When faced with unfamiliar reaction space, synthetic chemists typically apply the reported conditions (reagents, catalyst, solvent and additives) of a successful reaction to a desired, closely ...related reaction using a new substrate type. Unfortunately, this approach often fails owing to subtle differences in reaction requirements. Consequently, an important goal in synthetic chemistry is the ability to transfer chemical observations quantitatively from one reaction to another. Here we present a holistic, data-driven workflow for deriving statistical models of one set of reactions that can be used to predict out-of-sample reactions. As a validating case study, we combined published enantioselectivity datasets that employ 1,1'-bi-2-naphthol (BINOL)-derived chiral phosphoric acids for a range of nucleophilic addition reactions to imines and developed statistical models. These models reveal the general interactions that impart asymmetric induction and allow the quantitative transfer of this information to new reaction components. This technique creates opportunities for translating comprehensive reaction analysis to diverse chemical space, streamlining both catalyst and reaction development.
Chiral phosphoric acids have become powerful catalysts for the stereocontrolled synthesis of a diverse array of organic compounds. Since the initial report, the development of phosphoric acids as ...catalysts has been rapid, demonstrating the tremendous generality of this catalyst system and advancing the use of phosphoric acids to catalyze a broad range of asymmetric transformations ranging from Mannich reactions to hydrogenations through complementary modes of activation. These powerful applications have been developed without a clear mechanistic understanding of the reasons for the high level of stereocontrol. This Account describes investigations into the mechanism of the phosphoric acid catalyzed addition of nucleophiles to imines, focusing on binaphthol-based systems. In many cases, the hydroxyl phosphoric acid can form a hydrogen bond to the imine while the PO interacts with the nucleophile. The single catalyst, therefore, activates both the electrophile and the nucleophile, while holding both in the chiral pocket created by the binaphthol and constrained by substituents at the 3 and 3′ positions. Detailed geometric and energetic information about the transition states can be gained from calculations using ONIOM methods that combine the advantages of DFT with some of the speed of force fields. These high-level calculations give a quantitative account of the selectivity in many cases, but require substantial computational resources. A simple qualitative model is a useful complement to this complex quantitative model. We summarize our calculations into a working model that can readily be sketched by hand and used to work out the likely sense of selectivity for each reaction. The steric demands of the different parts of the reactants determine how they fit into the chiral cavity and which of the competing pathways is favored. The preferred pathway can be found by considering the size of the substituents on the nitrogen and carbon atoms of the imine electrophile, and the position of the nucleophilic site on the nucleophile in relation to the hydrogen-bond which holds it in the catalyst active site. We present a guide to defining the pathway in operation allowing the fast and easy prediction of the stereochemical outcome and provide an overview of the breadth of reactions that can be explained by these models including the latest examples.
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus known to cause epidemics resulting in predominantly symptomatic infections, which in rare cases cause long term debilitating arthritis and ...arthralgia. Significant progress has been made in understanding the roles of canonical RNA sensing pathways in the host recognition of CHIKV; however, less is known regarding antagonism of CHIKV by cytosolic DNA sensing pathways like that of cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING). With the use of cGAS or STING null cells we demonstrate that the pathway restricts CHIKV replication in fibroblasts and immune cells. We show that DNA accumulates in the cytoplasm of infected cells and that CHIKV blocks DNA dependent IFN-β transcription. This antagonism of DNA sensing is via an early autophagy-mediated degradation of cGAS and expression of the CHIKV capsid protein is sufficient to induce cGAS degradation. Furthermore, we identify an interaction of CHIKV nsP1 with STING and map the interaction to 23 residues in the cytosolic loop of the adaptor protein. This interaction stabilizes the viral protein and increases the level of palmitoylated nsP1 in cells. Together, this work supports previous publications highlighting the relevance of the cGAS-STING pathway in the early detection of (+)ssRNA viruses and provides direct evidence that CHIKV interacts with and antagonizes cGAS-STING signaling.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The health of Māori, the Indigenous peoples of Aotearoa, New Zealand, like that of almost all Indigenous peoples worldwide, is characterised by systematic inequities in health outcomes, differential ...exposure to the determinants of health, inequitable access to and through health and social systems, disproportionate marginalisation and inadequate representation in the health workforce. As health providers, we are often taught that ‘taking a history’ is a critical component of a patient consultation to ensure that the underlying conditions are treated rather than the often superficial presenting symptoms. In the same way, attempts to make sense of the health and well-being of Indigenous peoples is inadequate unless health providers engage critically with the history of their respective nations and any subsequent patterns of privilege or disadvantage. Understanding this history, within the framework of western imperialism and other similar colonial projects, allows us to make sense of international patterns of Indigenous health status.
