Efficient syntheses of climate relevant isoprene nitrates and (1R,5S)-(−)-myrtenol nitrate

Here we report the chemoselective synthesis of several important, climate relevant isoprene nitrates using silver nitrate to mediate a ’halide for nitrate’ substitution. Employing readily available starting materials, reagents and Horner–Wadsworth–Emmons chemistry the synthesis of easily separable, synthetically versatile ‘key building blocks’ (E)- and (Z)-3-methyl-4-chlorobut-2-en-1-ol as well as (E)- and (Z)-1-((2-methyl-4-bromobut-2-enyloxy)methyl)-4-methoxybenzene has been achieved using cheap, ’off the shelf’ materials. Exploiting their reactivity we have studied their ability to undergo an ‘allylic halide for allylic nitrate’ substitution reaction which we demonstrate generates (E)- and (Z)-3-methyl-4-hydroxybut-2-enyl nitrate, and (E)- and (Z)-2-methyl-4-hydroxybut-2-enyl nitrates (‘isoprene nitrates’) in 66–80% overall yields. Using NOESY experiments the elucidation of the carbon–carbon double bond configuration within the purified isoprene nitrates has been established. Further exemplifying our ‘halide for nitrate’ substitution chemistry we outline the straightforward transformation of (1R,2S)-(−)-myrtenol bromide into the previously unknown monoterpene nitrate (1R,2S)-(−)-myrtenol nitrate

Measurement of isoprene nitrates by GCMS

According to atmospheric chemistry models, isoprene nitrates play an important role in determining the ozone production efficiency of isoprene; however this is very poorly constrained through observations as isoprene nitrates have not been widely measured. Measurements have been severely restricted largely due to a limited ability to measure individual isoprene nitrate isomers. An instrument based on gas chromatography/mass spectrometry (GCMS) and the associated calibration methods are described for the speciated measurements of individual isoprene nitrate isomers. Five of the primary isoprene nitrates which formed in the presence of NOx by reaction of isoprene with the hydroxyl radical (OH) in the Master Chemical Mechanism are identified using known isomers on two column phases and are fully separated on the Rtx-200 column. Three primary isoprene nitrates from the reaction of isoprene with the nitrate radical (NO3) are identified after synthesis from the already identified analogous hydroxy nitrate. A Tenax adsorbent-based trapping system allows the analysis of the majority of the known hydroxy and carbonyl primary isoprene nitrates, although not the (1,2)-IN isomer, under field-like levels of humidity and showed no impact from typical ambient concentrations of NOx and ozone

“Dial Up and Lock In”: Asymmetric organo-Brønsted acid catalysis incorporating stable isotopes

An operationally simple organo-Brønsted-acid-catalyzed asymmetric and regioselective “dial up and lock in” of one or more stable isotopes into organic compounds is unknown. Here, we describe a newly designed, chemically versatile protocol mediating single- or multiple-isotope incorporation into aziridines via a one-pot, three-component, two-step process. By exploiting easy-to-generate isotope-derived starting materials, it allows complete control of isotope positioning, affords >95 atom % isotope incorporation, and generates cis-aziridines with excellent optical activities and regioselectivities. Demonstrating a “low entry point,” and thus easy access to a broad range of researchers, it requires no specialist laboratory equipment and employs readily attainable reaction conditions. Demonstrating their utility, the aziridines are easily transformed into sought-after chiral non-racemic α-amino acids appended with one to three (or more) identical or different isotopes. The widespread use of these compounds ensures that our methodology will be of interest to biological, medicinal, pharmaceutical, agrochemical, biotechnology, materials, and process chemists alike

Homogeneity and Heterogeneity as Situational Properties: Producing – and Moving Beyond? – Race in Post-Genomic Science

