All cases of Kola Bay freezing were documented over

a per

All cases of Kola Bay freezing were documented over

a period of more than 100 years, so it can be regarded as one of the indicators this website of climatic cycles in the Arctic seas. In the 20th century Kola Bay freezing occurred at intervals close to 30 years (Matishov et al. 2009). These situations were caused by a combination of meteorological and hydrographic factors. The presence of a stable anticyclone above Scandinavia for a long time (no less than ten days) is a significant factor in this. Certainly, climate cycles do not run like clockwork. An example of their disruption was the situation on the Bering Sea shelf at the beginning of 2012. Ice remained there for a record time, more than 100 days. During the history of satellite observations (since 1979), this happened for just the second time. The role of macrosynoptic processes in the formation of anomalies in the European climate, as well as hydrographic and ice extent regime of the Arctic seas, requires further research. The warming of 1990–2000 occurred under conditions of intensive western and eastern transfer in middle latitudes. During recent years, the recurrence and especially the duration of

anticyclonic blocking above Eurasia has increased, which has led to the forcing of a continental type of climate. At the same time the trajectories of north Atlantic cyclones have shifted to high latitudes, and that is favourable for positive anomalies of water temperatures and ice extent decrease in the Arctic seas in both the warm and cold seasons. In central and southern Europe, the Black and Caspian Seas, and also the Sea of Azov, such Y27632 situations cause strong Progesterone positive anomalies of air and water in summer, and sharp falls of temperature and extensive ice formation in winter. In the opinion of Shakina & Ivanova (2012) the development of a blocking situation can nowadays be successfully forecast only after it has actually come into

existence. Given the current level of knowledge is not possible to predict the emergence of such a situation, and especially its duration. Therefore, it is necessary to obtain a probabilistic estimate of such anomalies from both the synoptic meteorology point of view (the frequency and duration of blocking situations, the intensity and location of pressure fields at different levels) and the use of climatological criteria. In the course of research into the global climate and ocean regimes it is important to expedite the development of new technologies and software as well as the improvement of computation algorithms for climate norms and anomalies. Not just oceanological but also hydrobiological data should be used for marine climate assessments. Thus, according to the biomass changes of some species of polychaetes and crustaceans, it appears that fauna react to temperature anomalies with a 3–8 year delay (Matishov et al. 2012b).

05) than the corresponding

05) than the corresponding 17-AAG manufacturer values obtained without p-BPB). We have recently shown that B. b. smargadina venom produces potent neuromuscular blockade in avian (concentration range: 0.1–30 μg/ml) and mammalian (concentration range: 1–30 μg/ml) nerve–muscle preparations in vitro ( Rodrigues-Simioni et al., 2011). In mammalian preparations, the highest venom concentration

caused marked facilitation of the twitch-tension amplitude and increased the quantal content before the onset of progressive blockade, without altering the resting membrane potential; in avian preparations, the contractile responses to exogenous ACh and KCl were not significantly altered. These findings suggested a presynaptic action in both neuromuscular preparations that was attributed to the PLA2 activity of the venom. We have previously described the biochemical characterization and some biological activities of Bbil-TX, a basic PLA2 isolated from B. b. smargadina

venom, that induces muscle damage in mice (leading to CK release) and is pro-inflammatory, causing edema and stimulating the formation of TNFα, interleukin (IL)-1 and IL-6 ( Carregari et al., in press). As shown here, Bbil-TX also causes neuromuscular blockade in vertebrate nerve–muscle preparations. Indeed, Bbil-TX reproduced the major effects of the venom, i.e., time- and concentration-dependent neuromuscular blockade, with avian preparations being more sensitive than mammalian Navitoclax research buy preparations (0.5–10 μg/ml vs. 3–30 μg/ml; complete blockade with 10 μg/ml after 40 min in the former while 30 μg/ml caused only 52% blockade after 120 min in the latter). The Bbil-TX-induced blockade involved primarily a presynaptic action, the evidence for which included: (1) a lack of interference with postsynaptic nicotinic receptor function as indicated by unaltered responses to exogenous ACh and CCh, (2) a progressive decrease in the quantal content and MEPP frequency acetylcholine in diaphragm muscle during incubation with Bbil-TX [such a decrease is characteristic of classic presynaptic toxins such as β-bungarotoxin

(Oberg and Kelly, 1976) and crotoxin (Hawgood and Smith, 1989; Rodrigues-Simioni et al., 1990)], (3) an unaltered resting membrane potential (in diaphragm muscle) and unaltered (normal) twitch-tension response in directly stimulated BC and PND preparations preincubated with d-Tc, and (4) an unaltered response to exogenous (KCl), indicating skeletal muscle intactness that was corroborated by a lack of change in the baseline of twitch-tension responses. The contribution of muscle damage to the neuromuscular blockade caused by presynaptically-active Bothrops PLA2 is an aspect that has not been systematically investigated and is likely to vary considerably among these toxins in view of their differing abilities to damage muscle fibers ( Gallacci and Cavalcante, 2010; Correia-de-Sá et al., 2013).