While health commentators acknowledge the unequal health outcomes of Indigenous people, and an increasing number also link these inequities to Indigenous marginalisation resulting from historic events, very few go further and expose the deep relationship between racism and coloniality and how these continue to be the basic determinants of Indigenous health today. This work includes honest examination of the role that science and the health disciplines have played historically in colonisation through the subjugation of Indigenous ways of knowing and knowledge production, as well as being complicit in the creation and maintenance of a fabricated hierarchy of humankind. Despite the ‘science’ of this racial hierarchy being discredited, it retains a false validity in our societies. As long as oppressive systems that continue to re-inscribe racism and white privilege remain in communities, including our academic communities, coloniality continues its discrimination.
Indigenous voices on migration, ethnicity, racisma and health will always demand the elimination of inequities in health but to do so will require a parallel commitment to critically interrogating all of our histories and our disciplines, as well as examining how our practice, including research, disrupts or maintains global systems of racism and coloniality.
•Persistent, compelling health inequities exist for Indigenous peoples worldwide.•Science, ‘race’ and colonialism are intricately linked for Indigenous peoples.•Understanding colonial histories is critical to making sense of Indigenous health.•Indigenous voices offer challenges and opportunities in global health futures.
The importance of organic aerosol particles in the environment has been long established, influencing cloud formation and lifetime, absorbing and scattering sunlight, affecting atmospheric ...composition and impacting on human health. Conventionally, ambient organic particles were considered to exist as liquids. Recent observations in field measurements and studies in the laboratory suggest that they may instead exist as highly viscous semi-solids or amorphous glassy solids under certain conditions, with important implications for atmospheric chemistry, climate and air quality. This review explores our understanding of aerosol particle phase, particularly as identified by measurements of the viscosity of organic particles, and the atmospheric implications of phase state.
Surface tension influences the fraction of atmospheric particles that become cloud droplets. Although surfactants are an important component of aerosol mass, the surface tension of activating aerosol ...particles is still unresolved, with most climate models assuming activating particles have a surface tension equal to that of water. By studying picoliter droplet coalescence, we demonstrate that surfactants can significantly reduce the surface tension of finite-sized droplets below the value for water, consistent with recent field measurements. Significantly, this surface tension reduction is droplet size-dependent and does not correspond exactly to the macroscopic solution value. A fully independent monolayer partitioning model confirms the observed finite-size-dependent surface tension arises from the high surface-to-volume ratio in finite-sized droplets and enables predictions of aerosol hygroscopic growth. This model, constrained by the laboratory measurements, is consistent with a reduction in critical supersaturation for activation, potentially substantially increasing cloud droplet number concentration and modifying radiative cooling relative to current estimates assuming a water surface tension. The results highlight the need for improved constraints on the identities, properties, and concentrations of atmospheric aerosol surfactants inmultiple environments and are broadly applicable to any discipline where finite volume effects are operative, such as studies of the competition between reaction rates within the bulk and at the surface of confined volumes and explorations of the influence of surfactants on dried particle morphology from spray driers.
The complex interplay of processes that govern the size, composition, phase and morphology of aerosol particles in the atmosphere is challenging to understand and model. Measurements on single ...aerosol particles (2 to 100 μm in diameter) held in electrodynamic, optical and acoustic traps or deposited on a surface can allow the individual processes to be studied in isolation under controlled laboratory conditions. In particular, measurements can now be made of particle size with unprecedented accuracy (sub-nanometre) and over a wide range of timescales (spanning from milliseconds to many days). The physical state of a particle can be unambiguously identified and its composition and phase can be resolved with a high degree of spatial resolution. In this review, we describe the advances made in our understanding of aerosol properties and processes from measurements made of phase behaviour, hygroscopic growth, morphology, vapour pressure and the kinetics of water transport for single particles. We also show that studies of the oxidative aging of single particles, although limited in number, can allow the interplay of these properties to be investigated. We conclude by considering the contributions that single particle measurements can continue to make to our understanding of the properties and processes occurring in atmospheric aerosol.