In this article, we explore current thinking and practices around the logics of difference in gene–environment interaction research in the post-genomic era. We find that scientists conducting gene–environment interaction research continue to invoke well-worn notions of racial difference and diversity, but use them strategically to try to examine other kinds of etiologically significant differences among populations. Scientists do this by seeing populations not as inherently homogeneous or heterogeneous, but rather by actively working to produce homogeneity along some dimensions and heterogeneity along others in their study populations. Thus we argue that homogeneity and heterogeneity are situational properties – properties that scientists seek to achieve in their study populations, the available data, and other aspects of the research situation they are confronting, and then leverage to advance post-genomic science. Pointing to the situatedness of homogeneity and heterogeneity in gene–environment interaction research underscores the work that these properties do and the contingencies that shape decisions about research procedures. Through a focus on the situational production of homogeneity and heterogeneity more broadly, we find that gene–environment interaction research attempts to shift the logic of difference from solely racial terms as explanatory ends unto themselves, to racial and other dimensions of difference that may be important clues to the causes of complex diseases

Determinants of Heart Failure Self-Care Maintenance and Management in Patients and Caregivers: A Dyadic Analysis

Disease self-management is a critical component of maintaining clinical stability for patients with chronic illness. This is particularly evident in the context of heart failure (HF), which is the leading cause of hospitalization for older adults. HF self-management, commonly known as HF self-care, is often performed with the support of informal caregivers. However, little is known about how a HF dyad manages the patient\u27s care together. The purpose of this study was to identify determinants of patient and caregiver contributions to HF self-care maintenance (daily adherence and symptom monitoring) and management (appropriate recognition and response to symptoms), utilizing an approach that controls for dyadic interdependence. This was a secondary analysis of cross-sectional data from 364 dyads of Italian HF patients and caregivers. Multilevel modeling was used to identify determinants of HF self-care within patient-caregiver dyads. Patients averaged 76.2 (SD = 10.7) years old, and a slight majority (56.9%) was male, whereas caregivers averaged 57.4 (SD = 14.6) years old, and about half (48.1%) were male. Most caregivers were adult children (48.4%) or spouses (32.7%) of patients. Both patients and caregivers reported low levels of HF maintenance and management behaviors. Significant individual and dyadic determinants of self-care maintenance and self-care management included gender, quality of life, comorbid burden, impaired ADLs, cognition, hospitalizations, HF duration, relationship type, relationship quality, and social support. These comprehensive dyadic models assist in elucidating the complex nature of patient-caregiver relationships and their influence on HF self-care, leading to more effective ways to intervene and optimize outcomes

A Dyadic Approach to Managing Heart Failure with Confidence

Background: The majority of heart failure (HF) self-care research remains focused on patients, despite the important involvement of family caregivers. Although self-care confidence has been found to play an important role in the effectiveness of HF self-care management on patient outcomes, no known research has examined self-care confidence within a dyadic context. Objective: The purpose of this study was to identify individual and dyadic determinants of self-care confidence in HF care dyads. Methods: Multilevel modeling, which controls for the interdependent nature of dyadic data, was used to examine 329 Italian HF dyads (caregivers were either spouses or adult children). Results: Both patients and caregivers reported lower-than-adequate levels of confidence, with caregivers reporting slightly higher confidence than patients. Patient and caregiver levels of confidence were significantly associated with greater patient-reported relationship quality and better caregiver mental health. Patient confidence in self-care was significantly associated with patient female gender, nonspousal care dyads, poor caregiver physical health, and low care strain. Caregiver confidence to contribute to self-care was significantly associated with poor emotional quality of life in patients and greater perceived social support by caregivers. Conclusions: Findings are supportive of the need for a dyadic perspective of HF self-care in practice and research as well as the importance of addressing the needs of both members of the dyad to maximize optimal outcomes for both

Genetic and Biochemical Evidence That Haploinsufficiency of the Nf1 Tumor Suppressor Gene Modulates Melanocyte and Mast Cell Fates in Vivo

Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's “two hit” model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1−/− murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W and Nf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions in vivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W41 mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor, the ligand for c-kit. Furthermore, haploinsufficiency was associated with enhanced Ras–mitogen-activated protein kinase activity, a major downstream effector of Ras, via wild-type and mutant (W41) c-kit receptors. These observations identify a novel interaction between c-kit and neurofibromin in vivo, and offer experimental evidence that haploinsufficiency of Nf1 alters both cellular and biochemical phenotypes in two cell lineages that are affected in individuals with NF1. Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types

