computational quantum chemistry for decades, only recently have detailed pictures of the dynamic behavior of reacting Rh2L4-complexed molecules become accessible. Our computational studies on Rh2L4 catalyzed reactions are described here, with a focus on C–H insertion reactions of Rh2L4-carbenes. Several issues complicate the modeling of these reactions, each providing an opportunity for greater understanding and each revealing issues that should be incorporated into future rational design efforts. First, the fundamental mechanism of C–H insertion is discussed. While early quantum chemical studies pointed to transition structures with 3-center C–H–C substructures and asynchronous hydride transfer/C–C bond formation, recent examples of reactions with particularly flat potential energy surfaces and even discrete zwitterionic intermediates have been found. These reactions are associated with systems bearing π-donating groups at the site of hydride transfer, allowing for an intermediate with a carbocation substructure at that site to be selectively stabilized. Second, the possible importance of solvent coordination at the Rh atom distal to the carbene is discussed. While effects on reactivity and selectivity were found to be small, they turn out not to be negligible in some cases. Third, it is shown that, in contrast to many other transition metal promoted reactions, many Rh2L4 catalyzed reactions likely involve dissociation of the Rh2L4 catalyst before key chemical steps leading to products. When to expect dissociation is associated with specific features of substrates and the product-forming reactions in question. Often, dissociation precedes transition structures for pericyclic reactions that involve electrons that would otherwise bind to Rh2L4. Finally, the importance of nonstatistical dynamic effects, characterized through ab initio molecular dynamics studies, in some Rh2L4 catalyzed reactions is discussed. These are reactions where transition structures are shown to be followed by flat regions, very shallow minima, and/or pathways that bifurcate, all allowing for trajectories from a single transition state to form multiple different products. The likelihood of encountering such a situation is shown to be associated again with the likelihood of formation of zwitterionic structures along reaction paths, but ones for which pathways to multiple products are expected to be associated with very low or no barriers. The connection between these features and reduced yields of desired products are highlighted, as are the means by which some Rh2L4 catalysts modulate dynamic behavior to produce particular products in high yield.
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Differences in entropies of competing transition states can direct kinetic selectivity. Understanding and modeling such entropy differences at the molecular level is complicated by the fact that ...entropy is statistical in nature; i.e., it depends on multiple vibrational states of transition structures, the existence of multiple dynamically accessible pathways past these transition structures, and contributions from multiple transition structures differing in conformation/configuration. The difficulties associated with modeling each of these contributors are discussed here, along with possible solutions, all with an eye toward the development of portable qualitative models of use to experimentalists aiming to design reactions that make use of entropy to control kinetic selectivity.
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IJS, KILJ, NUK, PNG, UL, UM
The Collaborative Pediatric Critical Care Research Network (CPCCRN) was established by the Eunice Kennedy Shriver National Institute of Child Health and Human Development in May 2005 to develop an ...infrastructure for collaborative clinical trials and meaningful descriptive studies in pediatric critical care. This article describes the history of CPCCRN, discusses its financial and organizational structure, illustrates how funds were efficiently used to carry out studies, and describes CPCCRN public use datasets and future directions, concluding with the development of the PeRsonalizEd Immunomodulation in PediatriC SepsIS-InducEd MODS study.
COVID-19, the disease caused by the SARS-CoV-2 virus, can cause shortness of breath, lung damage, and impaired respiratory function. Containing the virus has proven difficult, in large part due to ...its high transmissibility during the pre-symptomatic incubation. The study's aim was to determine if changes in respiratory rate could serve as a leading indicator of SARS-CoV-2 infections. A total of 271 individuals (age = 37.3 ± 9.5, 190 male, 81 female) who experienced symptoms consistent with COVID-19 were included- 81 tested positive for SARS-CoV-2 and 190 tested negative; these 271 individuals collectively contributed 2672 samples (days) of data (1856 healthy days, 231 while infected with COVID-19 and 585 while negative for COVID-19 but experiencing symptoms). To train a novel algorithm, individuals were segmented as follows; (1) a training dataset of individuals who tested positive for COVID-19 (n = 57 people, 537 samples); (2) a validation dataset of individuals who tested positive for COVID-19 (n = 24 people, 320 samples); (3) a validation dataset of individuals who tested negative for COVID-19 (n = 190 people, 1815 samples). All data was extracted from the WHOOP system, which uses data from a wrist-worn strap to produce validated estimates of respiratory rate and other physiological measures. Using the training dataset, a model was developed to estimate the probability of SARS-CoV-2 infection based on changes in respiratory rate during night-time sleep. The model's ability to identify COVID-positive individuals not used in training and robustness against COVID-negative individuals with similar symptoms were examined for a critical six-day period spanning the onset of symptoms. The model identified 20% of COVID-19 positive individuals in the validation dataset in the two days prior to symptom onset, and 80% of COVID-19 positive cases by the third day of symptoms.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Peripheral arterial disease (PAD) represents a spectrum from asymptomatic stenosis to limb-threatening ischemia. The last decade has seen a tremendous increase in the variety of endovascular devices ...and techniques to treat occlusive disease. Like many evolving technologies, the literature surrounding therapy for endovascular arterial disease consists of mixed-quality manuscripts without clear standardization. Accordingly, critical evaluation of the reported results may be problematic. As such, providers and their patients make treatment decisions without the full benefit of a comparative effectiveness framework. The purpose of this document is to provide a summary for the reporting of endovascular revascularization techniques in the setting of chronic disease. Much of the work in this document is based on prior publications and standards proposed by the Society for Vascular Surgery. We have also made recommendations based on current literature and have attempted to acknowledge shortcomings and areas for future research. The various sections contain summaries of required reporting standards and should serve as a guide for the design of clinical trials and as reference for journal editors and reviewers when considering scientific work pertaining to endovascular therapy for chronic lower extremity arterial disease. An Appendix is provided with commonly used abbreviations in this document.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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