Dynamic Cross-Exchange in Halophosphonium Species: Direct Observation of Stereochemical Inversion in the Course of an SN 2 Process.

The complex fluxional interconversions between otherwise very similar phosphonium bromides and chlorides R3 PX+ X- (R=Alk, Ar, X=Cl or Br) were studied by NMR techniques. Their energy barriers are typically ca. 11 kcal mol-1 , but rise rapidly as bulky groups are attached to phosphorus, revealing the importance of steric factors. In contrast, electronic effects, as measured by Hammett analysis, are modest (ρ 1.46) but still clearly indicate negative charge flow towards phosphorus in the transition state. Most significantly, detailed analysis of the exchange pathways unequivocally, and for the first time in any such process, shows that nucleophilic attack of the nucleophilic anion on the tetrahedral centre results in inversion of configuration.

Two Independent Orthogonal Stereomutations at a Single Asymmetric Center: A Narcissistic Couple.

The energy barriers in our recently discovered Walden-type inversion of chlorophosphonium salts are similar to those for Cope rearrangements of caged cyclic hydrocarbons. Therefore, we have designed a molecular system that integrates the two processes, thereby producing the first embodiment of a chemical species that can undergo two entirely different and independent stereomutation mechanisms at the same nominal asymmetric center. Thus, the energy barrier to the rearrangement of 9-phenyl-9-phosphabarbaralane oxide, which is easily prepared by a new high-yielding synthesis, was found to be roughly 11 kcal mol-1 . This value is in contrast to the parent barbaralane (7.3 kcal mol-1 ) but in good agreement with our computational results for the rearrangement barriers. Crucially, in the corresponding chlorophosphonium derivative, two stereomutations occur simultaneously: a fast Cope rearrangement (barrier ≈12 kcal mol-1 ) and a slow Walden-type inversion of the phosphorus center (barrier ≈21 kcal mol-1 ). The computational model also revealed a relationship between the Cope rearrangement barrier and the bridgehead distance. The phenomenon of two independent and geometrically orthogonal stereomutations at a single asymmetric center provided important general insights into reaction pathway bifurcation, microscopic reversibility, and dynamic stereochemistry. This first example of coexisting alternative mechanisms that involve covalent bonds may encourage the design of new types of dynamic molecular structures.

Degenerate nucleophilic substitution in phosphonium salts.

Rates and energy barriers of degenerate halide substitution on tetracoordinate halophosphonium cations have been measured by NMR techniques (VT and EXSY) using a novel experimental design whereby a chiral substituent ((s)Bu) lifts the degeneracy of the resultant salts. Concomitantly, a viable computational approach to the system was developed to gain mechanistic insights into the structure and relative stabilities of the species involved. Both approaches strongly suggest a two-step mechanism of formation of a pentacoordinate dihalophosphorane via backside attack followed by dissociation, resulting in inversion of configuration at phosphorus. The experimentally determined barriers range from <9 kcal mol(-1) to nearly 20 kcal mol(-1), ruling out a mechansm via Berry pseudorotation involving equatorial halides. In all cases studied, epimerization of chlorophosphonium chlorides has a lower energy barrier (by 2 kcal mol(-1)) than the analogous bromo salts. Calculations determined that this was due to the easier accessibility in solution of pentacoordinate dichlorophosphoranes when compared to analogous dibromophosphoranes. In line with the proposed associative mechanism, bulky substituents slow the reaction in the order Me < Et < (i)Pr < (t)Bu. Bulky substituents affect the shape of the reaction energy profile so that the pentacoordinate intermediate is destabilized eventually becoming a transition state. The magnitude of the steric effects is comparable to that of the same substituents on substitution at primary alkyl halides, which can be rationalized by the relatively longer P-C bonds. The reaction displays first-order kinetics due to the prevalence of tight- or solvent-separated ion pairs in solution. Three-dimensional reaction potential energy profiles (More O'Ferrall-Jencks plots) indicated a relatively shallow potential well corresponding to the trigonal bipyramid intermediate flanked by two transition states.

