The first mechanistic investigation of electrophilic amide activation of α,α-disubstituted tertiary lactams and the direct observation of key intermediates by in situ FTIR, 1H, 13C, and 19F NMR in ...our interrupted Bischler–Napieralski-based synthetic strategy to the aspidosperma alkaloids, including a complex tetracyclic diiminium ion, is discussed. The reactivity of a wide range of pyridines with trifluoromethanesulfonic anhydride was systematically examined, and characteristic IR absorption bands for the corresponding N-trifluoromethanesulfonylated pyridinium trifluoromethanesulfonates were assigned. The reversible formation of diiminium ether intermediates was studied, providing insight into divergent mechanistic pathways as a function of the steric environment of the amide substrate and stoichiometry of reagents. Importantly, when considering base additives during electrophilic amide activation, more hindered α-quaternary tertiary lactams require the use of non-nucleophilic pyridine additives in order to avoid deactivation via a competing desulfonylation reaction. The isolation and full characterization of a tetracyclic iminium trifluoromethanesulfonate provided additional correlation between in situ characterization of sensitive intermediates and isolable compounds involved in this synthetic transformation.
In preparation for implementing the Nitric-Glycolic (NG) acid flowsheet for the Savannah River Site (SRS) Liquid Waste System (LWS), analytical methods for determining glycolate at low concentration, ...below 20 mg/L in radioactive samples, were developed to support system management and safety. To accommodate the wide range of LWS matrix conditions, two alternative methods were developed, refined, and demonstrated for glycolate analysis in radioactive waste samples: ion chromatography (IC) and a proton nuclear magnetic resonance (H NMR). Investigators validated IC and H NMR methods for glycolate analysis, defined the range of applicability, and demonstrated key supporting analytical protocols. The deployed IC method is applicable in low to moderate ionic strength samples and requires sample pretreatment using a Dionex OnGuard II H
+
cartridge. The deployed H NMR method is more labor intensive but provides options for a broader range of matrices. Based on the results, high quality glycolate analysis of the Defense Waste Processing Facility (DWPF) condensate in Tank 22 is feasible by IC down to approximately 12 mg/L. Using H NMR, glycolate may be determined to 8 mg/L or lower depending on the run time with the potential for broader applicability of the method to higher ionic strength conditions in other tanks of the SRS LWS.
Ependymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates ...stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who survive treatment often suffer long-term neurological side effects as a result of therapy. It is evident that there is a need for safer, more effective treatments for pediatric EPN patients. There are ten distinct subgroups of EPN, each with their own molecular and prognostic features. To identify and facilitate the testing of new treatments for EPN,
laboratory models representative of the diverse molecular subtypes are required. Here, we describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of posterior fossa A (PFA) EPN, derived from a metastatic cranial lesion.
Patient and PDOX tumors were analyzed using immunohistochemistry, DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing.
Both patient and PDOX tumors classified as PFA EPN by methylation profiling, and shared similar histological features consistent with this molecular subgroup. RNA sequencing revealed that gene expression patterns were maintained across the primary and metastatic tumors, as well as the PDOX. Copy number profiling revealed gains of chromosomes 7, 8 and 19, and loss of chromosomes 2q and 6q in the PDOX and matched patient tumor. No clinically significant single nucleotide variants were identified, consistent with the low mutation rates observed in PFA EPN. Overexpression of
RNA and protein, a common feature of PFA EPN, was also observed. Despite the aggressive nature of the tumor in the patient, this PDOX was unable to be maintained past two passages
.
Others who have successfully developed PDOX models report some of the lowest success rates for EPN compared to other pediatric brain cancer types attempted, with loss of tumorigenicity not uncommon, highlighting the challenges of propagating these tumors in the laboratory. Here, we discuss our collective experiences with PFA EPN PDOX model generation and propose potential approaches to improve future success in establishing preclinical EPN models.
The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug ...development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described.
The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs.
Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60-100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10-30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg.
SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.
