Deoxyfluorination using CuF2 : enabled by a Lewis base activating group strategy

We thank the University of St Andrews for PhD studentships (D.E.S and S.C.), GlaxoSmithKline and the University of Glasgow for financial support.Deoxyfluorination is a primary method for the formation of C–F bonds. Bespoke reagents are commonly used due to issues associated with the low reactivity of metal fluorides. Here, we report the development of a simple strategy for deoxyfluorination using first‐row transition metal fluorides that overcomes these limitations. Using CuF2 as an exemplar, activation of an O ‐alkylisourea adduct formed in situ allows effective nucleophilic fluoride transfer to a range of primary and secondary alcohols. Spectroscopic investigations have been used to probe the origin of the enhanced reactivity of CuF2 . The utility of the process towards enabling 18F‐radiolabeling is also presented.PostprintPeer reviewe

Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

Aims Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions. Methods and results It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels. Conclusions These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.Fil: Kelley, Eric E.. University of Pittsburgh; Estados UnidosFil: Baust, Jeff. University of Pittsburgh; Estados UnidosFil: Bonacci, Gustavo Roberto. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Golin Bisello, Franca. University of Pittsburgh; Estados UnidosFil: Devlin, Jason E.. University of Pittsburgh; Estados UnidosFil: Croix, Claudette M. St.. University of Pittsburgh; Estados UnidosFil: Watkins, Simon C.. University of Pittsburgh; Estados UnidosFil: Gor, Sonia. University of Pittsburgh; Estados UnidosFil: Cantu Medellin, Nadiezhda. University of Pittsburgh; Estados UnidosFil: Weidert, Eric R.. University of Pittsburgh; Estados UnidosFil: Frisbee,Jefferson C.. University of Virginia; Estados UnidosFil: Gladwin, Mark T.. University of Pittsburgh; Estados UnidosFil: Champion, Hunter C.. University of Pittsburgh; Estados UnidosFil: Freeman, Bruce A.. University of Pittsburgh; Estados UnidosFil: Khoo, Nicholas K.H.. University of Pittsburgh; Estados Unido

Perfluorocarbon Particle Size Influences Magnetic Resonance Signal and Immunological Properties of Dendritic Cells

The development of cellular tracking by fluorine (19F) magnetic resonance imaging (MRI) has introduced a number of advantages for following immune cell therapies in vivo. These include improved signal selectivity and a possibility to correlate cells labeled with fluorine-rich particles with conventional anatomic proton (1H) imaging. While the optimization of the cellular labeling method is clearly important, the impact of labeling on cellular dynamics should be kept in mind. We show by 19F MR spectroscopy (MRS) that the efficiency in labeling cells of the murine immune system (dendritic cells) by perfluoro-15-crown-5-ether (PFCE) particles increases with increasing particle size (560>365>245>130 nm). Dendritic cells (DC) are professional antigen presenting cells and with respect to impact of PFCE particles on DC function, we observed that markers of maturation for these cells (CD80, CD86) were also significantly elevated following labeling with larger PFCE particles (560 nm). When labeled with these larger particles that also gave an optimal signal in MRS, DC presented whole antigen more robustly to CD8+ T cells than control cells. Our data suggest that increasing particle size is one important feature for optimizing cell labeling by PFCE particles, but may also present possible pitfalls such as alteration of the immunological status of these cells. Therefore depending on the clinical scenario in which the 19F-labeled cellular vaccines will be applied (cancer, autoimmune disease, transplantation), it will be interesting to monitor the fate of these cells in vivo in the relevant preclinical mouse models

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

A Review of Edward Luce's In Spite of the Gods: The Strange Rise of Modern India

India poses a development puzzle on a grand scale. Sixty years of electoral democracy, thirty years of rapid growth, and a number of world class institutions (such as the Institutes of Technology or Election Commission) have led to talk of India as a superpower in a league with the United States and China. Yet, on many fronts, India's indicators of human well-being (e.g., malnutrition, immunization) are at, or below, those of much poorer sub-Saharan African countries. Measures of the administrative capacity of the state on basics like attendance, performance, and corruption reveal a potentially "flailing state" whose brilliantly formulated policies are disconnected from realities on the ground. This review essay of Ed Luce's In Spite of the Gods attempts to articulate the puzzle that is modern India and pose questions about the development trajectory of a country whose fortunes will shape our century.

