The mechanism of nucleophilic substitution at silicon

Using multinuclear n.m.r. spectroscopy (1H, 13C, 29Si and 170 ), the interactions of diastereotopic (PhCHMeSiMe2X; X=CL, Br, 0S02CF3) and chiral (PhMeHSiX; X=CL, 0S02CF3) silanes with a diverse range of nucleophile (Nu = amides, ureas, pyridines, phosphine oxide and amines) are examined in detail. The dominant species in the diastereotopic silylating solutions are four coordinate 1:1 ionic [PhCHMeSiMe2-Nu]+X- adducts. These complexes undergo exchange with nucleophiles and their parent silanes at a rate limited by the initial attack of nucleophile or counterion at the silicon atom of the adduct. The halide counterions of stable silane-nucleophile adducts can also induce isomerization of uncomplexed silanes. The kinetic and thermodynamic results are consistent with the operation of two different mechanisms for the racemizations of PhCHMeSiMe2X (X=CL, Br). Racemization involving Less stable silane-nucleophile complexes may proceed via rate determining attack by a second molecule of nucleophile at the adduct, formed in the initial, rapid, pre-equilibrium step. Two molecules of nucleophile are utilized resulting in an order of 2 or 1.5 in nucleophile, depending upon the degree of ion-pair dissociation. An alternative pathway is preferred with increasing stability of the silane-nucleophile salt. Adduct formation is followed by halide exchange leading to racemization of silane. One molecule of nucleophile is required in this case corresponding to a first or a half order in nucleophile. The kinetic results are correlated with the rate of alcoholysis reported by Frye, the relative equilibrium constant for the formation of [Me3Si-Nu]+X- complexes and the donor strength of nucleophile as measured by Taft's Beta values. The good correlation with the Beta values provides evidence that the rate of racemization is dependent upon the nucleophilicity of the donor species. The excellent linear correlation with Frye's ln k1 values further verifies the mechanism first postulated by Chojnowski. Rapid pre-equilibrium formation of [R3Si-Nu]+X- adducts is followed by slow attack of a second molecule of nucleophile. With strong nucleophiles, four coordinate ionic [PhMeHSi-Nu]+Cl- salts undergo second nucleophilic attacks yielding stable pentacoordinate [PhMeHSi-(Nu)2]+CL- ionic adducts. The collapse of the N-methyl resonances of DMF observed in the interactions of PhMeRSiCl (R=H, Me) with DMF may serve as an indication of N-silylation of DMF

Update on the Hague Convention on the Recognition & Enforcement of Foreign Judgments

This comment is based on remarks at the Eighth Regional Meeting of the American Society of International Law, at Golden Gate University School of Law, on March 19, 2000

Update on the Hague Convention on the Recognition & Enforcement of Foreign Judgments

This comment is based on remarks at the Eighth Regional Meeting of the American Society of International Law, at Golden Gate University School of Law, on March 19, 2000

Use of heart failure medical therapy before and after a cancer diagnosis:A longitudinal study

Aims: We aim to evaluate change in the use of prognostic guideline-directed medical therapies (GDMTs) for heart failure (HF) before and after a cancer diagnosis as well as the matched non-cancer controls, including renin-angiotensin-system inhibitors (RASIs), beta-blockers, and mineralocorticoid receptor antagonists (MRAs). Methods and results: We conducted a longitudinal study in patients with HF in the UK Clinical Practice Research Datalink between 2005 and 2021. We selected patients with probable HF with reduced ejection fraction (HFrEF) based on diagnostic and prescription records. We described the longitudinal trends in the use and dosing of GDMTs before and after receiving an incident cancer diagnosis. HF patients with cancer were matched with a 1:1 ratio to HF patients without cancer to investigate the association between cancer diagnosis and treatment adherence, persistence, initiation, and dose titration as odds ratios (ORs) with 95% confidence intervals (CIs) using multivariable logistic regression models. Of 8504 eligible HFrEF patients with incident cancer, 4890 were matched to controls without cancer. The mean age was 75.7 (±8.4) years and 73.9% were male. In the 12 months following a cancer diagnosis, patients experienced reductions in the use and dosing of GDMT. Compared with the non-cancer controls, patients with cancer had higher risks for poor adherence for all three medication classes (RASIs: OR = 1.51, 95% CI = 1.35–1.68; beta-blockers: OR = 1.22, 95% CI = 1.08–1.37; MRAs: OR = 1.31, 95% CI = 1.08–1.59) and poor persistence (RASIs: OR = 2.04, 95% CI = 1.75–2.37; beta-blockers: OR = 1.35, 95% CI = 1.12–1.63; MRAs: OR = 1.49, 95% CI = 1.16–1.93), and higher risks for dose down-titration for RASIs (OR = 1.69, 95% CI = 1.40–2.04) and beta-blockers (OR = 1.31, 95% CI = 1.05–1.62). Cancer diagnosis was not associated with treatment initiation or dose up-titration. Event rates for HF hospitalization and mortality were higher in patients with poor adherence or persistence to GDMTs. Conclusions: Following a cancer diagnosis, patients with HFrEF were more likely to have reduced use of GDMTs for HF.</p

Emerging biological archives can reveal ecological and climatic change in Antarctica

