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How does iron enter enterocytes? Ablating SLC11A2, the gene for the divalent metal ion transporter DMT1, supports evidence from the Belgrade rat and mk mouse models establishing DMT1 as the primary mechanism serving apical uptake of nonheme iron. DMT1 harnesses the energy from the proton electrochemical potential gradient to drive active transport of Fe2+ (and perhaps Mn2+ and other metal ions) into enterocytes. Fe(III) must first be reduced by ascorbic acid and surface ferrireductases. Among these is duodenal cytochrome B (DcytB), but lack of an obvious phenotype in DcytB (Cybrd1) knockout mice suggests ferrireductase redundancy. Our understanding of heme absorption has lagged, but the time is ripe for gains.
- anemia
- duodenal cytochrome B
- divalent metal ion transporter
- ferroportin
- hemochromatosis
- iron absorption
- Nramp2
iron deficiency is the most prevalent micronutrient deficiency worldwide. Meanwhile, iron overload associated with conditions such as hereditary hemochromatosis, thalassemia, or sickle cell disease poses a serious threat to many other individuals. The past decade has witnessed tremendous progress in our understanding of the intestinal absorption of iron and its contribution to iron homeostasis. Second in the series "Iron Imports," this article reviews the topic of iron uptake at the intestinal brush border. Although dietary iron in omnivores comprises both heme iron and nonheme iron, we focus here on the latter form because the major recent advances in the field have been in the molecular identification and characterization of the machinery responsible for absorption of nonheme iron. Apical uptake of iron is mediated by the divalent metal ion transporter DMT1. We describe its functional properties and review lessons from DMT1 mutant animal models and the first disease-causing DMT1 mutation to be identified in the human population.
The literature in this field contains hypotheses or issues that some researchers may avoid and others that are clearly controversial. Scientific rigor demands that investigators not ignore inconvenient observations or hypotheses; rather, we should develop tests that distinguish apparent alternatives (and sometimes both alternatives will survive or be found wanting) or look for technical difficulties that may explain why an observation is misleading. This viewpoint has pushed us to discuss a number of avoided or controversial claims.
Iron absorption occurs mainly in the duodenum and proximal jejunum, but iron uptake by enterocytes depends also on several upstream factors. These include the chemical form of dietary iron, organic acids, and gastric acid secretion. For those who consume meat, heme is a major dietary source of bioavailable iron, so its absorption is discussed later. Those who do not consume meat rely on nonheme dietary iron. This form is often loosely referred to as "inorganic" iron even though most nonheme Fe(II) or Fe(III) in food is complexed with organic acids (e.g., citrate) or peptides (e.g., ferritin and albumin) and is not limited to Fe(II) salts. Bioavailability of nonheme iron may be determined in large part by the solubility of such complexes and the affinity with which they bind iron. The part played by gastric acid secretion in iron absorption is almost certainly to promote solubility of iron complexes. Phytic acid (abundant in cereals) is a major inhibitor of iron absorption because of the poor solubility of its iron chelate at any pH. Iron fortification of foods is likely to be most successful with highly soluble (low molecular weight), high-affinity complexes such as Na-Fe-EDTA (the stability of which makes it suitable for long shelf-life foods).
Vitamin C (l-ascorbic acid) is important in iron absorption, as established by the early work of Conrad and others. Ascorbic acid, either derived from the diet or from gastric or biliary secretions, can efficiently reduce ferric ion in a low-pH environment. Even at higher pH, ascorbate forms soluble Fe(II) or Fe(III) complexes that promote iron absorption. Iron deficiency leads to an induction of the gene encoding the intestinal vitamin C transporter SVCT1 in the rat (2) and to increased enterocyte ascorbate levels in the mouse. One should not surmise that these changes represent vitamin C repletion in these animals because rats and mice (unlike humans) can synthesize this vitamin in the liver. More likely, the significance of these observations is that increased ascorbate in enterocytes could serve as an electron donor to duodenal cytochrome B (DcytB), a candidate ferrireductase at this apical membrane (18).
