A to Z of polymorphs related by proton transfer

The occurrence of tautomeric polymorphism in the Cambridge Structural Database (CSD) was established to be very rare in a previous study by A. J. Cruz-Cabeza and C. R. Groom (CrystEngComm, 2011, 13, 93). A decade has now elapsed and the CSD has seen a significant increase in its total number of crystal structures, useful CSD subsets have been introduced and the CSD Python API has been developed to allow for complex data mining. Given this, we wanted to revisit tautomeric polymorphs in the CSD alongside other polymorphs related by proton transfer and compare these results with those from an in-house pharmaceutical database in order to assess their prevalence and significance for pharmaceuticals. From A (amine–imine tautomeric polymorphs) to Z (zwitterionic polymorphs), here we study different types of polymorphs related by proton-transfer in the CSD, the CSD drug subset (DrugCSD), the single component drug subset of the CSD (SDrugCSD), and the GSK small molecule crystal structure database (GSD). First, we assess the potential of compounds to exist as tautomers. Whilst 51% of compounds in the CSD are capable of tautomerism, this number increases to 73% and 70% for the SDrugCSD and the GSD respectively. Tautomerism potential is, thus, more prevalent in pharmaceuticals than in common organic compounds in the CSD. Second, in mining the CSD we identify a total of 95 families of polymorphs related by proton transfer which can then be classified into six different categories depending on the type of proton transfer observed and the ionisation of species involved. The most common of such category is that of tautomeric polymorphs followed by zwitterionic polymorphs. The rarest type of proton transfer polymorphs is that of multi-zwitterionic polymorphs where two different zwitterions of the same compound are found in two different crystal structures. Overall, 3% of polymorphic compositions in the DrugCSD are found to be related by proton transfer which, although not very common, is of relevance to pharmaceuticals and drug development due to the potential impact on physical properties. Specific examples of each of the categories are discussed with calculations of lattice energies presented and consideration of ΔpKa values and likelihood of proton transfer and ionisation

Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR 1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk

A many-analysts approach to the relation between religiosity and well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N=10,535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β=0.120). For the second research question, this was the case for 65% of the teams (median reported β=0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

A Many-analysts Approach to the Relation Between Religiosity and Well-being

The relation between religiosity and well-being is one of the most researched topics in the psychology of religion, yet the directionality and robustness of the effect remains debated. Here, we adopted a many-analysts approach to assess the robustness of this relation based on a new cross-cultural dataset (N = 10, 535 participants from 24 countries). We recruited 120 analysis teams to investigate (1) whether religious people self-report higher well-being, and (2) whether the relation between religiosity and self-reported well-being depends on perceived cultural norms of religion (i.e., whether it is considered normal and desirable to be religious in a given country). In a two-stage procedure, the teams first created an analysis plan and then executed their planned analysis on the data. For the first research question, all but 3 teams reported positive effect sizes with credible/confidence intervals excluding zero (median reported β = 0.120). For the second research question, this was the case for 65% of the teams (median reported β = 0.039). While most teams applied (multilevel) linear regression models, there was considerable variability in the choice of items used to construct the independent variables, the dependent variable, and the included covariates

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Methyl methacrylate and respiratory sensitization: A Critical review

Methyl methacrylate (MMA) is a respiratory irritant and dermal sensitizer that has been associated with occupational asthma in a small number of case reports. Those reports have raised concern that it might be a respiratory sensitizer. To better understand that possibility, we reviewed the in silico, in chemico, in vitro, and in vivo toxicology literature, and also epidemiologic and occupational medicine reports related to the respiratory effects of MMA. Numerous in silico and in chemico studies indicate that MMA is unlikely to be a respiratory sensitizer. The few in vitro studies suggest that MMA has generally weak effects. In vivo studies have documented contact skin sensitization, nonspecific cytotoxicity, and weakly positive responses on local lymph node assay; guinea pig and mouse inhalation sensitization tests have not been performed. Cohort and cross-sectional worker studies reported irritation of eyes, nose, and upper respiratory tract associated with short-term peaks exposures, but little evidence for respiratory sensitization or asthma. Nineteen case reports described asthma, laryngitis, or hypersensitivity pneumonitis in MMA-exposed workers; however, exposures were either not well described or involved mixtures containing more reactive respiratory sensitizers and irritants.The weight of evidence, both experimental and observational, argues that MMA is not a respiratory sensitizer