Anthropogenic climate change is causing observable changes in Antarctica and the Southern Ocean including increased air and ocean temperatures, glacial melt leading to sea-level rise and a reduction in salinity, and changes to freshwater water availability on land. These changes impact local Antarctic ecosystems and the Earth's climate system. The Antarctic has experienced significant past environmental change, including cycles of glaciation over the Quaternary Period (the past similar to 2.6 million years), Understanding Antarctica's paleoecosystems, and the corresponding paleoenvironments and climates that have shaped them, provides insight into present day ecosystem change, and importantly, helps constrain model projections of future change. Biological archives such as extant moss beds and peat profiles, biological proxies in lake and marine sediments, vertebrate animal colonies, and extant terrestrial and benthic marine invertebrates, complement other Antarctic paleoclimate archives by recording the nature and rate of past ecological change, the paleoenvironmental drivers of that change, and constrain current ecosystem and climate models. These archives provide invaluable information about terrestrial ice-free areas, a key location for Antarctic biodiversity, and the continental margin which is important for understanding ice sheet dynamics. Recent significant advances in analytical techniques (e.g., genomics, biogeochemical analyses) have led to new applications and greater power in elucidating the environmental records contained within biological archives. Paleoecological and paleoclimate discoveries derived from biological archives, and integration with existing data from other paleoclimate data sources, will significantly expand our understanding of past, present, and future ecological change, alongside climate change, in a unique, globally significant region

Maternal Benzodiazepines and Z-Drugs Use during Pregnancy and Adverse Birth and Neurodevelopmental Outcomes in Offspring:A Population-Based Cohort Study

Introduction: The use of benzodiazepines and/or z-drugs in women of childbearing age has increased. Objective: The aim of the study was to evaluate whether gestational benzodiazepine and/or z-drug exposure is associated with adverse birth and neurodevelopmental outcomes. Methods: A population-based cohort including mother-child pairs from 2001 to 2018 in Hong Kong was analysed to compare gestationally exposed and nonexposed children on the risk of preterm birth, small for gestational age, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) through logistic/Cox proportional hazards regression with a 95% confidence interval (CI). Sibling-matched analyses and negative control analyses were applied. Results: When comparing gestationally exposed with gestationally nonexposed children, the weighted odds ratio (wOR) was 1.10 (95% CI = 0.97-1.25) for preterm birth and 1.03 (95% CI = 0.76-1.39) for small for gestational age, while the weighted hazard ratio (wHR) was 1.40 (95% CI = 1.13-1.73) for ASD and 1.15 (95% CI = 0.94-1.40) for ADHD. Sibling-matched analyses showed no association between gestationally exposed children and their gestationally nonexposed siblings for all outcomes (preterm birth: wOR = 0.84, 95% CI = 0.66-1.06; small for gestational age: wOR = 1.02, 95% CI = 0.50-2.09; ASD: wHR = 1.10, 95% CI = 0.70-1.72; ADHD: wHR = 1.04, 95% CI = 0.57-1.90). Similarly, no significant differences were observed when comparing children whose mothers took benzodiazepines and/or z-drugs during pregnancy to children whose mothers took benzodiazepines and/or z-drugs before but not during pregnancy for all outcomes. Conclusions: The findings do not support a causal relationship between gestational benzodiazepines and/or z-drugs exposure and preterm birth, small for gestational age, ASD, or ADHD. Clinicians and pregnant women should carefully balance the known risks of benzodiazepines and/or z-drugs use against those of untreated anxiety and sleep problems.</p

Conformation of a Polyelectrolyte Complexed to a Like-Charged Colloid

We report results from a molecular dynamics (MD) simulation on the conformations of a long flexible polyelectrolyte complexed to a charged sphere, \textit{both negatively charged}, in the presence of neutralizing counterions in the strong Coulomb coupling regime. The structure of this complex is very sensitive to the charge density of the polyelectrolyte. For a fully charged polyelectrolyte the polymer forms a dense two-dimensional "disk", whereas for a partially charged polyelectrolyte the monomers are spread over the colloidal surface. A mechanism involving the \textit{overcharging} of the polyelectrolyte by counterions is proposed to explain the observed conformations.Comment: 4 pages, 4 figures (6 EPS files

Evolutionary innovations in Antarctic brittle stars linked to glacial refugia

The drivers behind evolutionary innovations such as contrasting life histories and morphological change are central questions of evolutionary biology. However, the environmental and ecological contexts linked to evolutionary innovations are generally unclear. During the Pleistocene glacial cycles, grounded ice sheets expanded across the Southern Ocean continental shelf. Limited ice-free areas remained, and fauna were isolated from other refugial populations. Survival in Southern Ocean refugia could present opportunities for ecological adaptation and evolutionary innovation. Here, we reconstructed the phylogeographic patterns of circum-Antarctic brittle stars Ophionotus victoriae and O. hexactis with contrasting life histories (broadcasting vs brooding) and morphology (5 vs 6 arms). We examined the evolutionary relationship between the two species using cytochrome c oxidase subunit I (COI) data. COI data suggested that O. victoriae is a single species (rather than a species complex) and is closely related to O. hexactis (a separate species). Since their recent divergence in the mid-Pleistocene, O. victoriae and O. hexactis likely persisted differently throughout glacial maxima, in deep-sea and Antarctic island refugia, respectively. Genetic connectivity, within and between the Antarctic continental shelf and islands, was also observed and could be linked to the Antarctic Circumpolar Current and local oceanographic regimes. Signatures of a probable seascape corridor linking connectivity between the Scotia Sea and Prydz Bay are also highlighted. We suggest that survival in Antarctic island refugia was associated with increase in arm number and a switch from broadcast spawning to brooding in O. hexactis, and propose that it could be linked to environmental changes (such as salinity) associated with intensified interglacial-glacial cycles