Ferric iron not reduced by ascorbate before reaching the intestinal brush border must be reduced by surface ferrireductases to be transported via DMT1 into the enterocyte. DcytB, the first candidate for this role (Fig. 1), was isolated using a subtractive cloning strategy from the iron-deficient rat (18). So it is not surprising that DcytB, which is localized alongside DMT1 on the apical membrane, is upregulated under conditions of iron deprivation (2); however, targeted disruption of the Cybrd1 gene coding for the murine homolog of DcytB suggests that DcytB is not necessary for intestinal iron absorption in mice fed a normal-Fe diet (13). The study just cited had difficulty detecting a statistically significant effect of the Cybrd1 knockout on liver nonheme iron in mice fed a low-iron diet but did find such a decrease in 12-wk-old female mice fed an iron-deficient diet for 8 wk. This difficulty in detecting a phenotype led the authors to focus on DcytB not being necessary for dietary iron absorption in mice. We remind the reader that humans are a scorbutic (or vitamin C challenged) species that may rely more on surface ferrireductases than mice do. Crossing the Cybrd1 knockout mouse with one unable to synthesize vitamin C or one with a severe genetic iron deficiency may allow us to speculate further as to the role of DcytB in mice and humans.
The lack of a severe iron-deficient phenotype in the Cybrd1/DcytB knockout may suggest that DcytB is only one of several intestinal ferrireductases. Ferrireductase activity is found in many tissues and critical for iron utilization in the transferrin cycle, yet investigators have not been able to show that DcytB participates in the transferrin cycle. Now the absence of an erythroid phenotype when Cybrd1 is ablated encourages us to predict that additional ferrireductase gene(s) is (are) forthcoming.
DMT1 is a ferrous ion (Fe2+) transporter (9, 12, 15) that is energized by the H+ electrochemical potential gradient (Fig. 1). Ferric ion (Fe3+) is excluded (12). Its primary location in the gut is on the brush-border membrane of mature villous enterocytes of the proximal duodenum (see Ref. 15 for citations; most recent data in Ref. 14), where the expression of DMT1 is tightly regulated by body iron status. This same transporter is also responsible for the recovery of iron from recycling endosomes during transferrin receptor (TfR)-associated cellular uptake in erythroid (red blood cell) precursor cells and many other cell types.
There are at least five mutants with defective DMT1 expression; these comprise four animal models and the first disease-causing mutation to be identified in the human population. Studies of the intestinal (and broader) phenotypes of these mutants teach us much about the physiological role of DMT1 in apical iron uptake. The Belgrade (b) rat (9) and microcytic (mk) mouse have been studied for many years and provided the first insights into DMT1 function in the physiological setting. Both mutants have a Gly185→Arg substitution (this is the position in the NH2-terminal isoform initiated from exon 2 as "exon 1B" is untranslated; for the 1A exon variant, it corresponds to Gly216 in the rat and Gly215 in the mouse) (6, 7). Thus one expects extensive similarities between the two models, with differences reflecting the different species in which DMT1 functions or malfunctions. Here, we cover first the similarities as well as the lessons from the other mutants; next, we comment on differences.
The b and mk animals exhibit a severe hypochromic, microcytic anemia with diminished erythrocyte survival. The resemblance to iron deficiency teaches us that DMT1, found largely on the apical surface of enterocytes, is not allowing iron to enter. Although bypassing intestinal uptake by parenteral injection or careful iron supplementation improves red cell production, it does not eliminate the iron-deficient appearance. This part of the phenotype places emphasis on a role of DMT1 during erythroid iron acquisition. Exactly how critical DMT1 is depends on the effect of the mutation. Therein lies controversy (see Ref. 9): some reports indicate that considerable transport activity survives, whereas others show that activity is very low or undetectable. Similarly, some groups (often overlapping with those that find considerable transport remaining) observe that DMT1 localizes differently and turns over more readily, whereas others see much less of such a phenomenon. The latest report (14) indicates that transport activity is undetectable in brush-border membrane vesicles from homozygous Belgrade rats and that DMT1 is increased and, to a large degree, properly localized in the same preparations. Because the observations supporting poor localization and higher turnover are with DMT1 in, and DMT1 constructs from, the microcytic mouse, most recently in Ref. 23, we speculate that some of the discrepancy in these results represents a species-related difference. If so, exchange of constructs, cell lines, and specific antibodies could resolve the issues. The end effect, regardless, is that little functional DMT1 actually takes up iron at the apical surface of mutant enterocytes. From this body of work, we learn that DMT1 is the major intestinal nonheme iron transporter (Fig. 1), and we retain a suspicion that one or more alternative pathways exist that (barely) permit the rodent mutants to survive.
