Healing Policies for Black Boys and Young Men in St. Louis: Priorities in 2019

What policy reforms are needed to remove the structural barriers that make it difficult for Black boys and young men to thrive in St. Louis? Presenting findings from research with social service providers, this Brief Report from the Race and Opportunity Lab’s HomeGrown STL project seeks to inform policy decisions, advocacy efforts, and collective impact strategies in order to improve outcomes for Black boys and young men in the St. Louis region

Breast Milk from Tanzanian Women has Divergent Effects on Cell-Free and Cell-Associated HIV-1 Infection in Vitro.

Transmission of HIV-1 during breastfeeding is a significant source of new pediatric infections in sub-Saharan Africa. Breast milk from HIV-positive mothers contains both cell-free and cell-associated virus; however, the impact of breast milk on HIV-1 infectivity remains poorly understood. In the present study, breast milk was collected from HIV-positive and HIV-negative Tanzanian women attending antenatal clinics in Dar es Salaam. Milk was analyzed for activity in vitro against both cell-free and cell-associated HIV-1. Potent inhibition of cell-free R5 and X4 HIV-1 occurred in the presence of milk from all donors regardless of HIV-1 serostatus. Inhibition of cell-free HIV-1 infection positively correlated with milk levels of sialyl-Lewis(X) from HIV-positive donors. In contrast, milk from 8 of 16 subjects enhanced infection with cell-associated HIV-1 regardless of donor serostatus. Milk from two of these subjects contained high levels of multiple pro-inflammatory cytokines including TNFα, IL-1β, IL-6, IL-8, MIP-1α, MIP-1β, MCP-1 and IP-10, and enhanced cell-associated HIV-1 infection at dilutions as high as 1∶500. These findings indicate that breast milk contains innate factors with divergent activity against cell-free and cell-associated HIV-1 in vitro. Enhancement of cell-associated HIV-1 infection by breast milk may be associated with inflammatory conditions in the mother and may contribute to infant infection during breastfeeding

Environmental Impact Assessment: Boulevard Park Pedestrian Overpass Removal

The proposed action for the Boulevard Park Pedestrian Overpass is to remove the wooden structure and reroute the utilities underground. The utilities would be routed underneath the train tracks at the park entrance, connecting to Woods Coffee and up Bayview Drive. Irrigation and sewer will still be routed into the park but electricity, telecommunications and water will be routed out of the park. The utility conduits will be in separate trenches under the tracks. The park restrooms at the north end of the park will be abandoned to reduce utilities demands (especially water, electricity and sewer). Restrooms are still available in the park at Wood’s Coffee

Cognitive impairment and self-care in heart failure

BACKGROUND: Heart failure (HF) is a prevalent chronic disease in older adults that requires extensive self-care to prevent decompensation and hospitalization. Cognitive impairment may impact the ability to perform HF self-care activities. We examined the association between cognitive impairment and adherence to self-care in patients hospitalized for acute HF. DESIGN: Prospective cohort study. SETTING AND PARTICIPANTS: A total of 577 patients (mean age = 71 years, 44% female) hospitalized for HF at five medical centers in the United States and Canada. MEASUREMENTS AND METHODS: Participants were interviewed for information on self-reported adherence to self-care using the European Heart Failure Self-care Behaviour Scale. We assessed cognitive impairment in three domains (memory, processing speed, and executive function) using standardized measures. Patients\u27 demographic and clinical characteristics were obtained through medical record review. Multivariable linear regression was used to examine the association between cognitive impairment and self-care practices adjusting for demographic and clinical factors. RESULTS: A total of 453 patients (79%) were impaired in at least one cognitive domain. Average adherence to self-care activities among patients with global cognitive impairment did not differ significantly from those without cognitive impairment (30.5 versus 29.6; 45-point scale). However, impaired memory was associated with lower self-care scores (P = 0.006) in multivariable models. CONCLUSION: Cognitive impairment is highly prevalent among older patients hospitalized for HF. Memory impairment is associated with poorer adherence to self-care practices. Screening for memory impairment in patients with HF may help to identify patients at risk for poor self-care who may benefit from tailored disease management programs

Fibrodysplasia Ossificans Progressiva and Pregnancy: A Case Series and Review of the Literature

