Kinetically Inert Macrocyclic Europium(III) Receptors for Phosphate.

The significant role that phosphate plays in environmental water pollution and biomedical conditions such as hyperphosphatemia highlights the need to develop robust receptors that can sequester the anion effectively and selectively from complex aqueous media. Toward that goal, four macrocyclic tris-bidentate 1,2-hydroxypyridonate (HOPO) europium(III) complexes containing either a cyclen, cyclam, TACN, or TACD ligand cap were synthesized and evaluated as phosphate receptors. The solubility of EuIII-TACD-HOPO in water was insufficient for luminescent studies. Whereas EuIII-cyclen-HOPO is eight coordinate with two inner-sphere water molecules, both EuIII-cyclam-HOPO and EuIII-TACN-HOPO are nine coordinate with three inner-sphere water molecules, suggesting that the two coordination states are very close in energy. As observed previously with linear analogues of tripodal HOPO complexes, there is no relationship between the number of inner-sphere water molecules and the affinity of the complex for phosphate. Whereas all three complexes do bind phosphate, EuIII-cyclen-HOPO has the highest affinity for phosphate with the anion displacing both of its inner-sphere water molecules. On the other hand, only one or two of the three inner-sphere water molecules of EuIII-TACN-HOPO and EuIII-cyclam-HOPO are displaced by phosphate, respectively. All three complexes are highly selective for phosphate over other anions, including arsenate. All three complexes are highly stable. EuIII-cyclen-HOPO and, to a lesser extent, EuIII-TACN-HOPO are more kinetically inert than the linear EuIII-Ser-HOPO. EuIII-cyclam-HOPO, on the other hand, is not. This study highlights the significant effect that minor changes in the ligand cap can have on both the ligand exchange rate and affinity for phosphate of tripodal 1,2-dihydroxypyridinonate complexes.

Exploiting the Fluxionality of Lanthanide Complexes in the Design of Paramagnetic Fluorine Probes.

Fluorine-19 MRI is increasingly being considered as a tool for biomolecular imaging, but the very poor sensitivity of this technique has limited most applications. Previous studies have long established that increasing the sensitivity of 19F molecular probes requires increasing the number of fluorine nuclei per probe as well as decreasing their longitudinal relaxation time. The latter is easily achieved by positioning the fluorine atoms in close proximity to a paramagnetic metal ion such as a lanthanide(III). Increasing the number of fluorine atoms per molecule, however, is only useful inasmuch as all of the fluorine nuclei are chemically equivalent. Previous attempts to achieve this equivalency have focused on designing highly symmetric and rigid fluorinated macrocyclic ligands. A much simpler approach consists of exploiting highly fluxional lanthanide complexes with open coordination sites that have a high affinity for phosphated and phosphonated species. Computational studies indicate that LnIII-TREN-MAM is highly fluxional, rapidly interconverting between at least six distinct isomers. In neutral water at room temperature, LnIII-TREN-MAM binds two or three equivalents of fluorinated phosphonates. The close proximity of the 19F nuclei to the LnIII center in the ternary complex decreases the relaxation times of the fluorine nuclei up to 40-fold. Advantageously, the fluorophosphonate-bound lanthanide complex is also highly fluxional such that all 19F nuclei are chemically equivalent and display a single 19F signal with a small LIS. Dynamic averaging of fluxional fluorinated supramolecular assemblies thus produces effective 19F MR systems.

A General Design Strategy Enabling the Synthesis of Hydrolysis-Resistant, Water-Stable Titanium(IV) Complexes.

Despite its prevalence in the environment, the chemistry of the Ti4+ ion has long been relegated to organic solutions or hydrolyzed TiO2 polymorphs. A knowledge gap in stabilizing molecular Ti4+ species in aqueous environments has prevented the use of this ion for various applications such as radioimaging, design of water-compatible metal-organic frameworks (MOFs), and aqueous-phase catalysis applications. Herein, we show a thorough thermodynamic screening of bidentate chelators with Ti4+ in aqueous solution, as well as computational and structural analyses of key compounds. In addition, the hexadentate analogues of catechol (benzene-1,2-diol) and deferiprone (3-hydroxy-1,2-dimethyl-4(1H)-pyridone), TREN-CAM and THPMe respectively, were assessed for chelation of the 45 Ti isotope (t1/2 =3.08 h, ß+ =85 %, Eß+ =439 keV) towards positron emission tomography (PET) imaging applications. Both were found to have excellent capacity for kit-formulation, and [45 Ti]Ti-TREN-CAM was found to have remarkable stability in vivo.

