Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia

The transgenic and knockout (KO) animals involving Fgf23 have been highly informative in defining novel aspects of mineral metabolism, but are limited by shortened lifespan, inability of spatial/temporal FGF23 control, and infertility of the global KO. To more finely test the role of systemic and genetic influences in FGF23 production, a mouse was developed that carried a floxed ("f")-Fgf23 allele (exon 2 floxed) which demonstrated in vivo recombination when bred to global-Cre transgenic mice (eIIa-cre). Mice homozygous for the recombined allele ("Δ") had undetectable serum intact FGF23, elevated serum phosphate (p < 0.05), and increased kidney Cyp27b1 mRNA (p < 0.05), similar to global Fgf23-KO mice. To isolate cellular FGF23 responses during phosphate challenge, Fgf23(Δ/f) mice were mated with early osteoblast type Iα1 collagen 2.3-kb promoter-cre mice (Col2.3-cre) and the late osteoblast/early osteocyte Dentin matrix protein-1-cre (Dmp1-cre). Fgf23(Δ/f) /Col2.3-cre(+) and Fgf23(Δ/f) /Dmp1-cre(+) exhibited reduced baseline serum intact FGF23 versus controls. After challenge with high-phosphate diet Cre(-) mice had 2.1-fold to 2.5-fold increased serum FGF23 (p < 0.01), but Col2.3-cre(+) mice had no significant increase, and Dmp1-cre(+) mice had only a 37% increase (p < 0.01) despite prevailing hyperphosphatemia in both models. The Fgf23(Δ/f) /Col2.3-cre was bred onto the Hyp (murine X-linked hypophosphatemia [XLH] model) genetic background to test the contribution of osteoblasts and osteocytes to elevated FGF23 and Hyp disease phenotypes. Whereas Hyp mice maintained inappropriately elevated FGF23 considering their marked hypophosphatemia, Hyp/Fgf23(Δ/f) /Col2.3-cre(+) mice had serum FGF23 <4% of Hyp (p < 0.01), and this targeted restriction normalized serum phosphorus and ricketic bone disease. In summary, deleting FGF23 within early osteoblasts and osteocytes demonstrated that both cell types contribute to baseline circulating FGF23 concentrations, and that targeting osteoblasts/osteocytes for FGF23 production can modify systemic responses to changes in serum phosphate concentrations and rescue the Hyp genetic syndrome

Discovery of a Faint Companion to Alcor Using MMT/AO 5 μ\mum Imaging

We report the detection of a faint stellar companion to the famous nearby A5V star Alcor (80 UMa). The companion has M-band ($\lambda$ = 4.8 $\mu$m) magnitude 8.8 and projected separation 1".11 (28 AU) from Alcor. The companion is most likely a low-mass ($\sim$0.3 \msun) active star which is responsible for Alcor's X-ray emission detected by ROSAT (L$_{\rm X}$ $\simeq$ 10$^{28.3}$ erg/s). Alcor is a nuclear member of the Ursa Major star cluster (UMa; d $\simeq$ 25 pc, age $\simeq$ 0.5 Gyr), and has been occasionally mentioned as a possible distant (709") companion of the stellar quadruple Mizar ($\zeta$ UMa). Comparing the revised Hipparcos proper motion for Alcor with the mean motion for other UMa nuclear members shows that Alcor has a peculiar velocity of 1.1 km/s, which is comparable to the predicted velocity amplitude induced by the newly-discovered companion ($\sim$1 km/s). Using a precise dynamical parallax for Mizar and the revised Hipparcos parallax for Alcor, we find that Mizar and Alcor are physically separated by 0.36 $\pm$ 0.19 pc (74 $\pm$ 39 kAU; minimum 18 kAU), and their velocity vectors are marginally consistent ($\chi^2$ probability 6%). Given their close proximity and concordant motions we suggest that the Mizar quadruple and the Alcor binary be together considered the 2nd closest stellar sextuplet. The addition of Mizar-Alcor to the census of stellar multiples with six or more components effectively doubles the local density of such systems within the local volume (d $<$ 40 pc).Comment: 28 pages, 2 figures, AJ, in press; emulateapj short version at http://www.pas.rochester.edu/~emamajek/alcor.pd

Neonatal iron deficiency causes abnormal phosphate metabolism by elevating FGF23 in normal and ADHR mice.