A very similar phenotype results from a nonsense mutation in DMT1 in a zebrafish mutant called chardonnay (3). That chardonnay should have no DMT1 transport activity indicates that intestinal DMT1 is critical for the iron demand of the erythron but that alternative (as yet poorly defined) pathways can handle demands of iron homeostasis in most other tissues.
In the first example of a disease-causing mutation in human DMT1, a homozygous G→C substitution at nucleotide 1285 (or 1372 in the 1A isoform) led to the amino acid substitution E399D (E428D for 1A), but this change has little effect on DMT1 function per se (20). Similar to the prior mutations, however, the patient's erythroid phenotype was apparently iron deficient, but, even more remarkably, the patient exhibited signs of iron overload. The mutation also affected a splice donor site and provoked an increase in aberrant splicing in hematopoietic tissue involving skipping of exon 12. The predicted mRNA from this event produces a nonfunctional protein (20) so that the patient's erythroid cells should have much less DMT1 than do normal cells. One might explain the phenotype by assuming that the gut iron uptake regulatory system has sensed the iron-deficient erythron and upregulated DMT1 (and other parts of the transport pathway) so that increased transserosal iron diverts from its usual major target of red blood cell precursors to other tissues. Other possibilities deserve consideration, e.g., alterations in red blood cell turnover may also contribute to the patient's unusual phenotype.
Gunshin et al. (11) ablated the SLC11A2 gene coding for DMT1 in mice and made a series of mouse strains in which the gene was specifically removed in selected tissues. Their technically elegant work confirms and further solidifies the implications researchers derived from the earlier DMT1 deficiencies. The sites where DMT1 is most critical for iron homeostasis are the intestinal tract (where it is clearly the major transporter for iron entry) and the red blood cell precursor (where it is essential for full hemoglobinization). These investigators had difficulty raising the knockout mice past weaning and found that specific DMT1 gene disruption in the intestinal tract led to an anemia nearly as severe. When they made a double mutant by crossing the DMT1 knockout with mice in which the HFE gene (known to modulate DMT1 expression) was also ablated, they observed mildly improved survival. Although SLC11A2 is clearly a target for regulation by the HFE pathway, an increase in its activity cannot account for this improvement. Hence, one must infer that, although DMT1 is normally essential for iron uptake, HFE must ultimately regulate other parts of the iron transport pathway, possibly including an alternative means of apical iron uptake that can be sufficiently upregulated to allow the observed improvement. Whereas the existence of alternatives for uptake had been raised often before, this conclusion was debated in part because of controversy about how much transport activity survived the G185R mutations in the Belgrade rat and microcytic mouse (above). Although they reiterated the importance of DMT1, Gunshin et al. have fueled suspicions that alternatives exist. What remains is to identify the alternative(s), no easy task!
The mucosal cell surface in the duodenum and proximal jejunum remains moderately acidic despite the progressive alkalinization of the luminal contents (17). This "acid microclimate" (which results from the activity of the Na+/H+ exchanger) is thought to provide the proton electrochemical potential gradient as the motive force for iron uptake (Fig. 1). Thus it was comforting when the first demonstration of the iron transport activity of DMT1 revealed an H+/Fe2+ cotransport mechanism that was stimulated at low pH (12).
Since then, at least one report has lessened the clarity of this coupling. Worthington et al. (25) found that Fe2+ transport was maximal at pH 6.75 in Caco-2 cells (as model enterocytes in which DMT1 is endogenously expressed) and in DMT1-transfected COS-7 cells. So, as these authors suggested, could the Fe2+-evoked current in the oocyte (12) reflect only a H+ current that was not coupled to Fe2+ transport? Countering this view, a recent study (16) in oocytes expressing DMT1 shows that the pH profile of 55Fe2+ uptake is no different from that of the Fe2+-evoked currents, and that both activities are maximally stimulated at low pH (at least to pH 5.2 without overstepping a pH optimum). Kinetic analyses showed that H+-Fe2+ cotransport is the favored activity, but DMT1 also mediated uncoupled Fe2+ or H+ fluxes in the absence of the cosubstrate (16). Uncoupled leaks of the driving ion (e.g., Na+ and H+), but not for the driven substrate, are commonplace among mammalian cotransporters. Fe2+ transport uncoupled from H+ is unlikely to be of much consequence at the apical membrane of the intestine (perhaps it is of consequence elsewhere) (16), but it does explain the residual Fe2+ transport activity at pH ≥ 7 observed by other groups reporting that DMT1-specific Fe2+ transport in Caco-2 cells is maximally stimulated at much lower pH (see Ref. 16 for citations). Why Worthington et al. (25), using the same cell system, obtained quite different results is not known, but possible reasons are suggested elsewhere (16). Results (M. D. Garrick, unpublished data) with an inducible DMT1 expression system confirm that transport occurs at pH 7.4 but still find a maximum around pH 5.5. (A much lower pH may denature the protein and inactivate the transport activity of DMT1.)