A Walk Across the Lanthanide Series: Trend in Affinity for Phosphate and Stability of Lanthanide Receptors from La(III) to Lu(III).

The trend in affinity of two 1,2-hydroxypyridinonate lanthanide(III) receptors-LnIII-2,2-Li-HOPO and LnIII-3,3-Gly-HOPO (LnIII = LaIII, PrIII, NdIII, SmIII, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, TmIII, YbIII, and LuIII)-for phosphate across the series was investigated by luminescence spectroscopy via competition against the central europium(III) analog. Regardless of the ligand, the rare earth receptors display a steep and continuous increase in affinity for their phosphate guest across the series, with the later lanthanides displaying the highest affinity for the oxyanion. This trend mirrors that of the stability of the lanthanide receptors, which also increases significantly and continuously from LaIII to LuIII. For these two ligands, the ionic radius of a rare earth, a parameter directly linked to its Lewis acidity, correlates strongly with its affinity for anions, regardless of whether that anion is the one coordinating it (in this case the 1,2-hydroxypyridinonate ligand) or the guest targeted by the lanthanide receptor (in this case phosphate). These observations are indicative of a lack of steric hindrance for coordination of phosphate. Advantageously, increased efficacy of the lanthanide receptor comes with increased stability. The remarkably high stability of LuIII-2,2-Li-HOPO, combined with its high affinity for phosphate, makes it a particularly promising candidate for translational application to medical or environmental sequestration of phosphate since the higher stability will further reduce the risk of the rare earth leaching during anion separation. The unusually large difference in stability between lanthanide complexes (the LuIII complex of 2,2-Li-HOPO is at least 7 orders of magnitude more stable than the LaIII one) bodes well for potential applications in rare earth separation.

Design and applications of metal-based molecular receptors and probes for inorganic phosphate.

Inorganic phosphate has numerous biomedical functions. Regulated primarily by the kidneys, phosphate reaches abnormally high blood levels in patients with advanced renal diseases. Since phosphate cannot be efficiently removed by dialysis, the resulting hyperphosphatemia leads to increased mortality. Phosphate is also an important component of the environmental chemistry of surface water. Although required to secure our food supply, inorganic phosphate is also linked to eutrophication and the spread of algal blooms with an increasing economic and environmental burden. Key to resolving both of these issues is the development of accurate probes and molecular receptors for inorganic phosphate. Yet, quantifying phosphate in complex aqueous media remains challenging, as is the development of supramolecular receptors that have adequate sensitivity and selectivity for use in either blood or surface waters. Metal-based receptors are particularly well-suited for these applications as they can overcome the high hydration enthalpy of phosphate that limits the effectiveness of many organic receptors in water. Three different strategies are most commonly employed with inorganic receptors for anions: metal extrusion assays, responsive molecular receptors, and indicator displacement assays. In this review, the requirements for molecular receptors and probes for environmental applications are outlined. The different strategies deployed to recognize and sense phosphate with metal ions will be detailed, and their advantages and shortfalls will be delineated with key examples from the literature.

A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT.

INTRODUCTION: Counteracting impaired brain glucose metabolism with ketones may improve cognition in mild cognitive impairment (MCI). METHODS: Cognition, plasma ketone response, and metabolic profile were assessed before and 6 months after supplementation with a ketogenic drink containing medium chain triglyceride (ketogenic medium chain triglyceride [kMCT]; 15 g twice/day; n = 39) or placebo (n = 44). RESULTS: Free and cued recall (Trial 1; P = .047), verbal fluency (categories; P = .024), Boston Naming Test (total correct answers; P = .033), and the Trail-Making Test (total errors; P = .017) improved significantly in the kMCT group compared to placebo (analysis of covariance; pre-intervention score, sex, age, education, and apolipoprotein E4 as covariates). Some cognitive outcomes also correlated positively with plasma ketones. Plasma metabolic profile and ketone response were unchanged. CONCLUSIONS: This kMCT drink improved cognitive outcomes in MCI, at least in part by increasing blood ketone level. These data support further assessment of MCI progression to Alzheimer's disease.

