A Semiempirical Investigation of Identity Reaction Proton Transfers

A semiempirical investigation of identity-reaction proton transfers using the AMI and PM3 methods has been carried out. Enthalpy differences between separated reactants and the ion-dipole complex (well depth) and between the complex and the transition structure (barrier height) were calculated. A comparison of carbon-to-carbon and oxygen-to-oxygen proton transfers led to the unexpected result that barriers were higher for the latter than for the former, in contrast to experimental observations in solution. The calculated values are compared with experiment and with ab initio calculations where possible, and the reliability of semiempirical calculations of well depths and barrier heights is assessed

Heavy Atom Isotope Effects in Elimination Reactions. An ab initio Study

Heavy atom kinetic isotope effects (KIEs) in bimolecular elimination (E2) reactions, both anti and syn, were calculated for the leaving group (LG, 18F/19F, 35Cl/37Cl), the carbon attached to the leaving group (C-1, 12C/13C), and the carbon bearing the proton removed in the reaction (C-2, 12C/13C) by ab initio methods at the MP2/6-31+G*//MP2/6-31+G* level. The substrates examined were EtF, EtF solvated by one H2O, and EtCl. The bases used were OH-, OH- solvated by one H2O, LiOH, NaOH, F-, and Cl-. The KIEs found for each reaction were compared with bond orders calculated by the Pauling equation and changes in NPA charges from reactant to transition structure. Qualitative and semiquantitative but few truly quantitative correlations are found. Restricted subsets of the data (e.g, only anti eliminations of EtF) give best results, but even here the C-2 KIEs correlate poorly. LG KIEs correlate well with ΔQ(X) and n(CX), C-1 KIEs with n(CX) and n(CC) but with scatter, and C-2 KIEs with ΔQ(C-2) and n(CC) + n(CH) but with much scatter. The dependence of KIEs on transition structure appears too complex to be expressed well by simple relationships with bond orders and charge distributions

Metabolism of a tropical rainforest stream

Gradients in photosynthesis (P) and respiration (R) were measured on an unperturbed portion of the Rio Mameyes, a tropical stream in the Luquillo Experimental Forest, northeastern Puerto Rico. Rates of P, which were similar to those of streams in temperate-deciduous forests, were low in the heavily canopied headwaters (\u3c70 g O2 m−2 y−1) and were higher (453–634 g O2 m−2 y−1) in middle and lower reaches. Periphyton biomass did not show the expected increase as the canopy opened downstream, probably because of increasing herbivory in downstream reaches. Rates of R, which were much higher than in most temperate streams, also were lower in the headwaters (767 g O2 m−2 y−1) than in the middle and lower reaches (1550–1660 g O2 m−2 y−1). High rates of R and suppressed periphyton abundance caused annual P/R to be \u3c\u3c1 from headwaters to lower reaches. Results for the Rio Mameyes suggest that intense herbivory, which is favored by the presence of large herbivores and consistently high temperatures, may be more typical of tropical than temperate streams. Results also show that the tropical rainforest provides the stream with sufficient amounts of labile organic C to support high rates of respiration over long distances across the basin

Equipping Health Professions Educators to Better Address Medical Misinformation

As part of a cooperative agreement with the US Centers for Disease Control and Prevention (Federal Award Identification Number [FAIN]: NU50CK000586), the Association of American Medical Colleges (AAMC) began a strategic initiative in 2022 both to increase confidence in COVID-19 vaccines and to address medical misinformation and mistrust through education in health professions contexts. Specifically, the AAMC solicited proposals for integrating competency-based, interprofessional strategies to mitigate health misinformation into new or existing curricula. Five Health Professions Education Curricular Innovations subgrantees received support from the AAMC in 2022 and reflected on the implementation of their ideas in a series of meetings over several months. Subgrantees included the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Florida International University Herbert Wertheim College of Medicine, the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo, the Maine Medical Center/Tufts University School of Medicine, and the University of Chicago Pritzker School of Medicine. This paper comprises insights from each of the teams and overarching observations regarding the challenges and opportunities involved with leveraging health professions education to address medical misinformation and improve patient health

Foamy Macrophages from Tuberculous Patients' Granulomas Constitute a Nutrient-Rich Reservoir for M. tuberculosis Persistence