H+ coupling in DMT1 provides a thermodynamic driving force for Fe2+ transport, with half-maximal H+ concentration of ≈1 μM (i.e., pH 6.0) (16). Whereas duodenal mucosal cell surface pH is 6.7, the microclimate pH reaches 6.0 in human proximal jejunum in vivo (17). H+ binding also increases the affinity with which DMT1 binds Fe2+ (16). So, although duodenal Fe2+ concentrations may be higher than those of the jejunum, the properties of DMT1 ought to make it an effective scavenger of the available Fe2+ in the proximal jejunum. Inward currents in DMT1-expressing cells exceed those expected for strict stoichiometric H+/Fe2+ cotransport (19). Such slippage in cotransport systems is normally thought of only in terms of the energetic penalty incurred, but the excess protons transported by DMT1 may serve additional roles. These may include localized intracellular acidification, maintaining the chemical state of Fe2+ before it is handed off to an intracellular chaperone. Nelson proposes that variable H+/Fe2+ coupling can help manage varying levels of metal ions in the lumen of the gut by affecting the internal pH of the enterocyte and possibly the nutritional needs for the metal ions. Support for this hypothesis comes from the observation that an F227I mutation can decrease the H+-to-Fe2+ coupling ratio (19), suggesting that evolution can potentially select for optimal slippage. Nevertheless, more analysis is required to assess fully the roles of H+, pH, and slippage.
Gunshin et al. (12) demonstrated that, in addition to Fe2+, a broad range of transition metals (Cd, Zn, Mn, Cu, Co, Ni, and Pb) can evoke inward currents in Xenopus oocytes expressing DMT1. Fe2+ transport was demonstrated in this study using a radiotracer assay. Nevertheless, like inhibition of uptake, evoked currents demonstrate DMT1 reactivity with these metals but do not demonstrate for each that it is actually transported. In fact, questions have been raised about most of the potential substrates except iron (10).
Radiotracer assays (in oocytes or in Caco-2 cells) have established that DMT1 is also capable of transporting Mn, Co, Zn, and Cd (16) (for earlier citations, see Refs. 10 and 15), but these observations require careful interpretation on more than one level. For example, DMT1 shows a strong preference for Fe2+ over Zn2+ (16), and Zn2+ is a very weak inhibitor, if at all, of Fe2+ uptake (10, 16). That Zn2+ is not a favored substrate for DMT1, together with the existence of alternative uptake pathways serving Zn2+, makes it unlikely that DMT1 is physiologically relevant to Zn absorption. On the other hand, Mn2+ may be a better substrate of DMT1, and the observation that intestinal Mn transport and reticulocyte Mn utilization also are impaired in the Belgrade rat (1, 14) points to a physiological role for DMT1 in Mn absorption. The question remains as to which other metal ions rely on DMT1 to enter enterocytes, but it is likely that Mn2+ does so and that Zn2+ does not.
Although current models place DMT1 on the apical surface of enterocytes consistent with its function in entry of iron there (Fig. 1), several observers see it elsewhere in or near these cells. Their observations require verification and, if reliable, interpretation. Simovich et al. (22) detected DMT1 not only in microvilli but also in goblet cells and associated with the luminal mucin in the duodenum. They suggest that the extracellular DMT1 originates in the goblet cells and aids in iron acquisition in what they designate a Pac-Man model. These intriguing observations need confirmation, and the model needs to be tested. In a subsequent review in this series, evidence that supplying a bolus of iron to the enterocyte causes DMT1 to internalize from the apical surface on its way to hand iron off ultimately to apotransferrin should be covered. This model is intriguing, but it appears to redefine DMT1 as an iron-binding protein and introduces confusion about its membrane-transport role. Nevertheless, Sharp et al. (21) have also detected DMT1 departing from the brush border after exposure of Caco-2 cells exposed to iron, but they interpret this departure as regulatory rather than part of a handoff. Here, we have similar observations leading to two distinct hypotheses. Devising a test to distinguish the hypotheses (handoff vs. regulation) is in order.