The Ligand Cap Affects the Coordination Number but Not Necessarily the Affinity for Anions of Tris-Bidentate Europium Complexes.

To evaluate the effect of ligand geometry on the coordination number, number of inner-sphere water molecules, and affinity for anions of the corresponding lanthanide complex, six tris-bidentate 1,2-hydroxypyridonate (HOPO) europium(III) complexes with different cap sizes were synthesized and characterized. Wider or more flexible ligand caps, such as in EuIII-TREN-Gly-HOPO and EuIII-3,3-Gly-HOPO, enable the formation of nine-coordinate europium(III) complexes bearing three inner-sphere water molecules. In contrast, smaller or more rigid caps, such as in EuIII-TREN-HOPO, EuIII-2,2-Li-HOPO, EuIII-3,3-Li-HOPO, and EuIII-2,2-Gly-HOPO, favor eight-coordinate europium(III) complexes that have only two inner-sphere water molecules. Notably, there is no correlation between the number of inner-sphere water molecules and the affinity of the Eu(III) complexes for phosphate. Some q = 2 (EuIII-TREN-HOPO, EuIII-3,3-Li-HOPO, and EuIII-2,2-Gly-HOPO) and some q = 3 (EuIII-TREN-Gly-HOPO) complexes have no affinity for anions, whereas one q = 2 complex (EuIII-2,2-Li-HOPO) and one q = 3 complex (EuIII-3,3-Gly-HOPO) have a high affinity for phosphate. For the latter two systems, each inner-sphere water molecule is replaced with a phosphate anion, resulting in the formation of EuLPi2 and EuLPi3 adducts, respectively.

Catechol-Based Functionalizable Ligands for Gallium-68 Positron Emission Tomography Imaging.

Four tris-bidentate catecholamide (CAM) ligands were synthesized, characterized, and evaluated as ligands for radiolabeling of gallium-68 for positron emission tomography (PET). Three of those ligands, 2,2-Glu-CAM, 3,3-Glu-CAM, and TREN-bisGlyGlu-CAM, incorporate ligand caps that contain a pendant carboxylic group for further conjugation to targeting moieties. The acyclic ligands all exhibited high (>80%) radiolabeling yields after short reaction times (<10 min) at room temperature, a distinct advantage over macrocyclic analogues that display slower kinetics. The stabilities of the four GaIII complexes are comparable to or higher than those of other acyclic ligands used for gallium-68 PET imaging, such as desferrioxamine, with pGa values ranging from 21 to >24, although the functionalizable ligands are less stable than the parent GaIII-TREN-CAM. In vivo imaging studies and ex vivo pharmacokinetic and biodistribution studies indicate that the parent [68Ga]Ga-TREN-CAM is stable in vivo but is rapidly cleared in <15 min, probably via a renal pathway. The rapid and mild radiolabeling conditions, high radiolabeling yields, and high stability in human serum (>95%) render TREN-bisGlyGlu-CAM a promising candidate for gallium-68 chelation.

Resourceful masculinities: exploring heterosexual Black men's vulnerability to HIV in Ontario, Canada.