, 1992, Kajiwara et al , 1996, Simmons-Willis et al ,

, 1992, Kajiwara et al., 1996, Simmons-Willis et al., check details 2002, Adachi, 2006 and Yin et al., 2008). Corroborating this hypothesis, our group recently reported that mice chronically treated with the MeHg–Cys complex show enhanced Hg uptake, especially in the liver, when compared

to other organs, such as the brain and kidney (Roos et al., 2010). These results are most likely due to the fact that the liver is a central organ of protein metabolism and receives amino acids absorbed at the intestinal levels as well as those derived from other organs and systems (Duarte, 2003). Although hepatic cells contain some of the same carriers that have been implicated in the transport of Hg in other organs, the precise mechanisms underlying the MeHg uptake across the membrane into normal hepatocytes as well as the influence of the MeHg–Cys complex on Hg uptake and hepatoxicity have not previously been well defined. Consequently, our study was primarily designed to investigate the Hg content in hepatic cells, at both cytosolic and mitochondrial levels after exposure to MeHg or the MeHg–Cys complex. Several previous studies have investigated and reported on the toxicology of MeHg, but, to date, only chelating agents have been employed to facilitate

SB203580 the removal of Hg from the body (Pingree et al., 2001 and Carvalho et al., 2007). However, these drugs are of limited use because of their adverse side effects. In the present study, we have tested the possible use of Met as an efficacious agent capable of protecting against the deleterious effects of MeHg. We observed that the Hg concentration in liver slices and in the mitochondria isolated from liver slices was higher after exposure to the MeHg–Cys complex (Fig. 1). Notably, we observed that Met decreased MeHg uptake by liver slices (Fig. 1). These results are different from those reported by Adachi (2006) after exposure of mice to MeHg. Adachi reported that Met can increase the hepatic deposition of Hg 2 h

after intravenously administration of MeHg and/or methionine. Since we have used only a single time-point of exposure of liver slices to MeHg (30 min) and/or Met (45 min), Fenbendazole we cannot disregard the possibility that uptake of MeHg could be increased in the presence of Met. Alternatively, the decrease in Hg uptake in the slices by Met may be, at least in part, related to the relatively high concentration of Met in the medium and, consequently, to direct interaction between MeHg and Met, thus lowering the effective free concentration of MeHg. Accordingly, we can posit that the effect observed in the presence of Met may be related to a direct interaction of the sulfur atom and/or amino end of Met with MeHg (Rabenstein and Fairhurst 1975). Alternatively, Met may be reducing the uptake of MeHg complexed with endogenous cysteine in liver slices. In addition, here we have worked with an in vitro system derived from rats.

No attempt was made to treat the pelvic lymph nodes The most com

No attempt was made to treat the pelvic lymph nodes. The most common dose prescription was 46 Gy

in 23 fractions (46 Gy/23), delivering 10 fractions daily for a fortnight, prescribed at the International Commission on Radiation Units Tanespimycin concentration and Measurements prescription point, using 18 MV photons. Patients were given instructions to have an empty rectum and “comfortably” full bladder for the treatment. Gold fiducial markers were used with a daily image-guided setup protocol since 2007. In all patients, the HDRB was used as a “boost” in combination with EBRT. Since initiation of the HDRB program, three progressive, escalated fractionation schedules were used. From November 1998 to August 2000 a schedule of 20 Gy/4 was used. From September 2000 to June 2006, the schedule changed to 18 Gy/3. From July 2006 until November 2008,

