Supplementary data for the article: Pitts, A. L.; Wriglesworth, A.; Sun, X.-Z.; Calladine, J. A.; Zarić, S. D.; George, M. W.; Hall, M. B. Carbon-Hydrogen Activation of Cycloalkanes by Cyclopentadienylcarbonylrhodium-A Lifetime Enigma. Journal of the American Chemical Society 2014, 136 (24), 8614–8625. https://doi.org/10.1021/ja5014773

Supplementary material for: [https://doi.org/10.1021/ja5014773]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1792

The PERMA well-being model and music facilitation practice: Preliminary documentation for well-being through music provision in Australian schools

The aim of this study was to consider how we can invest in music-making to promote well-being in school contexts. Web-based data collection was conducted where researchers identified 17 case studies that describe successful music programs in schools in Australia. The researchers aligned content from these case studies into the five categories of the PERMA well-being model: Positive emotions, Engagement, Relationships, Meaning, and Accomplishment, in order to understand how each well-being element was realised through the music programs. The results indicate that the element of the PERMA well-being model that relates to relationships was described most often. Collaboration and partnership between students, teachers, and staff in schools, and local people in the community such as parents, local entrepreneurs, and musicians were repeatedly identified as a highly significant contributing factor in the success of the music program. The school leaders? roles in providing opportunities for students to experience musical participation and related activities (engagement) and valuing these experiences (meaning) were also crucial in the facilitation of the music programs. The findings of this study indicate that tailored music and relationship-centred music programs in schools not only increase skills and abilities of the students, but also improve the psychosocial well-being of the students and the community

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

A comprehensive re-assessment of the association between vitamin D and cancer susceptibility using Mendelian randomization

Abstract: Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible

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

Investigating the Electronic Structure of the Atox1 Copper(I) Transfer Mechanism with Density Functional Theory

To maintain correct copper homeostasis, the body relies on ion binding metallochaperones, cuprophilic ligands, and proteins to move copper around as a complexed metal. The most common binding site for Cu­(I) proteins is the CX₁X₂C motif, where X₁ and X₂ are nonconserved residues. Although this binding site motif is well established, the mechanistic and electronic details for the transfer of Cu­(I) between two binding sites have not been fully established, in particular, whether the transfer is dissociative or associative or if the electron-rich Cu­(I)–Cys interactions influence the transfer. In this work, we investigated the electronic structure of the Cu­(I)–S interactions during the copper transfer between Atox1 and a metal binding domain on the ATP7A or ATP7B protein. Initially, three Cu­(I) methylthiolate complexes, [Cu­(SCH₃)₂]⁻¹, [Cu­(SCH₃)₃]⁻², [Cu­(SCH₃)₄]⁻³, were investigated with density functional theory (DFT) to fully elucidate the electronic structure and bonding between Cu­(I) and thiolate species. The two-coordinate, linear species with a C–S–S–C dihedral angle of ∼90° is the lowest energy conformation because the filled π antibonding orbitals are stabilized in this geometry. The importance of π-overlap is also seen with the trigonal planar, three-coordinate Cu­(I) complex, which is similarly stabilized. A corresponding four-coordinate species could not be consistently optimized, so it was concluded that tetrahedral coordination was not likely to be stable. The transfer of Cu­(I) from the Atox1 metallochaperone to a metal binding domain of the ATP7A or ATP7B protein was then modeled by using the CGGC Atox1 binding site for the donor model and the dithiotreitol ligand (DTT) for the acceptor model. The two- and three-coordinate intermediates calculated along the five-step transfer mechanism converged to near optimal Cu–S π-overlap for the respective geometries, which demonstrates that the electronic structure in this electron-rich environment influences the intermediate’s geometries in the transfer mechanism

Carbon–Hydrogen Bond Activation in Bis(2,6-dimethylbenzenethiolato)­tris(trimethylphosphine)ruthenium(II): Ligand Dances and Solvent Transformations

Density functional theory (DFT) calculations are used to predict the mechanism for the intramolecular carbon–hydrogen bond activation of an ortho methyl group on the Ru^II(SC₆H₃Me₂-2,6-κ¹S)₂(PMe₃)₃ complex to form the cycloruthenated product <i>cis</i>-Ru­[SC₆H₃-(2-CH₂)­(6-Me)-κ²S₂C]­(PMe₃)₄ and HSC₆H₃Me₂-2,6 in the presence of PMe₃. The DFT calculations also show how changing the solvent from benzene to methanol prevents C–H activation and results in the unactivated six-coordinate product Ru­(SC₆H₃Me₂-2,6-κ¹S)₂(PMe₃)₄ in 100% yield. The reactant was determined to have two plausible σ-bond metathesis pathways in which to react, one for each of the two thiolate ligands. The steps in both mechanisms were influenced by the electronic interactions between the sulfur lone pairs and the Ru 4d orbitals and the steric repulsion between the methyl groups on the five ligands in such a way that the methyl group in the SAr (Ar = SC₆H₃Me₂-2,6) ligand closest to the Ru pirouettes away to activate the other methyl group. The equatorial pathway was calculated to be the lower energy mechanism and, therefore, the dominant pathway for the overall reaction. The difference between reaction mediums was predicted, by both implicit and explicit solvation modeling, to be a result of the polarity and binding of methanol, which transforms the geometry of the reactant from a less polar distorted trigonal-bipyramidal geometry to a more polar distorted square-pyramidal geometry. This change in geometry favors the more rapid addition of a fourth PMe₃ ligand to the more open coordination site, which prevents the C–H activation

Carbon-Hydrogen Activation of Cycloalkanes by Cyclopentadienylcarbonylrhodium-A Lifetime Enigma

Carbon-hydrogen bond activation reactions of four cycloalkanes (C5H10, C6H12, C7H14, and C8H16) by the Cp'Rh(CO) fragments (Cp' = eta(5)-C5H5 (Cp) or eta(5)-C5Me5 (Cp*)) were modeled theoretically by combining density functional and coupled cluster theories, and their reaction rates were measured by fast time-resolved infrared spectroscopy. The reaction has two steps, starting with the formation of a a-complex intermediate, followed by oxidative addition of the C-H bond by the rhodium. A range of a-complex stabilities among the electronically unique C-H bonds in a cycloalkane were calculated and are related to the individual strengths of the C-H bond's interactions with the Rh fragment and the steric repulsion that is incurred upon forming the specific a-complex. The unexpectedly large increase in the lifetimes of the a-complexes from cyclohexane to cycloheptane was predicted to be due to the large range of stabilities of the different sigma-complexes found for cycloheptane.. The reaction lifetimes were simulated with two mechanisms, with and without migrations among the different complexes, to determine if ring migrations prior to C-H activation were influencing the rate. Both mechanisms predicted similar lifetimes for cyclopentane, cyclohexane, and, to a lesser extent, cycloheptane, suggesting ring migrations do not have a large impact on the rate of C-H activation for these cycloalkanes. For cyclooctane, the inclusion of ring migrations in the reaction mechanism led to a more accurate prediction of the lifetime, indicating that ring migrations did have an effect on the rate of C-H activation for this alkane, and that migration among the a-complexes is faster than the C-H activation for this larger cycloalkane.Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3685