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

H - X bond activation via hydrogen transfer to hydride in ruthenium N-heterocyclic carbene complexes:Density functional and synthetic studies

The reactions of tcc-Ru(IMes)2(AsPh3)(CO)H 2 (1, IMes = bis(l,3-(2,4,6-trimethylphenyl)imidazol-2-ylidene)) with HX substrates (X = OH, OEt, SH, SnPr) have been reinvestigated and shown to lead directly to the formation of the 16-electron species Ru(IMes) 2(CO)(X)H (4-X). The fluoro analogue Ru-(IMes)2(CO)(F)H (4-F) has also been synthesized, and X-ray and neutron diffraction studies show that this exhibits a square-pyramidal geometry with hydride in the axial site. Density functional calculations have been performed on one possible mechanism for the formation of 4-X from 1 with various HX (X = F, Cl, OH, SH, NH 2, PH2, CH3, and SiH3), involving initial AsPh3/HX substitution followed by H-transfer to hydride and H2 loss. With X = SH, H-transfer in both tcc-Ru(IMes) 2(CO)(H2S)(H)2 and ttt-Ru(IMes) 2-(CO)(H2S)(H)2 was considered and shown to be kinetically accessible and thermodynamically favored, suggesting that such dihydrides should not be stable with respect to this step. The calculations indicate that the ease of formation of 4-X becomes more kinetically and thermodynamically favored according to the trends F &gt; OH &gt; NH2 &gt; CH3 and Cl &gt; SH &gt; PH2 &lt; SiH3, with the reactions of second-row HX substrates being more favored than the first-row analogues. Calculated reaction exothermicities allow the derivation of relative Ru - X bond strengths in 4-X, and comparison with experimentally determined M - X relative bond strengths in the literature highlights the importance of X → M π-donation in determining trends in M - X bond dissociation energies in unsaturated systems.</p

H - X bond activation via hydrogen transfer to hydride in ruthenium N-heterocyclic carbene complexes:Density functional and synthetic studies

The reactions of tcc-Ru(IMes)2(AsPh3)(CO)H 2 (1, IMes = bis(l,3-(2,4,6-trimethylphenyl)imidazol-2-ylidene)) with HX substrates (X = OH, OEt, SH, SnPr) have been reinvestigated and shown to lead directly to the formation of the 16-electron species Ru(IMes) 2(CO)(X)H (4-X). The fluoro analogue Ru-(IMes)2(CO)(F)H (4-F) has also been synthesized, and X-ray and neutron diffraction studies show that this exhibits a square-pyramidal geometry with hydride in the axial site. Density functional calculations have been performed on one possible mechanism for the formation of 4-X from 1 with various HX (X = F, Cl, OH, SH, NH 2, PH2, CH3, and SiH3), involving initial AsPh3/HX substitution followed by H-transfer to hydride and H2 loss. With X = SH, H-transfer in both tcc-Ru(IMes) 2(CO)(H2S)(H)2 and ttt-Ru(IMes) 2-(CO)(H2S)(H)2 was considered and shown to be kinetically accessible and thermodynamically favored, suggesting that such dihydrides should not be stable with respect to this step. The calculations indicate that the ease of formation of 4-X becomes more kinetically and thermodynamically favored according to the trends F &gt; OH &gt; NH2 &gt; CH3 and Cl &gt; SH &gt; PH2 &lt; SiH3, with the reactions of second-row HX substrates being more favored than the first-row analogues. Calculated reaction exothermicities allow the derivation of relative Ru - X bond strengths in 4-X, and comparison with experimentally determined M - X relative bond strengths in the literature highlights the importance of X → M π-donation in determining trends in M - X bond dissociation energies in unsaturated systems.</p