19 Gy/2 was the standard. Two patients planned to receive 18 Gy/3, but received one fraction selleck chemicals llc of 6 Gy and a second fraction of 10 Gy (16 Gy/2). This was because of the delays on Day 2, preventing a third fraction being delivered in a timely fashion. The technique has been previously described (8). Up until July 2006, metal needles were used. Subsequently, plastic catheters were used in an attempt to reduce trauma. These needles or catheters were placed transperineally using transrectal ultrasound and fluoroscopic imaging for guidance. The needles or catheters were placed within the bladder lumen to ensure adequate coverage of the prostate base. Before September 2005, replanning was not routine. Since then, patients were re-CT imaged on the simulator CT but only replanned if the needle movement

was estimated to be greater than 1 cm in the caudal ADP ribosylation factor direction. Since August 2008, all patients were replanned for each fraction. The identification of the apex in the planning images is essential to ensure adequate coverage of the prostate. Before September 2005, this was identified based on the planning CT images. Since September 2005, a fiducial marker has been placed at the apex under ultrasound guidance and used as a reference to improve the identification of the apex on the planning CT images. The target volume for the HDR component was the prostate with up to 6 mm in the cranial–caudal direction to account for microscopic extension and potential needle movement. Patients were planned using Plato (Nucletron, Veenendaal, The Netherlands) planning software until October 2009, since when the Nucletron Oncentra (Nucletron) planning system was routinely used. All fractions were given over one admission, at least 6 h apart. The HDRB was delivered by 192Ir source automatically afterloaded with a microSelectron 192Ir (Nucletron). As the prescribed dose changed over time, the dose to the urethra was limited so that no more than 10% of the urethral volume was to receive greater than 120% of the prescribed dose (D10 ≤ 120%).

The additional mixing is inversely proportional to the buoyancy f

The additional mixing is inversely proportional to the buoyancy frequency and proportional to the energy transfer from barotropic to baroclinic tides inferred from a tidal model (Carrère and Lyard, 2003). Its vertical structure is a bottom intensified exponential profile with an e-folding scale of 500 m. In Indonesian seas, Simmons (2004) parametrization is replaced by the one proposed specifically for semi enclosed seas by Koch-Larrouy et al. (2007). The latter has been BKM120 shown to improve water masses characteristics in this area (Koch-Larrouy et al., 2008a and Koch-Larrouy et al., 2008b) and to significantly

impact the climate simulated by global coupled GCMs (Koch-Larrouy et al., 2009). Concretely, using results from tidal models, this parametrization provides a four-dimensional (space and time) varying vertical tidal diffusivity, which is added to the vertical mixing in the semi-enclosed seas of the Indian Archipelago. The third modification deals with improving Selleckchem BLZ945 the surface boundary layer parameterization and light penetration into the ocean and has been implemented in F4. Mixing in the surface boundary

layer is based on a Turbulent Kinetic Energy (TKE) scheme (Blanke and Delecluse, 1993) which has been improved as follows (Madec, 2008). First, in mid-latitudes, a small fraction (5%) of the surface input of TKE is enabled to penetrate in the ocean (surface intensified exponential profile with an e-folding scale of 30 m). This change generates mixing below the base of shallow mixed layer in windy condition, and thus improved the mixed layer depth representation in summer below the storm track area. Second, the TKE scheme includes both the effect of Langmuir cell (Axell, 2002) and of surface wave breaking parameterization (Mellor and Blumberg, 2004), and third, the scheme uses a time and space discretization which is energetically consistent with the ocean model equations

(Burchard, 2002Marsaleix crotamiton et al., 2008). Technical details about these modifications can be found in Madec (2008). Along with these mixing parameterization changes, penetration of downward irradiance has also been improved in F4. In F1_CMIP3, F2 and F3, a simple 2-waveband scheme is assumed for the downward irradiance, following Paulson and Simpson (1977). The values of these extinction coefficients correspond to type I water Jerlov, 1968, see also Madec et al., 1999. Such assumption provides a very crude and simplistic representation of observed light penetration profiles (see Morel, 1988). Light absorption in the ocean indeed depends on particle concentration and is spectrally selective. A simplified version of the accurate representation of light penetration using 61 waveband formulation proposed by Morel (1988) was developed by Lengaigne et al. (2006).