Objectives: Heterosexually active Black men are alleged to endorse masculine norms that increase their and their female partners' vulnerability to HIV. These norms include Black men's inability or reluctance to productively engage their own health-related personal and interpersonal vulnerabilities. We draw on data from the iSpeak research study in Ontario, Canada, to assess whether and how heterosexual Black men cope with personal and inter-personal vulnerability, namely that heterosexual Black men: avoid emotionally supportive relationships with other men (and women), which diminishes their capacity to productively acknowledge and resolve their health-related challenges; are reticent to productively acknowledge and address HIV and health on a personal level; and are pathologically secretive about their health, which compounds their vulnerability and precipitates poor health outcomes.Design: iSpeak was implemented in 2011 to 2013, and included two focus groups with HIV-positive and HIV-negative self-identified heterosexual men (N = 14) in Toronto and London, a focus group with community-based health promotion practitioners who provide HIV-related services to Black communities in Ontario (N = 6), and one-on-one interviews with four researchers distinguished for their scholarship with/among Black communities in Toronto. Participants in the men's focus group were recruited discretely through word-of-mouth. Focus groups were audiotaped and transcribed verbatim. Team members independently read the transcripts, and then met to identify, discuss and agree on the emerging themes.Results: We demonstrate that iSpeak participants (a) engage their personal and interpersonal vulnerabilities creatively and strategically, (b) complicate and challenge familiar interpretations of Black men's allegedly transgressive masculinity through their emotional and practical investment in their health, and (c) demonstrate a form of resourceful masculinity that ambiguously aligns with patriarchy.Conclusion: We conclude with a range of actionable recommendations to strengthen the discursive framework for understanding heterosexual Black men in relation to HIV and health, and substantively engaging them in community responses to HIV.

Comparing Strategies in the Design of Responsive Contrast Agents for Magnetic Resonance Imaging: A Case Study with Copper and Zinc.

Magnetic resonance imaging (MRI) has emerged over the years as one of the preferred modalities for medical diagnostic and biomedical research. It has the advantage over other imaging modalities such as positron emission tomography and X-ray of affording high resolution three-dimensional images of the body without using harmful radiation. The use of contrast agents has further expanded this technique by increasing the contrast between regions where they accumulate and background tissues. As MRI most often measures the relaxation rate of water throughout the body, contrast agents function by modulating the intensity of the water signal either via improved relaxation or via saturation transfer to selected exchangeable proton. Among the growing class of MRI contrast agents, a subset of them called "smart" contrast agents function as responsive probes. Their ability to increase or decrease their signal intensity is modulated by the presence of an analyte. These probes offer the unique ability to image the distribution of an analyte in vivo, thereby opening new possibilities for diagnostics and for elucidating the role of specific analytes in various pathologies or biological processes. A number of different strategies can be exploited to design responsive MRI contrast agents. The majority of contrast agents are based on GdIII complexes. These complexes can be rendered responsive in either of two ways: either by modulating the number of inner-sphere water molecules, q, or via modulating the rotational correlation time, τR, of the contrast agent upon substrate binding. The longitudinal relaxivity increases with the number of inner-sphere water molecules. GdIII complexes can be rendered responsive if they contain a recognition moiety that can bind to both the open coordination site of GdIII and to the analyte. When the recognition moiety leaves the lanthanide ion to bind to the analyte, q increases and therefore so does the relaxivity. The dependence of relaxivity on rotational correlation time is more complex and more pronounced at lower magnetic fields. In general, slower tumbling macromolecules have longer rotational correlation times and higher relaxivities. Analyte-triggered formation of macromolecules thus also increases relaxivity. Such macromolecules can either be analyte-templated supramolecular assemblies, or analyte-enhanced protein-contrast agent complexes. Chemical Exchange Saturation Transfer (CEST) agents are a newer class of contrast agents that offer the possibility of multifrequency and thus ratiometric imaging, which in turn enables quantitative mapping of the concentration of an analyte in vivo under conditions where the concentration of the contrast agent is not known. Such agents can be rendered responsive if the analyte changes the number of exchangeable proton(s), its exchange rate, or its chemical shift. All of these approaches have been successfully employed for detecting and imaging both copper and zinc, including in vivo. Magnetic Iron Oxide Nanoparticles (MIONs) are powerful MRI transverse relaxation agents. They can also be rendered responsive to an analyte if the latter can control the aggregation of the nanoparticles. For metal ions, this can be achieved via chemical functionalities that only react to form conjugates in the presence of the metal ion analyte.

A Combination of Factors: Tuning the Affinity of Europium Receptors for Phosphate in Water.