Tuberculosis (TB) is characterized by a tight interplay between Mycobacterium tuberculosis and host cells within granulomas. These cellular aggregates restrict bacterial spreading, but do not kill all the bacilli, which can persist for years. In-depth investigation of M. tuberculosis interactions with granuloma-specific cell populations are needed to gain insight into mycobacterial persistence, and to better understand the physiopathology of the disease. We have analyzed the formation of foamy macrophages (FMs), a granuloma-specific cell population characterized by its high lipid content, and studied their interaction with the tubercle bacillus. Within our in vitro human granuloma model, M. tuberculosis long chain fatty acids, namely oxygenated mycolic acids (MA), triggered the differentiation of human monocyte-derived macrophages into FMs. In these cells, mycobacteria no longer replicated and switched to a dormant non-replicative state. Electron microscopy observation of M. tuberculosis–infected FMs showed that the mycobacteria-containing phagosomes migrate towards host cell lipid bodies (LB), a process which culminates with the engulfment of the bacillus into the lipid droplets and with the accumulation of lipids within the microbe. Altogether, our results suggest that oxygenated mycolic acids from M. tuberculosis play a crucial role in the differentiation of macrophages into FMs. These cells might constitute a reservoir used by the tubercle bacillus for long-term persistence within its human host, and could provide a relevant model for the screening of new antimicrobials against non-replicating persistent mycobacteria

A systems analysis of the chemosensitivity of breast cancer cells to the polyamine analogue PG-11047

<p>Abstract</p> <p>Background</p> <p>Polyamines regulate important cellular functions and polyamine dysregulation frequently occurs in cancer. The objective of this study was to use a systems approach to study the relative effects of PG-11047, a polyamine analogue, across breast cancer cells derived from different patients and to identify genetic markers associated with differential cytotoxicity.</p> <p>Methods</p> <p>A panel of 48 breast cell lines that mirror many transcriptional and genomic features present in primary human breast tumours were used to study the antiproliferative activity of PG-11047. Sensitive cell lines were further examined for cell cycle distribution and apoptotic response. Cell line responses, quantified by the GI₅₀(dose required for 50% relative growth inhibition) were correlated with the omic profiles of the cell lines to identify markers that predict response and cellular functions associated with drug sensitivity.</p> <p>Results</p> <p>The concentrations of PG-11047 needed to inhibit growth of members of the panel of breast cell lines varied over a wide range, with basal-like cell lines being inhibited at lower concentrations than the luminal cell lines. Sensitive cell lines showed a significant decrease in S phase fraction at doses that produced little apoptosis. Correlation of the GI₅₀values with the omic profiles of the cell lines identified genomic, transcriptional and proteomic variables associated with response.</p> <p>Conclusions</p> <p>A 13-gene transcriptional marker set was developed as a predictor of response to PG-11047 that warrants clinical evaluation. Analyses of the pathways, networks and genes associated with response to PG-11047 suggest that response may be influenced by interferon signalling and differential inhibition of aspects of motility and epithelial to mesenchymal transition.</p> <p>See the related commentary by Benes and Settleman: <url>http://www.biomedcentral.com/1741-7015/7/78</url></p

Combinatorial Mismatch Scan (CMS) for loci associated with dementia in the Amish

BACKGROUND: Population heterogeneity may be a significant confounding factor hampering detection and verification of late onset Alzheimer's disease (LOAD) susceptibility genes. The Amish communities located in Indiana and Ohio are relatively isolated populations that may have increased power to detect disease susceptibility genes. METHODS: We recently performed a genome scan of dementia in this population that detected several potential loci. However, analyses of these data are complicated by the highly consanguineous nature of these Amish pedigrees. Therefore we applied the Combinatorial Mismatch Scanning (CMS) method that compares identity by state (IBS) (under the presumption of identity by descent (IBD)) sharing in distantly related individuals from such populations where standard linkage and association analyses are difficult to implement. CMS compares allele sharing between individuals in affected and unaffected groups from founder populations. Comparisons between cases and controls were done using two Fisher's exact tests, one testing for excess in IBS allele frequency and the other testing for excess in IBS genotype frequency for 407 microsatellite markers. RESULTS: In all, 13 dementia cases and 14 normal controls were identified who were not related at least through the grandparental generation. The examination of allele frequencies identified 24 markers (6%) nominally (p ≤ 0.05) associated with dementia; the most interesting (empiric p ≤ 0.005) markers were D3S1262, D5S211, and D19S1165. The examination of genotype frequencies identified 21 markers (5%) nominally (p ≤ 0.05) associated with dementia; the most significant markers were both located on chromosome 5 (D5S1480 and D5S211). Notably, one of these markers (D5S211) demonstrated differences (empiric p ≤ 0.005) under both tests. CONCLUSION: Our results provide the initial groundwork for identifying genes involved in late-onset Alzheimer's disease within the Amish community. Genes identified within this isolated population will likely play a role in a subset of late-onset AD cases across more general populations. Regions highlighted by markers demonstrating suggestive allelic and/or genotypic differences will be the focus of more detailed examination to characterize their involvement in dementia