2A) When relative area was compared

2A). When relative area was compared Selleckchem Vemurafenib between different stages, embryos at expanded blastocyst stage underwent higher (P < 0.05) reduction in area at T5 than embryos at blastocyst stage. However, area recovery was greater (P < 0.05) for embryos at blastocyst stage at T10 and T120 ( Fig. 2B). Expression of ATPase1 and Aqp3 genes was compared between embryos with greater (1.18 ± 0.02; n = 15) and lower (0.82 ± 0.03; n = 15) area recovery after 5 min in hypertonic medium

followed by 120 min in isotonic medium ( Fig. 3) in order to detect an association between level of rehydration and gene expression. No difference (P > 0.05) on relative abundance of ATPase1 and Aqp3 transcripts between embryos with high and low rehydration was found ( Fig. 4A). Viability of vitrified-warmed embryos and relative abundance of ATPase1 and Aqp3 transcripts were evaluated after culturing embryos for 72 h. Embryos survival was lower (P < 0.05) following vitrification (57.9%; n = 57) than for fresh (non-vitrified) embryos

Pifithrin-�� cell line (84.6%; n = 52). The relative abundance of Aqp3 was lower (P < 0.01) for vitrified-warmed embryos, but no difference (P > 0.05) on ATPase1 was found ( Fig. 4B). Membrane permeability is crucial for cell survival during cryopreservation. The current study shows that culture medium can influence the ability of in vitro fertilized bovine embryos to undergo shrinkage and swelling. Such ability can also be influenced by embryo stage. In addition, it shows that the embryo rehydrating ability after exposure to a NaCl hypertonic medium is not associated with the expression of Aqp3 Casein kinase 1 and ATPase1 genes; the amount of Aqp3 transcripts, however, can be altered following a vitrification/warming procedure. CR2aa and SOFaac are media commonly used for culture of in vitro-fertilized bovine embryos [32], [14], [27] and [6] and both produce similar embryos rates. The present study used these media in the co-culture system and also observed no difference on embryo production. Embryo ability to undergo dehydration, however, was affected by these different culture media, with higher dehydration

being found for embryos cultured in SOFaac medium. These finding suggest that embryos co-cultured in SOFaac medium may have greater permeability to water when exposed to hypertonic solutions. We showed that embryos at expanded blastocyst stage undergo greater dehydration in hypertonic medium but slower rehydration after returning to an isotonic medium than those at blastocysts stage. These characteristic can favor the expanded blastocysts during cryopreservation, making them less sensitive to an osmotic shock after thawing than embryos at blastocyst stage. Such slower rehydration may occur because embryos in expanded blastocyst stage have lower area/volume ratio than those in blastocyst stage. Embryos at late stage of development have more cells and greater blastocoel, resulting in a higher volume, which may take longer for initial recovery following dehydration.

–MA Tiller mortality began at PI, reached a peak in the PI–BT st

–MA. Tiller mortality began at PI, reached a peak in the PI–BT stage, and then gradually decreased with time until maturity. At the Max.–PI stage, DS rice showed higher tiller mortality than TP rice but

lower at BT–HD and HD–12DAH under either CT or NT. At PI–BT, higher tiller mortality was observed for CTTP (29.1%) and CTDS (29.4%) and NTDS showed lower tiller mortality than NTTP but with no significant difference. At the Max.–MA stage, the difference in tiller mortality between DS and TP was the smallest (Fig. 3). Both tillering duration (TD) and tillering rate (TR) varied significantly among the treatments. The TD was longer under TP than DS but TR was higher under DS than TP in either CT or NT. TD was longer in CTTP (59 days) followed by NTTP and lower duration was observed for

NTDS Fluorouracil purchase and CTDS methods. NTDS had higher TR (15.3 m− 2 day− 1) followed by CTDS. There was no significant difference in TR between CTTP and NTTP (8.8 and 8.0 m− 2 day− 1) respectively (Fig. 4). There was a significant correlation between panicle number per m2 Small molecule library and maximum tiller number per m2, but not between maximum tiller number and panicle-bearing tiller rate (Fig. 5). The dry weight of the vegetative part of tillers varied significantly among the treatments at all crop growth stages. The tiller dry weight gradually increased until HD and decreased at the MA stage. TP under either CT or NT had higher tiller dry weight than DS except at the tillering stage. NTTP had higher tiller dry weight than CTTP at all growth stages Etomidate except the tillering and MA stages. However, CTDS produced higher tiller dry weight than NTDS at all growth stages except the tillering and HD stages. Tiller dry weight was higher at the HD stage in all treatments and NTTP had

higher (4.3 g) tiller dry weight which was statistically not different from that of CTTP. Also there was no significant difference in tiller dry weight between NTDS and CTDS at the HD stage (Fig. 6). Leaf area (cm2 tiller− 1) varied significantly among the treatments at all growth stages of the crop. There were significant differences among establishment methods on all sampling dates. Leaf area increased sharply from the Max. to the BT stage, then slightly increased at the HD stage, and then gradually decreased with time. Leaf area per tiller was always higher under TP than DS at all growth stages. CTTP always had higher leaf area than NTTP, and CTDS than NTDS (Fig. 7). Number of spikelet per cm of panicle varied significantly among the treatments. CTTP and NTTP had significantly higher numbers of spikelet per cm of panicle than CTDS and NTDS. Panicle dry weight at maturity varied significantly among the treatments. Panicle dry weight under TP was higher than that under DS under either CT or NT. CTTP had heavier panicles (4.3 g) than NTTP. NTDS and CTDS were similar in panicle dry weight. The TP method resulted in 12% longer and heavier panicles than DS.