Objective: To evaluate maternal and fetal outcomes in pregnant patients with fibrodysplasia ossificans progressiva (FOP; OMIM#135100), an ultrarare genetic disorder characterized by progressive heterotopic ossification of soft tissues and cumulative disability. Methods: This is a retrospective case series of three patients with FOP who were admitted to Grady Memorial Hospital in Atlanta, Georgia, from to February 2011 to July 2021. Results: Three women delivered preterm infants at our institution. These cases posed unique anesthetic and obstetric technical challenges, particularly when securing the airway and performing cesarean delivery. Importantly, each patient received perioperative glucocorticoids for prevention of further heterotopic ossification. Conclusion: FOP is a unique clinical diagnosis encountered by obstetricians and requires multidisciplinary management for optimal outcomes

Releasing activity disengages Cohesin’s Smc3/Scc1 interface in a process blocked by Acetylation

Sister chromatid cohesion conferred by entrapment of sister DNAs within a tripartite ring formed between cohesin’s Scc1, Smc1, and Smc3 subunits is created during S and destroyed at anaphase through Scc1 cleavage by separase. Cohesin’s association with chromosomes is controlled by opposing activities: loading by Scc2/4 complex and release by a separase- independent releasing activity as well as by cleavage. Coentrapment of sister DNAs at replication is accompanied by acetylation of Smc3 by Eco1, which blocks releasing activity and ensures that sisters remain connected. Because fusion of Smc3 to Scc1 prevents release and bypasses the requirement for Eco1, we suggested that release is mediated by disengagement of the Smc3/Scc1 interface. We show that mutations capable of bypassing Eco1 in Smc1, Smc3, Scc1, Wapl, Pds5, and Scc3 subunits reduce dissociation of N-terminal cleavage fragments of Scc1 (NScc1) from Smc3. This process involves interaction between Smc ATPase heads and is inhibited by Smc3 acetylation

Activation pathway to amino acid adducts

Funding: This work was supported in part by Fundação para a Ciência e a Tecnologia (FCT), Portugal (PTDC/QUI-QUI/113910/2009, RECI/QEQ-MED/0330/2012, UID/QUI/00100/2013 and IF/ 01091/2013/CP1163/CT0001), and by Interagency Agreement Y1ES1027 between the National Center for Toxicological Research/Food and Drug Administration and the National Institute of Environmental Health Sciences/National Toxicology Program. The opinions expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration. RW, ALG, ILM and SGH thank FCT for postdoctoral and doctoral fellowships (SFRH/BPD/70953/2010, SFRH/BD/72301/2010, SFRH/BD/75426/2010 and SFRH/BD/ 80690/2011, respectively). AMM also acknowledges Programa Operacional Potencial Humano from FCT and the European Social Fund (IF/01091/2013), and the LRI Innovative Science Award. We thank the Portuguese NMR and MS networks (IST nodes) for providing access to the facilities.Nevirapine (NVP) is the non-nucleoside HIV-1 reverse transcriptase inhibitor most commonly used in developing countries, both as a component of combined antiretroviral therapy and to prevent mother-to-child transmission of the virus; however, severe hepatotoxicity and serious adverse cutaneous effects raise concerns about its safety. NVP metabolism yields several phenolic derivatives conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid derivatives prone to react with bionucleophiles and initiate toxic responses. We investigated the ability of two phenolic NVP metabolites, 2-hydroxy-NVP and 3-hydroxy-NVP, to undergo oxidation and subsequent reaction with bionucleophiles. Both metabolites yielded the same ring-contraction product upon oxidation with Frémy's salt in aqueous medium. This is consistent with the formation of a 2,3-NVP-quinone intermediate, which upon stabilization by reduction was fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. Additionally, we established that the oxidative activation of 2-hydroxy-NVP involved the transient formation of both the quinone and a quinone-imine, whereas 3-hydroxy-NVP was selectively converted into 2,3-NVP-quinone. The oxidations of 2-hydroxy-NVP and 3-hydroxy-NVP in the presence of the model amino acids ethyl valinate (to mimic the highly reactive N-terminal valine of hemoglobin) and N-acetylcysteine were also investigated. Ethyl valinate reacted with both 2,3-NVP-quinone and NVP-quinone-imine, yielding covalent adducts. By contrast, neither 2,3-NVP-quinone nor NVP-derived quinone-imine reacted with N-acetylcysteine. The product profile observed upon Frémy's salt oxidation of 2-hydroxy-NVP in the presence of ethyl valinate was replicated with myeloperoxidase-mediated oxidation. Additionally, tyrosinase-mediated oxidations selectively yielded 2,3-NVP-quinone-derived products, while quinone-imine-derived products were obtained upon lactoperoxidase catalysis. These observations suggest that the metabolic conversion of phenolic NVP metabolites into quinoid electrophiles is biologically plausible. Moreover, the lack of reaction with sulfhydryl groups might hamper the in vivo detoxification of NVP-derived quinone and quinone-imine metabolites via glutathione conjugation. As a result, these metabolites could be available for reaction with nitrogen-based bionucleophiles (e.g., lysine residues of proteins) ultimately eliciting toxic events.publishersversionpublishe