Summary
The potential aerosolised transmission of severe acute respiratory syndrome coronavirus‐2 is of global concern. Airborne precaution personal protective equipment and preventative measures are ...universally mandated for medical procedures deemed to be aerosol generating. The implementation of these measures is having a huge impact on healthcare provision. There is currently a lack of quantitative evidence on the number and size of airborne particles produced during aerosol‐generating procedures to inform risk assessments. To address this evidence gap, we conducted real‐time, high‐resolution environmental monitoring in ultraclean ventilation operating theatres during tracheal intubation and extubation sequences. Continuous sampling with an optical particle sizer allowed characterisation of aerosol generation within the zone between the patient and anaesthetist. Aerosol monitoring showed a very low background particle count (0.4 particles.l−1) allowing resolution of transient increases in airborne particles associated with airway management. As a positive reference control, we quantitated the aerosol produced in the same setting by a volitional cough (average concentration, 732 (418) particles.l−1, n = 38). Tracheal intubation including facemask ventilation produced very low quantities of aerosolised particles (average concentration, 1.4 (1.4) particles.l−1, n = 14, p < 0.0001 vs. cough). Tracheal extubation, particularly when the patient coughed, produced a detectable aerosol (21 (18) l−1, n = 10) which was 15‐fold greater than intubation (p = 0.0004) but 35‐fold less than a volitional cough (p < 0.0001). The study does not support the designation of elective tracheal intubation as an aerosol‐generating procedure. Extubation generates more detectable aerosol than intubation but falls below the current criterion for designation as a high‐risk aerosol‐generating procedure. These novel findings from real‐time aerosol detection in a routine healthcare setting provide a quantitative methodology for risk assessment that can be extended to other airway management techniques and clinical settings. They also indicate the need for reappraisal of what constitutes an aerosol‐generating procedure and the associated precautions for routine anaesthetic airway management.
Choosing the optimal catalyst for a new transformation is challenging because the ideal molecular requirements of the catalyst for one reaction do not always simply translate to another. Large groups ...at the 3,3′ positions of the binaphthol rings are important for efficient stereoinduction but if they are too large this can lead to unusual or poor results. By applying a quantitative steric assessment of the substituents at the 3,3′ positions of the binaphthol ring, we have systematically studied the effect of modulating this group on enantioselectivity for a wide range of reactions involving imines, and verified this analysis using ONIOM calculations. We have shown that in most reactions, the stereochemical outcome depends on both proximal and remote sterics. Summarising detailed calculations into a simple qualitative model identifies and explains the steric features required for high selectivity. This model is consistent with seventy seven papers reporting reactions (over 1000 transformations in total), and provides a straightforward decision tree for selecting the best catalyst.
How to choose a cat: A general model to guide the best choice of phosphoric acid catalyst for nucleophilic addition to imines has been developed. These rules are consistent for seventy‐seven papers containing over 1000 examples, explaining enantioselectivity trends with varying 3,3′ group and correctively identifying steric features essential for efficient stereoinduction.
Increased exposure of Antarctica's coastal environment to open ocean and waves due to loss of a protective sea-ice "buffer" has important ramifications for ice-shelf stability, coastal erosion, ...important ice-ocean-atmosphere interactions and shallow benthic ecosystems. Here, we introduce a climate and environmental metric based on the ongoing long-term satellite sea-ice concentration record, namely Coastal Exposure Length. This is a daily measure of change and variability in the length and incidence of Antarctic coastline lacking any protective sea-ice buffer offshore. For 1979-2020, ~50% of Antarctica's ~17,850-km coastline had no sea ice offshore each summer, with minimal exposure in winter. Regional summer/maximum contributions vary from 45% (Amundsen-Bellingshausen seas) to 58% (Indian Ocean and Ross Sea), with circumpolar annual exposure ranging from 38% (2019) to 63% (1993). The annual maximum length of Antarctic coastal exposure decreased by ~30 km (~0.32%) per year for 1979-2020, composed of distinct regional and seasonal contributions.
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