The eleven participating patients chose the gradient with the dar

The eleven participating patients chose the gradient with the darker side on the right on average in 98% of trials (as opposed to Selleckchem Quizartinib an average of 88% rightward preferences in the chimeric face task). This very strong rightward bias in the gradients task remained fully present and totally unaffected after the prism adaptation procedure, similarly to the results found for the lateral preference task with chimeric face tasks. Although the 98% bias might be considered as so strong that it represents a ‘ceiling’ or ‘floor’ effect, note that there was in fact plenty of room for the bias to be reduced by prism therapy, yet no benefit of prisms was found on the preference tasks. Finally,

we report here an initial existence proof for a positive effect

of prism adaptation (for some patients at least) on a different task employing chimeric face tasks, suggesting that it is possible to improve perception for the contralesional side of face stimuli with prism adaptation to some extent, in at least some cases. Using a simple task requiring explicit discrimination of the ‘chimeric’ or ‘non-chimeric’ nature of face stimuli (the same face stimuli MK0683 concentration as used in the lateral preference task, but now presented individually), we found a tendency for neglect patients to report ‘chimeric’ faces as ‘non-chimeric’, presumably due to neglect for the left half leading to a failure to notice the difference between left and the right halves. Prism adaptation had a significantly positive effect on performance in this particular task, in three out of six cases tested. The patients who did not show this prism-induced improvement tended to have larger lesions (which also appeared to be more anterior, on a descriptive lesion subtraction), although any exact relation to lesion anatomy would require further study in a larger group. But for present purposes, the key point is Low-density-lipoprotein receptor kinase simply that adaptation to right-shifting

prisms can substantially improve visual awareness even for the contralesional side of chimeric face tasks, in at least some patients with left neglect after right-hemisphere damage, depending on the task employed. This finding further indicates that the lack of any prism effect whatsoever on patient performance in the two lateral preference tasks did not merely reflect a general failure of our prism adaptation procedure to produce neglect-related benefits. This point received further convergent support from the significant beneficial effects of our prism intervention on line bisection and subjective straight-ahead pointing, two commonly used clinical measures for assessment of spatial neglect. Taken together, the present results suggest that prism adaptation may not be effective in changing rightward biases in neglect for lateral preference tasks (see Mattingley et al., 1993 and Mattingley et al.

5 Half of the culture was then infected with 20 MOI M13KO7 and i

5. Half of the culture was then infected with 20 MOI M13KO7 and incubated at 37 °C for 1 h (30 min with no shaking and 30 min with shaking at 100 rpm). The culture was then centrifuged at 3000 Vorinostat mw RCF for 20 min. The pellets were resuspended in the same volume of 2xYT medium with 100 μg/mL carbenicillin and 50 μg/mL kanamycin. These cultures were grown 18 h at 25 °C with shaking at 250 rpm. Next, the cultures were centrifuged at 9000 RCF for 30 min and phage particles were purified

from the supernatant by two PEG-precipitations (Sambrook and Russell, 2001). After the second precipitation, phage were resuspended in 1% of the initial volume with 15% glycerol in PBS and stored at − 80 °C. Selections against biotinylated gastrin 14-mer (Anaspec), β-galactosidase (Sigma), TIE-1-Fc chimera (R&D Systems), TIE-2 (R&D Systems), TIE-2/Ang2 (R&D Systems) and TIE-2/Ang1 (R&D Systems) were performed using solid or solution phase panning as previously described (Hawkins et al., 1992 and Vaughan et al., Lumacaftor clinical trial 1996). Complexes of TIE-2 with Ang1 and Ang2 were formed in a 1:1 molar ratio prior to incubation with magnetic beads. Prior to panning, TIE1-Fc and TIE2 were biotinylated with the EZ-Link Sulfo-NHS-LC-Biotin,