BACKGROUND: Deoxynivalenol (DON) is a toxic fungal metabolite that frequently contaminates cereal crops. DON is toxic to animals, but the effects on humans are poorly understood, in part because ...exposure estimates are of limited precision. OBJECTIVES: In this study we used the U.K. adult National Diet and Nutrition Survey to compare 24-hr urinary DON excretion with cereal intake. METHODS: One hundred subjects were identified for each of the following cereal consumption groups: low (mean, 107 g cereal/day; range, 88-125), medium (mean, 179 g/day; range, 162-195) and high (mean, 300 g/day; range, 276-325). DON was analyzed in 24-hr urine samples by liquid chromatography-mass spectrometry after purification on immunoaffinity columns. RESULTS: DON was detected in 296 of 300 (98.7%) urine samples. Cereal intake was significantly associated with urinary DON (p < 0.0005), with the geometric mean urinary levels being 6.55 µg DON/day 95% confidence interval (CI), 5.71-7.53; 9.63 µg/day (95% CI, 8.39-11.05); and 13.24 µg/day (95% CI, 11.54-15.19) for low-, medium-, and high-intake groups, respectively. In multivariable analysis, wholemeal bread (p < 0.0005), white bread (p < 0.0005), "other" bread (p < 0.0005), buns/cakes (p = 0.003), high-fiber breakfast cereal (p = 0.016), and pasta (p = 0.017) were significantly associated with urinary DON. Wholemeal bread was associated with the greatest percent increase in urinary DON per unit of consumption, but white bread contributed approximately twice as much as wholemeal bread to the urinary DON levels because it was consumed in higher amounts. CONCLUSION: The majority of adults in the United Kingdom appear to be exposed to DON, and on the basis of the urinary levels, we estimate that some individuals may exceed the European Union (EU) recommended maximum tolerable daily intake of 1,000 ng DON/kg (bw). This exposure biomarker will be a valuable tool for biomonitoring as part of surveillance strategies and in etiologic studies of DON and human disease risk.
Background: Orthostatic hypotension (OH) has been independently associated with increased risk of stroke and other cardiovascular events. We sought to investigate the relationship between OH at ...follow-up and recurrent stroke risk in SPS3 (Secondary Prevention of Small Subcortical Strokes) trial patient cohort. This is a retrospective cohort analysis. Methods: We included all SPS3 trial participants with blood pressure measurements in both sitting and standing position per protocol at baseline, with at least 1 follow-up visit to establish the relationship between OH at follow-up and recurrent stroke risk (primary outcome). Secondary outcomes included major vascular events, myocardial infarction, all-cause mortality, and, ischemic and hemorrhagic stroke subtypes. Participants were classified as having OH at baseline and at each follow-up visit based on a systolic BP decline ≥20 mm Hg or a diastolic BP decline ≥10 mm Hg on position change from sitting to standing. We used Cox proportional hazards regression modeling to compare the risk of outcomes among those with and without OH. Results: A total of 2275 patients were included with a mean follow up time 3.2 years (standard deviation = 1.6 years). 39% (881/2275) had OH at some point during their follow-up. Of these, 41% (366/881) had orthostatic symptoms accompanying the BP drop. In a fully adjusted model, those with OH had a 1.8 times higher risk of recurrent stroke than those without OH (95% confidence interval: 1.1-3.0). The risk of ischemic stroke, major vascular events, and all-cause mortality was similarly elevated among the OH group. Conclusion: OH was associated with increased recurrent stroke risk, vascular events, and all-cause death in this large cohort of lacunar stroke patients. Whether minimizing OH in the management of poststroke hypertension in patients with lacunar stroke reduces recurrent stroke risk deserves further study.
Phytochemical investigations on the stem bark and roots of the tropical shrub Clausena anisata led to the isolation and characterization three carbazole alkaloids: girinimbine, murrayamine-A and ...ekeberginine; two peptide derivatives: aurantiamide acetate and N-benzoyl-L-phenylalaninyl-N-benzoyl-L-phenylalaninate; and a mixture of two phytosterols: sitosterol and stigmasterol. The structures of these compounds were established by nuclear magnetic resonance (1H-NMR, 13C-NMR, COSY, HSQC, HMQC, HMBC and NOESY) spectroscopy and electrospray ionization mass spectrometry (MS).
A Mule Cloned from Fetal Cells by Nuclear Transfer Woods, Gordon L.; White, Kenneth L.; Vanderwall, Dirk K. ...