Cleavage of P=O in the presence of P-N: aminophosphine oxide reduction with in situ boronation of the P(III) product.

In contrast to tertiary phosphine oxides, the deoxygenation of aminophosphine oxides is effectively impossible due to the need to break the immensely strong and inert PO bond in the presence of a relatively weak and more reactive PN bond. This long-standing problem in organophosphorus synthesis is solved by use of oxalyl chloride, which chemoselectively cleaves the PO bond forming a chlorophosphonium salt, leaving the PN bond(s) intact. Subsequent reduction of the chlorophosphonium salt with sodium borohydride forms the P(III) aminophosphine borane adduct. This simple one-pot procedure was applied with good yields for a wide range of PN-containing phosphoryl compounds. The borane product can be easily deprotected to produce the free P(III) aminophosphine. Along with no observed PN bond cleavage, the use of sodium borohydride also permits the presence of ester functional groups in the substrate. The availability of this methodology opens up previously unavailable synthetic options in organophosphorus chemistry, two of which are exemplified.

Characterization of trans-3-Methylglutaconyl CoA-Dependent Protein Acylation.

3-methylglutaconyl (3MGC) CoA hydratase (AUH) is the leucine catabolism pathway enzyme that catalyzes the hydration of trans-3MGC CoA to 3-hydroxy, 3-methylglutaryl (HMG) CoA. In several inborn errors of metabolism (IEM), however, metabolic dysfunction can drive this reaction in the opposite direction (the dehydration of HMG CoA). The recent discovery that trans-3MGC CoA is inherently unstable and prone to a series of non-enzymatic chemical reactions provides an explanation for 3MGC aciduria observed in these IEMs. Under physiological conditions, trans-3MGC CoA can isomerize to cis-3MGC CoA, which is structurally poised to undergo intramolecular cyclization with the loss of CoA, generating cis-3MGC anhydride. The anhydride is reactive and has two potential fates; (a) hydrolysis to yield cis-3MGC acid or (b) a reaction with lysine side-chain amino groups to 3MGCylate substrate proteins. An antibody elicited against a 3MGC hapten was employed to investigate protein acylation in incubations containing recombinant AUH, HMG CoA, and bovine serum albumin (BSA). The data obtained show that, as AUH dehydrates HMG CoA to trans-3MGC CoA, BSA is acylated. Moreover, α-3MGC IgG immunoblot signal intensity correlates with AUH concentration, HMG CoA substrate concentration, and incubation time. Thus, protein 3MGCylation may contribute to the phenotypic features associated with IEMs that manifest 3MGC aciduria.

3-Methylglutarylcarnitine: A biomarker of mitochondrial dysfunction.

The acylcarnitines comprise a wide range of acyl groups linked via an ester bond to the hydroxyl group of L-carnitine. Mass spectrometry methods are capable of measuring the relative abundance of hundreds of acylcarnitines in a single drop of blood. As such, acylcarnitines can serve as sensitive biomarkers of disease. For certain acylcarnitines, however, their biochemical origin, and biomedical significance, remain unclear. One such example is 3-methylglutaryl (3MG) carnitine (C5-3M-DC). Whereas 3MG carnitine levels are normally very low, elevated levels are detected in discrete inborn errors of metabolism (IEM) as well as different forms of heart disease. Moreover, acute injury, including γ radiation exposure, paraquat poisoning, and traumatic brain injury manifest elevated levels of 3MG carnitine in blood and/or urine. Recent evidence indicates that two distinct biosynthetic routes to 3MG carnitine exist. The first, caused by an inherited deficiency in the leucine catabolism pathway enzyme, 3-hydroxy-3-methylglutaryl (HMG) CoA lyase, leads to a buildup of trans-3-methylglutaconyl (3MGC) CoA. Reduction of the double bond in trans-3MGC CoA generates 3MG CoA, which is then converted to 3MG carnitine by carnitine acyltransferase. This route, however, cannot explain why 3MG carnitine levels increase in IEMs that do not affect leucine metabolism or various chronic and acute disease states. In these cases, disease-related defects in aerobic energy metabolism result in diversion of acetyl CoA to trans-3MGC CoA. Once formed, trans-3MGC CoA is reduced to 3MG CoA and esterified to form 3MG carnitine. Thus, 3MG carnitine, represents a potential biomarker of disease processes associated with compromised mitochondrial energy metabolism.