Fibroblast growth factor 23 (FGF23) gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed onset following puberty or pregnancy. We previously demonstrated that the combination of iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced FGF23 expression and hypophosphatemia that paralleled the late-onset ADHR phenotype. Because anemia in pregnancy and in premature infants is common, the goal of this study was to test whether iron deficiency alters phosphate handling in neonatal life. Wild-type (WT) and ADHR female breeder mice were provided control or iron-deficient diets during pregnancy and nursing. Iron-deficient breeders were also made iron replete. Iron-deficient WT and ADHR pups were hypophosphatemic, with ADHR pups having significantly lower serum phosphate (p 50 fold; p < 0.01). WT and ADHR pups receiving low iron had elevated intact serum FGF23; ADHR mice were affected to a greater degree (p < 0.01). Iron-deficient mice also showed increased Cyp24a1 and reduced Cyp27b1, and low serum 1,25-dihydroxyvitamin D (1,25D). Iron repletion normalized most abnormalities. Because iron deficiency can induce tissue hypoxia, oxygen deprivation was tested as a regulator of FGF23, and was shown to stimulate FGF23 mRNA in vitro and serum C-terminal FGF23 in normal rats in vivo. These studies demonstrate that FGF23 is modulated by iron status in young WT and ADHR mice and that hypoxia independently controls FGF23 expression in situations of normal iron. Therefore, disturbed iron and oxygen metabolism in neonatal life may have important effects on skeletal function and structure through FGF23 activity on phosphate regulation

Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD

The phosphaturic hormone FGF23 is elevated in chronic kidney disease (CKD). The risk of premature death is substantially higher in the CKD patient population, with cardiovascular disease (CVD) as the leading mortality cause at all stages of CKD. Elevated FGF23 in CKD has been associated with increased odds for all-cause mortality; however, whether FGF23 is associated with positive adaptation in CKD is unknown. To test the role of FGF23 in CKD phenotypes, a late osteoblast/osteocyte conditional flox-Fgf23 mouse (Fgf23fl/fl/Dmp1-Cre+/-) was placed on an adenine-containing diet to induce CKD. Serum analysis showed casein-fed Cre+ mice had significantly higher serum phosphate and blood urea nitrogen (BUN) versus casein diet and Cre- genotype controls. Adenine significantly induced serum intact FGF23 in the Cre- mice over casein-fed mice, whereas Cre+ mice on adenine had 90% reduction in serum intact FGF23 and C-terminal FGF23 as well as bone Fgf23 mRNA. Parathyroid hormone was significantly elevated in mice fed adenine diet regardless of genotype, which significantly enhanced midshaft cortical porosity. Echocardiographs of the adenine-fed Cre+ hearts revealed profound aortic calcification and cardiac hypertrophy versus diet and genotype controls. Thus, these studies demonstrate that increased bone FGF23, although associated with poor outcomes in CKD, is necessary to protect against the cardio-renal consequences of elevated tissue phosphate

Agroecology for the Shrinking City

Many cities are experiencing long-term declines in population and economic activity. As a result, frameworks for urban sustainability need to address the unique challenges and opportunities of such shrinking cities. Shrinking, particularly in the U.S., has led to extensive vacant land. The abundance of vacant land reflects a loss of traditional urban amenities, economic opportunity, neighbors, businesses, and even basic city services and often occurs in neighborhoods with socially and economically vulnerable or underserved populations. However, vacant land also provides opportunities, including the space to invest in green infrastructure that can provide ecosystem services and support urban sustainability. Achieving desirable amenities that provide ecosystem services from vacant land is the central tenet of a recent urban sustainability framework termed ecology for the shrinking city. An agroecological approach could operationalize ecology for the shrinking city to both manage vacancy and address ecosystem service goals. Developing an agroecology in shrinking cities not only secures provisioning services that use an active and participatory approach of vacant land management but also transforms and enhances regulating and supporting services. The human and cultural dimensions of agroecology create the potential for social-ecological innovations that can support sustainable transformations in shrinking cities. Overall, the strength of agroecological principles guiding a green infrastructure strategy stems from its explicit focus on how individuals and communities can shape their environment at multiple scales to produce outcomes that reflect their social and cultural context. Specifically, the shaping of the environment provides a pathway for communities to build agency and manage for resilience in urban social-ecological systems. Agroecology for the shrinking city can support desirable transformations, but to be meaningful, we recognize that it must be part of a greater strategy that addresses larger systemic issues facing shrinking cities and their residents

Circulating αKlotho influences phosphate handling by controlling FGF23 production