Science (American Association for the Advancement of Science),
08/2003, Letnik:
301, Številka:
5636
Journal Article
Recenzirano
Woods et al discuss the results of a study that cloned mule foal that is a sterile hybrid from fetal cells by nuclear transfer. The results showed the developmental competence of mule somatic cells ...for nuclear transfer and that the reproductive failure of mules is attributed to the odd number of chromosome 7. The study also shows that the nucleus can direct complete embryonic and fetal development.
Loneliness and low social support can be detrimental to the health of individuals living with Alzheimer's and related dementias (ADRD) and family care partners. Restrictions on gatherings to prevent ...the spread of COVID-19 create an even greater risk for social isolation. Memory Cafés are a highly replicated program that provide individuals living with ADRD and care partners an opportunity to socialize in an inclusive and supportive environment without fear of judgment, pressure, or stigma. Following restrictions on in-person gatherings, virtual Memory Cafés offer regular social engagement opportunities in an online format. While the Memory Café model has been replicated globally, their effects on loneliness and perceived social support are generally unknown. Even less is known about their impact when operating in a virtual environment.
Semi-structured interviews in Spanish and English were conducted with individuals living with dementia and family care partners who regularly attend Memory Cafés hosted by partners in a Texas Memory Café Network. Interviews took place online using video conferencing software, were transcribed, then analyzed for common themes using a combined inductive and deductive approach.
A total of 17 interviews were conducted with persons living with dementia (
= 5) and family care partners (
= 12) who attend Memory Cafés to learn about their perceived experiences of social connectedness since COVID-19. Care partners included spouses (
= 8) and adult children (
= 4). Interviews included attendees of different Memory Café models, including in-person only (
= 2), virtual only (
= 9), and those who attend both models (
= 6). Five key themes were identified: (1) Reprieve; (2) What is still possible; (3) Connectedness; (4) Inclusivity; and (5) Value added, with ten sub-themes supporting these main themes.
Findings substantiate evidence that Memory Cafés offer important benefits for families living with dementia, providing vital new insight into the potential for virtual Memory Cafés to offer similar benefits. Findings have implications beyond the context of COVID-19, where virtual models may support the social connectedness of those living in geographically marginalized and underserved areas. Virtual models may not address the needs of all families experiencing dementia due to lack of access to technology and limitations for virtual engagement with those experiencing later stage dementia.
Globally, amphibian populations are threatened by a diverse range of factors including habitat destruction and alteration. Forestry practices have been linked with low diversity and abundance of ...amphibians. The effect of exotic Eucalyptus spp. plantations on amphibian communities has been studied in a number of biodiversity hotspots, but little is known of its impact in the Mediterranean region. Here, we identify the environmental factors influencing the presence of six species of amphibians (the Caudata Pleurodeles waltl, Salamandra salamandra, Lissotriton boscai, Triturus marmoratus and the anurans Pelobates cultripes and Hyla arborea/meridionalis) occupying 88 ponds. The study was conducted in a Mediterranean landscape dominated by eucalypt plantations alternated with traditional use (agricultural, montados and native forest) at three different scales: local (pond), intermediate (400 metres radius buffer) and broad (1000 metres radius buffer). Using the Akaike Information Criterion for small samples (AICc), we selected the top-ranked models for estimating the probability of occurrence of each species at each spatial scale separately and across all three spatial scales, using a combination of covariates from the different magnitudes. Models with a combination of covariates at the different spatial scales had a stronger support than those at individual scales. The presence of predatory fish in a pond had a strong effect on Caudata presence. Permanent ponds were selected by Hyla arborea/meridionalis over temporary ponds. Species occurrence was not increased by a higher density of streams, but the density of ponds impacted negatively on Lissotriton boscai. The proximity of ponds occupied by their conspecifics had a positive effect on the occurrence of Lissotriton boscai and Pleurodeles waltl. Eucalypt plantations had a negative effect on the occurrence of the newt Lissotriton boscai and anurans Hyla arborea/meridionalis, but had a positive effect on the presence of Salamandra salamandra, while no effect on any of the other species was detected. In conclusion, eucalypts had limited effects on the amphibian community at the intermediate and broad scales, but predatory fish had a major impact when considering all the scales combined. The over-riding importance of introduced fish as a negative impact suggests that forest managers should prevent new fish introductions and eradicate fish from already-occupied ponds whenever possible.
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