Although recognition of hard anions by hard metal ions is primarily achieved via direct coordination, electrostatic and hydrogen-bonding interactions also play essential roles in tuning the affinity of such supramolecular receptors for their target. In the case of EuIII hydroxypyridinone-based complexes, the addition of a single charged group (-NH3+, -CO2-, or -SO3-) or neutral hydrogen-bonding moiety (-OH) peripheral to the open coordination site substantially affects the affinity of the metal receptor for phosphate in water at neutral pH. A single primary ammonium increases the first association constant for phosphate in neutral water by 2 orders of magnitude over its neutral analogue. The addition of a peripheral alcohol group also increases the affinity of the receptor but to a lesser degree (21-fold). On the other hand, negatively charged complexes bearing either a carboxylate or sulfate moiety have negligible affinity for phosphate. Interestingly, the peripheral group also influences the stoichiometry of the lanthanide receptor for phosphate. While the complex bearing a -NH3+ group binds phosphate in a 1:2 ratio, those with -OH and H (control) both form 1:3 complexes. Although the positively charged EuIII-Lys-HOPO has the highest Ka1 for phosphate, a greater increase in luminescence intensity (36-fold) is observed with the neutral EuIII-Ser-HOPO complex. Notably, whereas the affinity of the EuIII complexes for phosphate is substantially influenced by the presence of a single charged group or hydrogen-bond donor, their selectivity for phosphate over competing anions remains unaffected by the addition of the peripheral groups.

The Stability of the Complex and the Basicity of the Anion Impact the Selectivity and Affinity of Tripodal Gadolinium Complexes for Anions.

The affinities and selectivities of lanthanide complexes with open coordination sites for anions vary considerably with the chelate. In order to determine the effect of the stability of a lanthanide complex on its affinity for anions, five different complexes featuring different bidentate chelating moieties were synthesized, and their affinity for anions in water at neutral pH were evaluated by longitudinal relaxometry measurements. The chelates comprise both oxygen and nitrogen donors including maltol, 1,2-hydroxypyridinone, hydroxamic acid, pyridin-2-ylmethanol, and carbamoylmethylphosphonate diester. They were chosen to span a range of basicities all the while maintaining a similar tripodal tris-bidentate architecture, thereby allowing for a direct study of the role of the coordinating motif on the supramolecular recognition of anions by the corresponding GdIII complex. Overall, for ligands containing the same number of protonation steps, and therefore the same charge at neutral pH, the lower the acidity of the chelate (higher ∑pKa's), the less stable the corresponding GdIII complex, and the higher its affinity for anions. Regardless of the number of protonation steps, the more stable GdIII complexes form ternary or quaternary assemblies with coordinating anions. In contrast, the same anions readily displace the chelate of the least stable complexes, resulting instead in the formation of GdIII·anion precipitates. Irrespective of the chelate, in the absence of steric hindrance at the open coordination site, the affinity of GdIII complexes for anions follows the order phosphate > arsenate > bicarbonate > fluoride. Hence, the selectivity and affinity of GdIII complexes of tripodal tris-bidentate chelates for anions is a function of the stability of the GdIII complex and the basicity of the anion.

A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment.

INTRODUCTION: Unlike for glucose, uptake of the brain's main alternative fuel, ketones, remains normal in mild cognitive impairment (MCI). Ketogenic medium chain triglycerides (kMCTs) could improve cognition in MCI by providing the brain with more fuel. METHODS: Fifty-two subjects with MCI were blindly randomized to 30 g/day of kMCT or matching placebo. Brain ketone and glucose metabolism (quantified by positron emission tomography; primary outcome) and cognitive performance (secondary outcome) were assessed at baseline and 6 months later. RESULTS: Brain ketone metabolism increased by 230% for subjects on the kMCT (P < .001) whereas brain glucose uptake remained unchanged. Measures of episodic memory, language, executive function, and processing speed improved on the kMCT versus baseline. Increased brain ketone uptake was positively related to several cognitive measures. Seventy-five percent of participants completed the intervention. DISCUSSION: A dose of 30 g/day of kMCT taken for 6 months bypasses a significant part of the brain glucose deficit and improves several cognitive outcomes in MCI.