The FGF23 coreceptor αKlotho (αKL) is expressed as a membrane-bound protein (mKL) that forms heteromeric complexes with FGF receptors (FGFRs) to initiate intracellular signaling. It also circulates as an endoproteolytic cleavage product of mKL (cKL). Previously, a patient with increased plasma cKL as the result of a translocation [t(9;13)] in the αKLOTHO (KL) gene presented with rickets and a complex endocrine profile, including paradoxically elevated plasma FGF23, despite hypophosphatemia. The goal of this study was to test whether cKL regulates phosphate handling through control of FGF23 expression. To increase cKL levels, mice were treated with an adeno-associated virus producing cKL. The treated groups exhibited dose-dependent hypophosphatemia and hypocalcemia, with markedly elevated FGF23 (38 to 456 fold). The animals also manifested fractures, reduced bone mineral content, expanded growth plates, and severe osteomalacia, with highly increased bone Fgf23 mRNA (>150 fold). cKL activity in vitro was specific for interactions with FGF23 and was FGFR dependent. These results demonstrate that cKL potently stimulates FGF23 production in vivo, which phenocopies the KL translocation patient and metabolic bone syndromes associated with elevated FGF23. These findings have important implications for the regulation of αKL and FGF23 in disorders of phosphate handling and biomineralization

Erythropoietin and a hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHDi) lowers FGF23 in a model of chronic kidney disease (CKD)

Iron‐deficiency anemia is a potent stimulator of the phosphaturic hormone Fibroblast growth factor‐23 (FGF23). Anemia, elevated FGF23, and elevated serum phosphate are significant mortality risk factors for patients with chronic kidney disease (CKD). However, the contribution of anemia to overall circulating FGF23 levels in CKD is not understood. Our goal was to investigate the normalization of iron handling in a CKD model using the erythropoiesis stimulating agents (ESAs) Erythropoietin (EPO) and the hypoxia‐inducible factor prolyl hydroxylase inhibitor (HIF‐PHDi) FG‐4592, on the production of, and outcomes associated with, changes in bioactive, intact FGF23 (“iFGF23”). Our hypothesis was that rescuing the prevailing anemia in a model of CKD would reduce circulating FGF23. Wild‐type mice were fed an adenine‐containing diet to induce CKD, then injected with EPO or FG‐4592. The mice with CKD were anemic, and EPO improved red blood cell indices, whereas FG‐4592 increased serum EPO and bone marrow erythroferrone (Erfe), and decreased liver ferritin, bone morphogenic protein‐6 (Bmp‐6), and hepcidin mRNAs. In the mice with CKD, iFGF23 was markedly elevated in control mice but was attenuated by >70% after delivery of either ESA, with no changes in serum phosphate. ESA treatment also reduced renal fibrosis markers, as well as increased Cyp27b1 and reduced Cyp24a1 mRNA expression. Thus, improvement of iron utilization in a CKD model using EPO and a HIF‐PHDi significantly reduced iFGF23, demonstrating that anemia is a primary driver of FGF23, and that management of iron utilization in patients with CKD may translate to modifiable outcomes in mineral metabolism

Detailed SZ study of 19 LoCuSS galaxy clusters: masses and temperatures out to the virial radius

We present 16-GHz AMI SZ observations of 19 clusters with L_X >7x10^37 W (h50=1) selected from the LoCuS survey (0.142<z<0.295) and of A1758b, in the FoV of A1758a. We detect 17 clusters with 5-23sigma peak surface brightnesses. Cluster parameters are obtained using a Bayesian cluster analysis. We fit isothermal beta-models to our data and assume the clusters are virialized (with all the kinetic energy in gas internal energy). Our gas temperature, T_AMI, is derived from AMI SZ data, not from X-ray spectroscopy. Cluster parameters internal to r500 are derived assuming HSE. We find: (i) Different gNFW parameterizations yield significantly different parameter degeneracies. (ii) For h70 = 1, we find the virial radius r200 to be typically 1.6+/-0.1 Mpc and the total mass M_T(r200) typically to be 2.0-2.5xM_T(r500).(iii) Where we have found M_T X-ray (X) and weak-lensing (WL) values in the literature, there is good agreement between WL and AMI estimates (with M_{T,AMI}/M_{T,WL} =1.2^{+0.2}_{-0.3} and =1.0+/-0.1 for r500 and r200, respectively). In comparison, most Suzaku/Chandra estimates are higher than for AMI (with M_{T,X}/M_{T,AMI}=1.7+/-0.2 within r500), particularly for the stronger mergers.(iv) Comparison of T_AMI to T_X sheds light on high X-ray masses: even at large r, T_X can substantially exceed T_AMI in mergers. The use of these higher T_X values will give higher X-ray masses. We stress that large-r T_SZ and T_X data are scarce and must be increased. (v) Despite the paucity of data, there is an indication of a relation between merger activity and SZ ellipticity. (vi) At small radius (but away from any cooling flow) the SZ signal (and T_AMI) is less sensitive to ICM disturbance than the X-ray signal (and T_X) and, even at high r, mergers affect n^2-weighted X-ray data more than n-weighted SZ, implying significant shocking or clumping or both occur even in the outer parts of mergers.Comment: 45 pages, 33 figures, 13 tables Accepted for publication in MNRA