Deoxyfluorination Using CuF2

Deoxyfluorination is a primary method for the formation of C–F bonds. Bespoke reagents are commonly used due to issues associated with the low reactivity of metal fluorides. Here, we report the development of a simple strategy for deoxyfluorination using first-row transition metal fluorides that overcomes these limitations. Using CuF2 as an exemplar, activation of an O-alkylisourea adduct formed in situ allows effective nucleophilic fluoride transfer to a range of primary and secondary alcohols. Spectroscopic investigations have been used to probe the origin of the enhanced reactivity of CuF2. The utility of the process towards enabling 18F-radiolabeling is also presented.</div

Clinical Reasoning: A Teenage Girl With Progressive Hyperkinetic Movements, Seizures, and Encephalopathy

The 'epilepsy-dyskinesia' spectrum is increasingly recognized in neurogenetic and neurometabolic conditions. It can be challenging to diagnose due to clinical and genetic heterogeneity, atypical or nonspecific presentations, and the rarity of each diagnostic entity. This is further complicated by the lack of sensitive or specific biomarkers for most nonenzymatic neurometabolic conditions. Nevertheless, clinical awareness and timely diagnosis are paramount to facilitate appropriate prognostication, counselling, and management.This report describes a case of a teenage girl who had presented at 14 months with a protracted illness manifesting as gastrointestinal upset and associated motor and cognitive regression. A choreoathetoid movement disorder, truncal ataxia, and microcephaly evolved after the acute phase. Neurometabolic and inflammatory investigations, EEG, brain MRI, muscle biopsy (including respiratory chain enzyme studies), and targeted genetic testing were unremarkable. A second distinct regression phase ensued at 14 years, consisting of encephalopathy, multifocal motor seizures, absent deep tendon reflexes and worsening movements, as well as gut dysmotility and dysphagia. Video EEGs showed an evolving developmental and epileptic encephalopathy with multifocal seizures and nonepileptic movements. A brain MRI revealed evolving and fluctuating patchy bi-hemispheric cortical changes, cerebellar atrophy with signal change, mild generalized brain volume loss, and abnormal lactate on MR spectroscopy.The article discusses the differential diagnostic approach and management options for patients presenting with neurological regression, encephalopathy, seizures, and hyperkinetic movements. It also emphasizes the utility of next generation sequencing in providing a rapid, efficient, cost-effective way of determining the underlying etiology of complex neurologic presentations

Effect of conservative treatment on the renal outcome of children with primary hyperoxaluria type 1

Primary hyperoxaluria type 1 results from alanine:glyoxylate aminotransferase deficiency. Due to genotype/phenotype heterogeneity in this autosomal recessive disorder, the renal outcome is difficult to predict in these patients and the long-term impact of conservative management in children is unknown. We report here a multicenter retrospective study on the renal outcome in 27 affected children whose biological diagnosis was based on either decreased enzyme activity or identification of mutations in the patient or his siblings. The median age at first symptoms was 2.4 years while that at initiation of conservative treatment was 4.1 years; 6 children were diagnosed upon family screening. The median follow-up was 8.7 years. At diagnosis, 15 patients had an estimated glomerular filtration rate (eGFR) below 90, and 7 children already had stage 2-3 chronic kidney disease. The median baseline eGFR was 74, which rose to 114 with management in the 22 patients who did not require renal replacement therapy. Overall, 20 patients had a stable eGFR, however, 7 exhibited a decline in eGFR of over 20 during the study period. In a Cox regression model, the only variable significantly associated with deterioration of renal function was therapeutic delay with a relative risk of 1.7 per year. Our study strongly suggests that early and aggressive conservative management may preserve renal function of compliant children with this disorder, thereby avoiding dialysis and postponing transplantation. © 2009 Inernational Society of Nephrology.SCOPUS: ar.jinfo:eu-repo/semantics/publishe