Decolonizing Scoping Review Methodologies for Literature With, for, and by Indigenous Peoples and the African Diaspora: Dialoguing With the Tensions.

This article summarizes our deepened understanding of decolonizing research with, for, and by Indigenous peoples and peoples of African descent that emerged from conducting a scoping review of the methodological literature and reflecting on our review process. Although our review identified decolonizing methodologies as a promising approach, we questioned if our scoping review process engaged in decolonizing knowing. To unpack the epistemological tensions between decolonizing knowing and Western ways of doing scoping reviews, we engaged in individual and collective reflective processes- dialoguing with the tensions-moving from individual immersion in the literature to transformative dialogues among the team. In reflecting upon our tensions with the scoping review process, themes that emerged included (a) ontological/epistemological disjunctures, (b) tensions with concepts and language, and (c) relationships with the literature and beyond. This reflexive process provides valuable insight into ways in which review methods might be made a decolonizing research experience.

Eight-Coordinate, Stable Fe(II) Complex as a Dual 19F and CEST Contrast Agent for Ratiometric pH Imaging.

Accurate mapping of small changes in pH is essential to the diagnosis of diseases such as cancer. The difficulty in mapping pH accurately in vivo resides in the need for the probe to have a ratiometric response so as to be able to independently determine the concentration of the probe in the body independently from its response to pH. The complex FeII-DOTAm-F12 behaves as an MRI contrast agent with dual 19F and CEST modality. The magnitude of its CEST response is dependent both on the concentration of the complex and on the pH, with a significant increase in saturation transfer between pH 6.9 and 7.4, a pH range that is relevant to cancer diagnosis. The signal-to-noise ratio of the 19F signal of the probe, on the other hand, depends only on the concentration of the contrast agent and is independent of pH. As a result, the complex can ratiometrically map pH and accurately distinguish between pH 6.9 and 7.4. Moreover, the iron(II) complex is stable in air at room temperature and adopts a rare 8-coordinate geometry.

Fe- and Ln-DOTAm-F12 Are Effective Paramagnetic Fluorine Contrast Agents for MRI in Water and Blood.

A series of fluorinated macrocyclic complexes, M-DOTAm-F12, where M is LaIII, EuIII, GdIII, TbIII, DyIII, HoIII, ErIII, TmIII, YbIII, and FeII, was synthesized, and their potential as fluorine magnetic resonance imaging (MRI) contrast agents was evaluated. The high water solubility of these complexes and the presence of a single fluorine NMR signal, two necessary parameters for in vivo MRI, are substantial advantages over currently used organic polyfluorocarbons and other reported paramagnetic 19F probes. Importantly, the sensitivity of the paramagnetic probes on a per fluorine basis is at least 1 order of magnitude higher than that of diamagnetic organic probes. This increased sensitivity is due to a substantial-up to 100-fold-decrease in the longitudinal relaxation time (T1) of the fluorine nuclei. The shorter T1 allows for a greater number of scans to be obtained in an equivalent time frame. The sensitivity of the fluorine probes is proportional to the T2/T1 ratio. In water, the optimal metal complexes for imaging applications are those containing HoIII and FeII, and to a lesser extent TmIII and YbIII. Whereas T1 of the lanthanide complexes are little affected by blood, the T2 are notably shorter in blood than in water. The sensitivity of Ln-DOTAm-F12 complexes is lower in blood than in water, such that the most sensitive complex in water, HoIII-DOTAm-F12, could not be detected in blood. TmIII yielded the most sensitive lanthanide fluorine probe in blood. Notably, the relaxation times of the fluorine nuclei of FeII-DOTAm-F12 are similar in water and in blood. That complex has the highest T2/T1 ratio (0.57) and the lowest limit of detection (300 µM) in blood. The combination of high water solubility, single fluorine signal, and high T2/T1 of M-DOTAm-F12 facilitates the acquisition of three-dimensional magnetic resonance images.