Diversion of Acetyl CoA to 3-Methylglutaconic Acid Caused by Discrete Inborn Errors of Metabolism.

A growing number of inborn errors of metabolism (IEM) have been identified that manifest 3-methylglutaconic (3MGC) aciduria as a phenotypic feature. In primary 3MGC aciduria, IEM-dependent deficiencies in leucine pathway enzymes prevent catabolism of trans-3MGC CoA. Consequently, this metabolite is converted to 3MGC acid and excreted in urine. In secondary 3MGC aciduria, however, no leucine metabolism pathway enzyme deficiencies exist. These IEMs affect mitochondrial membrane structure, electron transport chain function or ATP synthase subunits. As a result, acetyl CoA oxidation via the TCA cycle slows and acetyl CoA is diverted to trans-3MGC CoA, and then to 3MGC acid. Whereas the trans diastereomer of 3MGC CoA is the only biologically relevant diastereomer, the urine of affected subjects contains both cis- and trans-3MGC acids. Studies have revealed that trans-3MGC CoA is susceptible to isomerization to cis-3MGC CoA. Once formed, cis-3MGC CoA undergoes intramolecular cyclization, forming an anhydride that, upon hydrolysis, yields cis-3MGC acid. Alternatively, cis-3MGC anhydride can acylate protein lysine side chains. Once formed, cis-3MGCylated proteins can be deacylated by the NAD+-dependent enzyme, sirtuin 4. Taken together, the excretion of 3MGC acid in secondary 3MGC aciduria represents a barometer of defective mitochondrial function.

Back to the drawing board-The relationship between self-report and neuropsychological tests of cognitive flexibility in clinical cohorts: A systematic review and meta-analysis.

OBJECTIVE: Cognitive flexibility has been previously described as the ability to adjust cognitive and behavioral strategies in response to changing contextual demands. Cognitive flexibility is typically assessed via self-report questionnaires and performance on neuropsychological tests in research and clinical practice. A common assumption among researchers and clinicians is that self-report and neuropsychological tests of cognitive flexibility assess the same or similar constructs, but the extent of the relationship between these two assessment approaches in clinical cohorts remains unknown. We undertook a systematic review and meta-analysis to determine the relationship between self-report and neuropsychological tests of cognitive flexibility in clinical samples. METHOD: We searched 10 databases and relevant gray literature (e.g., other databases and pearling) from inception to October 2020 and used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Eleven articles including 405 participants satisfied our eligibility criteria. RESULTS: A multilevel random-effects meta-analysis revealed no relationship between self-report and neuropsychological tests of cognitive flexibility (0.01, 95% CI [-0.16 to 0.18]). Individual random-effects meta-analyses between 12 different tests pairs also found no relationship. CONCLUSION: Based on our results, it is clear that the two assessment approaches of cognitive flexibility provide independent information-they do not assess the same construct. These findings have important ramifications for future research and clinical practice-there is a need to reconsider what constructs self-report and neuropsychological tests of "cognitive flexibility" actually assess, and avoid the interchangeable use of these assessments in clinical samples. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Financial Hardship, Hope, and Life Satisfaction Among Un/Underemployed Individuals With Psychiatric Diagnoses: A Mediation Analysis.