Mechanisms of hypertension during and after orthotopic liver transplantation in children

The aim of this study was to assess the hormonal alterations that may mediate the systemic hypertension that develops in patients during the perioperative period of orthotopic liver transplantation. We studied nine pediatric patients without previous hypertension or renal disease during six time points, starting before transplantation and ending at 48 hours after surgery. Hypertension developed in all patients in association with central venous pressures <10 mm Hg. Free water clearance was negative in all nine patients. Vasopressin levels increased intraoperatively but fell as hypertension developed. Atrial natriuretic factor levels increased as systemic blood pressure rose. A high level of plasma renin activity was observed in four patients with renal insufficiency. In six patients, postoperative 24-hour urinary norepinephrine excretion was within the normal age-adjusted range. These findings suggest that the combination of cyclosporine, corticosteroids, and, in some patients, an elevated plasma renin activity prevents the kidney from responding to the acute volume and salt overload with an appropriate diuresis and natriuresis, thus leading to systemic hypertension. The treatment of hypertension after liver transplantation may include salt restriction, diuretics, and, in those patients with a low creatinine excretion index, anglotensin coverting enzyme inhibitors. © 1989 The C. V. Mosby Company

Association of Heart Failure With Outcomes Among Patients With Peripheral Artery Disease: Insights From EUCLID.

Background Peripheral artery disease (PAD) and heart failure (HF) are each independently associated with poor outcomes. Risk factors associated with new-onset HF in patients with primary PAD are unknown. Furthermore, how the presence of HF is associated with outcomes in patients with PAD is unknown. Methods and Results This analysis examined risk relationships of HF on outcomes in patients with symptomatic PAD randomized to ticagrelor or clopidogrel as part of the EUCLID (Examining Use of Ticagrelor in Peripheral Arterial Disease) trial. Patients were stratified based on presence of HF at enrollment. Cox models were used to determine the association of HF with outcomes. A separate Cox model was used to identify risk factors associated with development of HF during follow-up. Patients with PAD and HF had over twice the rate of concomitant coronary artery disease as those without HF. Patients with PAD and HF had significantly increased risk of major adverse cardiovascular events (hazard ratio [HR], 1.31; 95% CI, 1.13-1.51) and all-cause mortality (HR, 1.39; 95% CI, 1.19-1.63). In patients with PAD, the presence of HF was associated with significantly less bleeding (HR, 0.65; 95% CI, 0.45-0.96). Characteristics associated with HF development included age ≥66 (HR, 1.29; 95% CI, 1.18-1.40 per 5 years), diabetes mellitus (HR, 1.85; 95% CI, 1.41-2.43), and weight (bidirectionally associated, ≥76 kg, HR, 0.77; 95% CI, 0.64-0.93; <76 kg, HR, 1.12; 95% CI, 1.07-1.16). Conclusions Patients with PAD and HF have a high rate of coronary artery disease with a high risk for major adverse cardiovascular events and death. These data support the possible need for aggressive treatment of (recurrent) atherosclerotic disease in PAD, especially patients with HF

Biopolitics meets Terrapolitics: Political Ontologies and Governance in Settler-Colonial Australia

Crises persist in Australian Indigenous affairs because current policy approaches do not address the intersection of Indigenous and European political worlds. This paper responds to this challenge by providing a heuristic device for delineating Settler and Indigenous Australian political ontologies and considering their interaction. It first evokes Settler and Aboriginal ontologies as respectively biopolitical (focused through life) and terrapolitical (focused through land). These ideal types help to identify important differences that inform current governance challenges. The paper discusses the entwinement of these traditions as a story of biopolitical dominance wherein Aboriginal people are governed as an “included-exclusion” within the Australian political community. Despite the overall pattern of dominance, this same entwinement offers possibilities for exchange between biopolitics and terrapolitics, and hence for breaking the recurrent crises of Indigenous affairs