Gadolinium Complex for the Catch and Release of Phosphate from Water.

The ability of complexes of hard and labile metal ions with one or more open coordination sites to capture phosphates with high affinity and selectivity directly in water at neutral pH and release them under acidic conditions is evaluated with Gadolinium- 2,2',2''-(((nitrilotris(ethane-2,1-diyl))tris(azanediyl))tris(carbonyl))tris(4-oxo-4H-pyran-3-olate) (Gd-TREN-MAM). This model lanthanide complex has two open coordination sites that, at neutral pH, are filled with water molecules. In water at neutral pH, Gd-TREN-MAM binds phosphate with high affinity (Ka = 1.3 × 104) via the formation of a ternary complex in which one phosphate replaces both inner-sphere water molecules. The formation of this complex is highly pH-dependent; the phosphate is completely released from Gd-TREN-MAM below pH 2. Because the GdIII ion remains complexed by its ligand, even under strong acidic conditions, Gd-TREN-MAM can be used at least 10 times in a pH-based recycling scheme that enables the catch and release of one phosphate per cycle. Gd-TREN-MAM is highly selective for phosphate over other anions of environmental concerns, including HCO3-, HCO2-, CH3CO2-, SO42-, NO3-, NO2-, BrO3-, AsO4-, F-, Cl-, and Br- and, to a lesser extent, ClO3-. The development of such receptors that bind phosphate reversibly in a pH-dependent manner opens the possibility to design catch-and-release systems for the purification of surface waters.

Caffeine intake increases plasma ketones: an acute metabolic study in humans.

Brain glucose uptake declines during aging and is significantly impaired in Alzheimer's disease. Ketones are the main alternative brain fuel to glucose so they represent a potential approach to compensate for the brain glucose reduction. Caffeine is of interest as a potential ketogenic agent owing to its actions on lipolysis and lipid oxidation but whether it is ketogenic in humans is unknown. This study aimed to evaluate the acute ketogenic effect of 2 doses of caffeine (2.5; 5.0 mg/kg) in 10 healthy adults. Caffeine given at breakfast significantly stimulated ketone production in a dose-dependent manner (+88%; +116%) and also raised plasma free fatty acids. Whether caffeine has long-term ketogenic effects or could enhance the ketogenic effect of medium chain triglycerides remains to be determined.

Microvascular endothelial dysfunction is associated with albuminuria and CKD in older adults.

BACKGROUND: Impairment in glomerular endothelial function likely plays a major role in the development of albuminuria and CKD progression. Glomerular endothelial dysfunction may reflect systemic microvascular dysfunction, accounting in part for the greater cardiovascular risk in patients with albuminuria. Prior studies of vascular function in CKD have focused on conduit artery function or those with ESRD, and have not examined microvascular endothelial function with albuminuria. METHODS: We conducted a cross-sectional study among older hypertensive male veterans with stage 1-4 CKD, and hypertensive controls without CKD. Microvascular function was quantified by two distinct Laser-Doppler flowmetry (LDF) measures: peak responses to 1) post-occlusive reactive hyperemia (PORH) and 2) thermal hyperemia (TH), measured on forearm skin. Associations of each LDF measure with albuminuria, eGFR, and CKD status were estimated using correlation coefficients and multiple linear regression, accounting for potential confounders. RESULTS: Among 66 participants (mean age 69.2 years), 36 had CKD (mean eGFR 46.1 cc/min/1.73 m(2); 30.6 % with overt albuminuria). LDF responses to PORH and TH were 43 and 39 % significantly lower in multivariate analyses among those with macroalbuminuria compared to normoalbuminuria, (ß= - 0.42, p = 0.009 and ß= -0.37, p = 0.01, respectively). Those with CKD had a 23.9 % lower response to PORH compared to controls (p = 0.02 after adjustment). In contrast, TH responses did not differ between those with and without CKD. CONCLUSIONS: Microvascular endothelial function was strongly associated with greater albuminuria and CKD, independent of diabetes and blood pressure. These findings may explain in part the excess systemic cardiovascular risk associated with albuminuria and CKD.