Background: Individuals with psychiatric diagnoses who are unemployed or underemployed are likely to disproportionately experience financial hardship and, in turn, lower life satisfaction (LS). Understanding the mechanisms though which financial hardship affects LS is essential to inform effective economic empowerment interventions for this population. Aim: To examine if subjective financial hardship (SFH) mediates the relationship between objective financial hardship (OFH) and LS, and whether hope, and its agency and pathways components, further mediate the effect of SFH on LS among individuals with psychiatric diagnoses seeking employment. Methods: We conducted structured interviews with participants (N = 215) of two peer-run employment programs using indicators of OFH and SFH and standardized scales for hope (overall hope, hope agency, and hope pathways) and LS. Three structural equation models were employed to test measurement models for OFH and SFH, and mediational relationships. Covariates included gender, age, psychiatric diagnosis, race/ethnicity, education, income, employment status, SSI/SSDI receipt, and site. Results: Confirmatory factor analysis (CFA) for items measuring OFH and SFH supported two separate hypothesized factors. OFH had a strong and significant total effect on SFH [standardized beta (B) = 0.68] and LS (B = 0.49), and a weak-to-moderate effect on hope (B = -0.31). SFH alone mediated up to 94% of the effect of OFH on LS (indirect effect B = -0.46, p < 0.01). The effect of SFH on LS through hope was small (indirect effect B = -0.09, p < 0.05), primarily through hope agency (indirect effect B = -0.13, p < 0.01) and not hope pathways. Black and Hispanic ethno-racial identification seemed to buffer the effect of financial hardship on hope and LS. Individuals identifying as Black reported significantly higher overall hope (B = 0.41-0.47) and higher LS (B = 0.29-0.46), net of the effect of OFH and SFH. Conclusion: SFH is a strong mediator of the relationship between OFH and LS in our study of unemployed and underemployed individuals with psychiatric diagnoses. Hope, and particularly its agency component, further mediate a modest but significant proportion of the association between SFH and LS. Economic empowerment interventions for this population should address objective and subjective financial stressors, foster a sense of agency, and consider the diverse effects of financial hardship across ethno-racial groups.

Same room - different windows? A systematic review and meta-analysis of the relationship between self-report and neuropsychological tests of cognitive flexibility in healthy adults.

Cognitive flexibility can be thought of as the ability to effectively adapt one's cognitive and behavioural strategies in response to changing task or environmental demands. To substantiate the common inference that self-report and neuropsychological tests of cognitive flexibility provide 'different windows into the same room', we undertook a systematic review and meta-analysis to determine whether self-report and neuropsychological tests of cognitive flexibility are related in healthy adults. Ten databases and relevant grey literature were searched from inception. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were adhered to. Twenty-one articles satisfied our inclusion criteria. A multi-level random-effects meta-analysis revealed no relationship (0.05, 95% CI = -0.00 to 0.10). Random-effects meta-analyses raised the possibility that the Cognitive Flexibility Scale and the Trail Making Test - part B (time) may be related (0.19, 95% CI = 0.06 to 0.31). We conclude that the relationship between self-report and neuropsychological tests of cognitive flexibility is not large enough to be considered convincing evidence for the two assessment approaches sharing construct validity. These results have clear implications for assessing and interpreting cognitive flexibility research and clinical practice.

A Note on Penalized Regression Spline Estimation in the Secondary Analysis of Case-Control Data.

Primary analysis of case-control studies focuses on the relationship between disease (D) and a set of covariates of interest (Y, X). A secondary application of the case-control study, often invoked in modern genetic epidemiologic association studies, is to investigate the interrelationship between the covariates themselves. The task is complicated due to the case-control sampling, and to avoid the biased sampling that arises from the design, it is typical to use the control data only. In this paper, we develop penalized regression spline methodology that uses all the data, and improves precision of estimation compared to using only the controls. A simulation study and an empirical example are used to illustrate the methodology.

Bayesian methods for expression-based integration of various types of genomics data.

: We propose methods to integrate data across several genomic platforms using a hierarchical Bayesian analysis framework that incorporates the biological relationships among the platforms to identify genes whose expression is related to clinical outcomes in cancer. This integrated approach combines information across all platforms, leading to increased statistical power in finding these predictive genes, and further provides mechanistic information about the manner in which the gene affects the outcome. We demonstrate the advantages of the shrinkage estimation used by this approach through a simulation, and finally, we apply our method to a Glioblastoma Multiforme dataset and identify several genes potentially associated with the patients' survival. We find 12 positive prognostic markers associated with nine genes and 13 negative prognostic markers associated with nine genes.