Knöpfel et al. (14) also looked for DMT1 activity in both brush-border and basolateral membrane vesicles from enterocytes. As expected from the presence of DMT1 on the apical membrane, activity was present in brush-border preparations from control rats but undetectable in those from homozygous Belgrade rats. Surprisingly, basolateral vesicles also yielded comparable results. In these preparations, DMT1 was detected on immunoblots by isoform-specific antibodies, including one targeting the COOH terminus specific to the protein encoded by the mRNA containing a consensus iron-responsive element (IRE) in the 3′-untranslated region, often designated the +IRE form. Other antibodies targeted the unique COOH terminus encoded by the mRNA that lacks an IRE (the −IRE form) and the NH2 terminus encoded by exon 1A. Immunofluorescent localization confirmed that DMT1 isoforms had distinct distributions and that the −IRE form was particularly well represented on membranes distinct from the apical surface.
DMT1 at other locations could be involved in supplying the nutritional needs of enterocytes from ferric-transferrin by the transferrin cycle run in its usual direction, but other more interesting possibilities merit investigation. These include a role in delivering iron to apotransferrin, a downstream role in a handoff from DMT1 internalized from the apical surface after exposure to iron, or even a direct role in the basolateral exit of iron. This handoff possibility should be explored in a subsequent review in the series, but what is not clear is how to reconcile a role in Fe transcytosis with its transport activity in vitro. Even in the absence of a proton gradient, electrical and concentration gradients are likely to ensure that DMT1 serves only as an uptake system (16). If DMT1 were to play a direct role in iron exit, it is not redundant with that of IREG1/ferroportin1 (slc40a1) because selective intestinal knockout of slc40a1 causes a lethal microcytic, hypochromic anemia (4).
DMT1 is dramatically upregulated in the intestine by dietary iron restriction or increased demand for iron and, despite high serum iron levels, is not appropriately downregulated in hereditary hemochromatosis, a defect associated with mutations in the HFE gene. The consensus IRE in the 3′-untranslated DMT1 mRNA of the predominant splice variant in intestine may underlie this iron-dependent regulation of DMT1. Binding of the IRE by an iron regulatory protein when intracellular iron is low could protect the mRNA from degradation. Although there is no doubt that the +IRE form is iron regulated, it is remarkable that investigators have known about the presence of the IRE for over eight years and yet have found little direct evidence that this regulation is mediated via the IRE itself.
It is now clear that the liver plays a major role in whole body iron homeostasis and that the hepatic hormone hepcidin is a key regulatory component (see other reviews in this series). Iron deficiency in the rat decreases hepcidin expression and stimulates intestinal iron absorption in parallel with increased duodenal expression of DMT1 and the basolateral efflux transporter IREG1/ferroportin1 (8). The prevailing view is that the effect of hepcidin on DMT1 is secondary to its action on IREG1/ferroportin1. Hepcidin binding by IREG1/ferroportin1 results in the internalization and degradation of IREG1/ferroportin1 protein, and consequent iron loading in the enterocyte could accelerate degradation of the +IRE DMT1 mRNA. DcytB levels also respond to hepcidin (8). Moreover, regulation of DMT1 expression at the protein level is observed in Caco-2 cells in response to iron loading (21). Further studies are required to explore the mechanisms by which apical iron uptake is regulated, and these are likely to include pathways that are independent of IREG1/ferroportin1.
Notwithstanding the dominant role of DMT1 in iron absorption, debate continues as to whether there exist alternative mechanisms for uptake of nonheme iron. Bacteria and yeast express many genes associated with iron transport; most of these are specific to certain chemical forms (salts, chelates, diferric transferrin, etc.). So it is plausible that uptake systems for specific iron complexes (among which are siderophores, ferritin, and lactoferrin) remain to be identified in humans.