The Vehicle, Fall 2010

Table of ContentsPoetryFill Your Mouth with BerriesAaron Whitepage 1 RelationsJamie Van Allenpage 2 ExodusMegan Marie Olsonpage 4 Single FileRashelle McNairpage 7 The Aesthetic Value of the Moon, by CandlelightKathy Deckerpage 15 FactalsGabrielle Keigherpage 16 Day 5David Jacksonpage 17 Esta LloviendoHeather Gerrishpage 19 FacebrokeDarrin Gordonpage 23 5:08 pmNikki Riechertpage 24 Train TunnelsAshton Tembypage 34 VariationsKathy Deckerpage 35 WantRashelle McNairpage 36 FriendshipScott Maypage 37 Golden LandJacob Swansonpage 38 Last Night I DreamtAshton Tembypage 39 Smallest GestureScott Maypage 44 Somebody\u27s Hut in MexicoGinamarie Lobiancopage 45 Some Things You Just Can\u27t Tap Dance AroundClint Walkerpage 53 Prose Lamparus de DiosAaron Whitepage 8 Learning CurveScott Maypage 18 RocktonKatelyn Pfaffpage 20 Fatal DistractionSolomohn Ennispage 25 Noodle NonsenseGabrielle Keigherpage 41 AntarcticaMichael Payeapage 46 Special Features James K Johnson Award Winners: God is GraciousJohn Klyczekpage 57 To My Ever Growing ChestJennifer Hindespage 74 God\u27s ScapegoatJennifer Hindespage 76 Rape (Verb, Noun)Jennifer Hindespage 78 Featured Artist: Ashton Tembypage 81 Editor\u27s Pick: The Shooter by Patrick Hallpage 87 Chapbook 2010 Author:Kim Hunter-Perkinspage 114 About the Contributorspage 118 About the Editorspage 122https://thekeep.eiu.edu/vehicle/1092/thumbnail.jp

The Vehicle, Fall 2010

Table of ContentsPoetryFill Your Mouth with BerriesAaron Whitepage 1 RelationsJamie Van Allenpage 2 ExodusMegan Marie Olsonpage 4 Single FileRashelle McNairpage 7 The Aesthetic Value of the Moon, by CandlelightKathy Deckerpage 15 FactalsGabrielle Keigherpage 16 Day 5David Jacksonpage 17 Esta LloviendoHeather Gerrishpage 19 FacebrokeDarrin Gordonpage 23 5:08 pmNikki Riechertpage 24 Train TunnelsAshton Tembypage 34 VariationsKathy Deckerpage 35 WantRashelle McNairpage 36 FriendshipScott Maypage 37 Golden LandJacob Swansonpage 38 Last Night I DreamtAshton Tembypage 39 Smallest GestureScott Maypage 44 Somebody\u27s Hut in MexicoGinamarie Lobiancopage 45 Some Things You Just Can\u27t Tap Dance AroundClint Walkerpage 53 Prose Lamparus de DiosAaron Whitepage 8 Learning CurveScott Maypage 18 RocktonKatelyn Pfaffpage 20 Fatal DistractionSolomohn Ennispage 25 Noodle NonsenseGabrielle Keigherpage 41 AntarcticaMichael Payeapage 46 Special Features James K Johnson Award Winners: God is GraciousJohn Klyczekpage 57 To My Ever Growing ChestJennifer Hindespage 74 God\u27s ScapegoatJennifer Hindespage 76 Rape (Verb, Noun)Jennifer Hindespage 78 Featured Artist: Ashton Tembypage 81 Editor\u27s Pick: The Shooter by Patrick Hallpage 87 Chapbook 2010 Author:Kim Hunter-Perkinspage 114 About the Contributorspage 118 About the Editorspage 122https://thekeep.eiu.edu/vehicle/1092/thumbnail.jp