No-Weigh Format (Thermo). InsR pannings were performed as previously described (Bhaskar et al., 2012). RCA sequencing was performed by either ELIM Biosciences or Sequetech. Sequences were analyzed for open reading frame (ORF), variable region family, and alignment to germline sequences. ORF and V-gene family were determined using SeqAgent™ (XOMA (US) LLC) following IMGT conventions. To determine percentage of germline representation in the naïve libraries and selected clones, V-Base germline DNA GNA12 sequences were used as references. For each V-gene sequence, BLAST was used to find the closest germline match, followed by alignment of the two sequences using Clustalw2. The differences between the two

sequences were then counted. Periplasmic extracts (PPE) of soluble scFvs and Fabs were prepared by growing 1 mL cultures of 2xYT medium with 0.1% glucose and 100 μg/mL carbenicillin to an OD600 of 0.5 at 37 °C with shaking in 96-well deep well plates. IPTG was then added to a final concentration of 1.25 mM and the cultures were grown 16 to 18 h at 30 °C with shaking. The cultures were pelleted and the supernatant removed. The pellets were resuspended in 75 μL PPB (Teknova) with protease inhibitors (Roche) and incubated for 10 min at 4 °C with shaking. Next, 225 μL of sterile water with protease inhibitors was added and incubated for 1 h at 4 °C with shaking. Cell debris was removed via centrifugation and the supernatant was removed as PPE. Phage displaying scFv and Fabs were prepared by growing 1 mL cultures of 2xYT medium with 2% glucose and 100 μg/mL carbenicillin to an OD600 of 0.5 at 37 °C with shaking, usually in 96-well deep well plates.

[104], [105] and [106] In a mixed genetic background,

[104], [105] and [106] In a mixed genetic background, INCB024360 in vitro HIF-2 knockout mice survived into adulthood, but developed hepatic steatosis, skeletal myopathy and cardiac hypertrophy, which

was associated with mitochondrial dysfunction and defects in reactive oxygen species (ROS) scavenging. 107 Furthermore, HIF-2 knockout mice were pancytopenic and displayed a hypocellular bone marrow. 108 Further analysis revealed that anemia in these mice did not result from a cell-autonomous defect in erythroid precursor maturation, but was due to inadequate renal EPO production, indicating that HIF-2 was indispensable for systemic EPO homoeostasis in adults. 70 In a different model, Morita and colleagues showed that local EPO production in the retina was also HIF-2-dependent, 69 suggesting a more general role for HIF-2 in the control of EPO regulation. While these mouse models demonstrated that EPO production in adults was HIF-2-dependent, developmental studies highlighted the importance of HIF-1 in

the regulation of erythropoiesis during embryonic development. HIF-1-deficient embryos were characterized by a reduction in myeloid multi-lineage cells and committed erythroid progenitors at E9.5. This was associated with decreased Epo mRNA levels in the embryo proper but not in the yolk sac, while EpoR mRNA was decreased in both tissues. 54 The most compelling support for the notion that HIF-2 is the main regulator of adult EPO synthesis comes from conditional knockout studies in mice. Utilization of a tamoxifen-inducible, ubiquitously

expressed Cre-recombinase transgene permitted a direct RO4929097 in vitro comparison of the effects of HIF-1 and HIF-2 inactivation on erythropoiesis. Acute postnatal Tideglusib global ablation of HIF-2α, but not of HIF-1α, resulted in anemia, which, similar to HIF-2α germ line inactivation, was responsive to treatment with recombinant EPO.71 While stimulation of renal EPO production in response to hemolysis (phenylhydrazine treatment) was blunted in HIF-2α-ablated mice, postnatal deletion of HIF-1α did not have any notable effect on erythropoiesis, which suggested that HIF-1 does not play a significant role in the regulation of systemic EPO homeostasis at baseline or in response to acute anemia.71 Our laboratory has generated cell type-specific knockout mice to investigate the differences between HIF-1 and HIF-2 in the regulation of renal and hepatic EPO synthesis. Inactivation of HIF-2α in the kidney completely ablated the renal EPO response in mice subjected to normobaric hypoxia (10% O2 for 10 days), phlebotomy-induced anemic hypoxia, or treatment with a HIF activating compound.24 Cell type-specific inactivation of the VHL-E3 ubiquitin ligase in hepatocytes resulted in HIF-2-, but not in HIF-1-dependent erythrocytosis, while pharmacological PHD inhibition caused a HIF-2-dependent increase in liver Epo mRNA levels.