One issue that needs experimental follow up is the role of mobilferrin, a protein that is either identical to the chaperone calreticulin or an unanchored form that has lost some COOH-terminal amino acid residues (see Ref. 22 for citations). Mobilferrin/calreticulin might be part of an uptake pathway for ferric ion (Fe3+), or it could participate along with DMT1 in Fe2+ uptake. The discussion above of what we learn from DMT1 mutants makes it unlikely that mobilferrin can substitute for DMT1 in Fe2+ uptake. Nevertheless, not substituting for DMT1 is not the same as playing no role. One cannot argue from the phenotype of calreticulin knockout mice because the knockout is lethal with a phenotype that points toward multiple roles for this chaperone (5). So how should one test the role of mobilferrin in iron metabolism? Investigators skilled at making tissue-specific ablation of genes in mice should do so for calreticulin in the gastrointestinal tract and ask what this does to iron homeostasis. Short of such a strong test, knockdown technology and studies of cell lines derived from embryonic stem cells from the calreticulin knockout mice are ways to learn whether mobilferrin/calreticulin plays a role in iron homeostasis.
Dietary heme iron has greater bioavailability than nonheme iron. Our understanding of iron absorption from heme has lagged behind that of nonheme iron absorption, and more research attention is clearly warranted. Heme (ferrous protoporphyrin IX) is liberated by the proteolytic digestion of hemoglobin and myoglobin in the lumen of the proximal small intestine. Heme is then taken up intact at the apical membrane (Fig. 1). Endocytosis of heme was originally demonstrated by tracking heme-associated peroxidase activity in the duodenum from animals fed hemoglobin or hemin chloride, and, around the same time, heme receptor activity was detected in the intestine (see Ref. 24 for citations). The stage is now set for molecular and genetic tools to enable identifying the intestinal heme receptor. Heme taken up into the endosome or lysosome is thought to be cleaved by heme oxygenase (to bilirubin and Fe2+), but how Fe2+ is mobilized from this compartment to the cytosol is not known. Whether DMT1 is among the candidates for this role (analogous to its role in transferrin-associated iron uptake in erythroid cells) could be tested by examining the intestinal handling of heme in the Belgrade rat and by determining whether one or more DMT1 isoforms are localized within the heme-containing endosomes/lysosomes.
Whether taken up by DMT1 at the brush border or mobilized from endosomes/lysosomes involved in heme uptake, Fe2+, we might speculate, meets the same cytosolic fate. Iron may be bound by ferritin, but the traditional view of ferritin as an iron storage protein may push us to look for other proteins that could chaperone the labile iron to the basolateral membrane for export. There are no obvious candidates, aside from Glass' proposal that DMT1 may itself take part in transcytosis. The finding that mRNA for a lipocalin receptor increases in iron-deficient rat enterocytes (2) could mean that the search should widen to internal siderophores. It is thought that the ferroxidase hephaestin is an electron acceptor associated with the basolateral export of Fe2+ by IREG1/ferroportin1 before handing off Fe3+ to transferrin (Fig. 1). It is interesting to note that most of the hephaestin protein, however, localizes to perinuclear vesicles rather than the basolateral membrane. This may simply reflect a regulatory redistribution, but it seems worth exploring whether hephaestin could also be involved in shuttling iron to IREG1/ferroportin1.
Three articles of particular relevance have appeared since the submission of our manuscript. Frazer et al. [Frazer DM, Wilkins SJ, Vulpe CD, and Anderson GJ. The role of duodenal cytochrome b in intestinal iron absorption remains unclear. Blood. In press.] present new evidence and discuss the conclusions made by Gunshin et al. in their study of the DcytB (Cybrd1) knockout mouse. Iolascon et al. report microcytic anemia and hepatic iron overload in a patient with novel compound heterozygous mutations in DMT1 [Iolascon A, d'Apolito M, Servedio V, Cimmino F. Piga A, and Camaschella C. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1. Blood. In press.]. Finally, Shayeghi et al. propose HCP1 as a candidate intestinal heme transporter/receptor [Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, Khan Y, Warley A, McCann FE, Hider RC, Frazer DM, Anderson GJ, Vulpe CD, Simpson RJ and McKie AT. Identification of an intestinal heme transporter. Cell 122: 789–801, 2005].
Work in the authors' laboratories was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-59794, United States Department of Agriculture Grant 2001-35200-10723 (to M. D. Garrick), and by the Univ. of Cincinnati (to B. Mackenzie).
We thank Dr. L. M. Garrick (Depts. of Biochemistry and Medicine, State University of New York) for constructive comments on this review.