Isothiourea-catalysed enantioselective pyrrolizine synthesis : synthetic and computational studies

We thank Syngenta and the EPSRC (grant code EP/K503162/1) (DGS), and the EPSRC Centre for Doctoral Training in Critical Resource Catalysis (CRITICAT, grant code EP/L016419/1) (ERG,SFM, RWFK) for funding. The European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013) ERC Grant Agreement No. 279850 is also acknowledged (JET). ADS thanks the Royal Society for a Wolfson Research Merit Award.The catalytic enantioselective synthesis of a range of cis-pyrrolizine carboxylate derivatives with outstanding stereocontrol (14 examples,>95:5 dr, >98:2 er) through an isothiourea-catalyzed intramolecular Michael addition-lactonisation and ring opening approach from the corresponding enone acid is reported. An optimised and straightforward three-step synthetic route to the enone acid starting materials from readily available pyrrole-2-carboxaldehydes is delineated, with benzotetramisole (5 mol%) proving the optimal catalyst for the enantioselective process. Ring-opening of the pyrrolizine dihydropyranone products with either MeOH or a range of amines leads to the desired products in excellent yield and enantioselectivity. Computation has been used to probe the factors leading to high stereocontrol, with the formation of the observed cis-steroisomer predicted to be kinetically and thermodynamically favoured.Publisher PDFPeer reviewe

Decadally resolved lateglacial radiocarbon evidence from New Zealand kauri

Author Posting. © The Author(s), 2016. This is the author's version of the work. It is posted here by permission of Arizona Board of Regents on behalf of the University of Arizona for personal use, not for redistribution. The definitive version was published in Radiocarbon 58 (2016): 709-733, doi: 10.1017/RDC.2016.86.The Last Glacial-Interglacial Transition (LGIT; 15,000-11,000 cal BP) was characterized by complex spatiotemporal patterns of climate change, with numerous studies requiring accurate chronological control to decipher leads from lags in global paleoclimatic, -environmental and archaeological records. However, close scrutiny of the few available tree-ring chronologies and 14C-dated sequences composing the IntCal13 radiocarbon calibration curve, indicates significant weakness in 14C calibration across key periods of the LGIT. Here, we present a decadally-resolved atmospheric 14C record derived from New Zealand kauri spanning the Lateglacial from ~13,100 - 11,365 cal BP. Two floating kauri 14C time series, curve-matched to IntCal13, serve as a radiocarbon backbone through the Younger Dryas. The floating Northern Hemisphere (NH) 14C datasets derived from the YD-B and Central European Lateglacial Master tree-ring series are matched against the new kauri data, forming a robust NH 14C time series to ~14,200 cal BP. Our results show that IntCal13 is questionable from ~12,200 - 11,900 cal BP and the ~10,400 BP 14C plateau is approximately five decades too short. The new kauri record and re-positioned NH pine 14C series offer a refinement of the international 14C calibration curves IntCal13 and SHCal13, providing increased confidence in the correlation of global paleorecords.This work was part funded by the Foundation for Research, Science and Technology (FRST)—now Ministry for Business, Innovation & Employment (MBIE)-PROP-20224-SFK-UOA), a Royal Society of New Zealand grant, the Australian Research Council (FL100100195 and DP0664898) and the Natural Environment Research Council (NE/H009922/1, NE/I007660/1, NER/A/S/2001/01037 and NE/H007865/1)