- Copyright © 2005 the American Physiological Society


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Average grade: 6.7 %
Length: 3.95 km
Altitude start: 2052 m
Altitude top: 2315 m
Ascent: 263 m
Maximum: 12 %
Forcola di Livigno rankings
Difficulty ranking world: 5580 (all)
Ranking Italy: 1614 (all)
Ranking Alps: 1679(all)
Difficulty score: 48.01 what?
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The Forcola di Livigno is situated in Lombardy. This climb belongs to the Alps.
Starting from da crossroad Bernina,
the Forcola di Livigno ascent is 3.95 km long. Over this distance, you climb 263 heightmeters.
The average percentage thus is 6.7 %.
The maximum slope is 12 %.
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Grand Funk Railroad - I'm Your Captain/Closer To Home MP3
Grand Funk Railroad's song I'm Your Captain/Closer To Home. Enjoy!
Grand Funk Railroad Grand Funk 1969 Full Album MP3
Grand Funk Railroad - Inside Looking Out 1969 MP3
http://www.petitiononline.com/GFRMDM/petition.html Grand Funk Railroad performing "Inside Looking Out" live from 1969. This clip was shot at "The Show" ...
Grand Funk Railroad Survival 1971 Full Album MP3
Grand Funk Railroad + Caught in the Act + Full Live Album MP3
Grand Fun Railroad - Caught in the act full album!!!!
Grand Funk Railroad Documentary MP3
Grand Funk Railroad (also known as Grand Funk) is an American rock band that was highly popular during the 1970s. Like us ...
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E Pluribus Funk (1971) 1. Footstompin' Music 2. People, Let's Stop the War 3. Upsetter 4. I Come Tumblin' 5. Save the Land 6. No Lies 7. Loneliness All songs ...
Grand Funk Railroad - We're An American Band LIVE - 1974 MP3
Another grest video live for this song! Have You comments?
Grand Funk Railroad - I'm Your Captain (Live 1971) MP3
Grand Funk Railroad - Im Your Captain. Shea Stadium 1971.
Grand Funk Railroad - Heartbreaker MP3
Live in 1974 Idols!
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All songs by Mark Farner. "Flight of the Phoenix" - 3:38 "Trying to Get Away" - 4:11 "Someone" - 4:04 "She Got to Move Me" - 4:48 "Rain Keeps Fallin'" - 3:25 "I ...
Grand Funk Railroad - Some Kind of Wonderful MP3
grand funk railroad's track from their album greatest hits.
Grand Funk Railroad - Inside Looking Out MP3
Grand Funk Railroad - Inside Looking Out (Grand Funk, 1969) Mark Farner - guitar, vocals Don Brewer - drums, vocals Mel Schacher - bass.
Minx Zine : Grand Funk Railroad Greatest Hits Full Album MP3
Tracklist: 1 - We're an American Band 00:00 - 03:27 2 - Time Machine 03:28 - 07:13 3 - Walk Like A Man (You Can Call Me Your Man) 07:14 - 11:19 4 - Some ...
Grand Funk Railroad cover In concert MP3
We pay tribute to the work of the group "Grand Funk Railroad and personally maestro MARK FARNER.
Grand Funk Railroad - We are an american band (FULL ALBUM) MP3
Grand Funk Railroad - Closer To Home (1970) (Full Album) MP3
Band: Grand Funk Railroad Album: Closer To Home Year: 1970 Genre: Hard Rock Released: (2008 Japan Mini LP TOCP-67923) Track List: 01. Sin's A Good ...
Grand Funk Railroad I'm Your Captain MP3
Album Closer to Home Lyrics: Everybody, listen to me, And return me, my ship. I'm your captain, I'm your captain, Though I'm feeling mighty sick. I've been lost ...
Grand funk railroad - Footstompin' Music MP3
Grand Funk Railroad - She's Some Kind Of Wonderful live MP3
Grand Funk Railroad live at the Palace, Auburn Hills, MI, 4/20/97.
Grand Funk Railroad - The Locomotion MP3
Shinin' On (1974)
Grand Funk - Live 1974 (From Japanese LaserDisc) MP3
Directamentes desde el LaserDisc japones a youtube. Directly from Japanese LaserDisc (Daiei 1986) to youtube.
Grand Funk Railroad - Heartbreaker With Lyrics MP3
Grand Funk Railroad - Into The Sun - 1970 MP3
As promised, here's Grand Funk Railroad's 'Into The Sun' video with all info available, re-edited and re-synchronized. Taping was done at the 'Pirates World ...
Grand Funk Railroad- Comfort Me MP3
Track 3 - Comfort Me From the 1971 album "Survival" Sign the petion to induct Grand Funk Railroad into the Rock and Roll Hall of Fame ...
Grand Funk Railroad, Full Concert 1972, Madison Square Garden MP3
Full Concert - Grand Funk Railroad - Madison Square Garden December 23rd 1972 - ABC In Concert. (I added Loneliness from a soundboard recording, it was ...


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I have a couple of .co domain registered via GoDaddy.
Unlike .com & .net domain SW cloud services is unable to successfully query information about theses domain. I'm getting "Unknown" instead of the actual info.
Anyone else seeing this?
This topic was created during version 5.2.
The latest version is 7.5.00101.
11 Replies
Oct 13, 2011 at 6:06 UTC
Can you confirm that you are able to ping your-domain.co from your SW machine successfully?
C:> ping your-domain.co
Don`t use ping www.your-domain.co!
Oct 13, 2011 at 6:23 UTC
Keep IT Simple Technology Group is an IT service provider.
Ping - Check :)
Oct 13, 2011 at 7:36 UTC
I can remeber to the BETA phase where I was not able to add any .de domains. I reported this and they fixed it.
Maybe it`s a similar bug? I suggest to contact the support team.
Oct 13, 2011 at 9:45 UTC
Niagara Technology Group (NTG) is an IT service provider.
We are a .co as well.
Oct 13, 2011 at 10:01 UTC
Yasaf, maybe SAM could add your domain to check if it works from outside?
Of course, only if he`s willing to do that & you trust him ;-)
Oct 13, 2011 at 10:13 UTC
Keep IT Simple Technology Group is an IT service provider.
I've sent email to support, but SAM can you look at - xlr8.co ?
Oct 13, 2011 at 3:20 UTC
Thanks for letting us know - we're working on this problem.
Could you guys send us details of which domains you are having trouble with? Posting domains here, PM'ing me, or emailing support are all acceptable - its up to you!
Oct 13, 2011 at 3:22 UTC
Also, as of now it looks like your domain will fail to add properly if this command returns nothing:
whois <domain> whois.internic.net
If you want to test the whois locally keep in mind Windows doesn't include whois by default (that doesn't have anything to do with the problem, though).
Oct 14, 2011 at 1:21 UTC
Could you implement Uwhois.com?
"...For Whois information about country-code (two-letter) top-level domains, try Uwhois.com."
Oct 14, 2011 at 1:25 UTC
Forget it. The domain Yasaf is using is not resolved by uwhois.com too. :-(
But who.is does resolve it ;-) http:/
Oct 14, 2011 at 11:13 UTC
My knowledge on the hierarchy there is limited - but I think the Internet is split into regions, with each region having its own whois authority.
So far most of the domains whois.internic.net fails to resolve can be successfully looked-up by whois.iana.org.
I wonder how sites like who.is and uwhois.com do their lookups?
This discussion has been inactive for over a year.
You may get a better answer to your question by starting a new discussion.


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The TinyWebGallery is a free php based gallery that is very easy to install, extremely user friendly, does not need a database (uses xml files) but still has all the features you should expect and much more. Besides the features you find in most other galleries TWG has e.g. - DHTML navigation with sliding thumbnails - xml based comments/captions/view counter/Top X/Rating with security image... - Keyboard navigation (arrow keys) - TWG Admin with file manager, color picker ... - embedded video and mp3 support - TWG Flash Uploader - 3 slideshow types - Protected galleries - Text and image watermarks - Fullscreen mode - Remote picture support - Low bandwith mode - Tags - Search, directory style sheets and lots of small things that makes this gallery unique right now. Check out the demo or the list of all features. Maybe TinyWebGallery is the gallery you where looking for so long.Visit publisher site: TinyWebGallery
Listing Details
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- 1.8.3
- Filed in:
Scripts / PHP / Scripts & Programs / Image Galleries
- Submitted on:
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- Jan 30, 2012
- Publisher:
- Michael Dempfle Other listings by this publisher
License & Pricing Information
- License Type:
- Freeware
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User ReviewsAdd/Edit Your Review
Displaying 1-5 out of 5 reviews
I like this script because it allows me to easily edit my webpage. It also let me upload images.
what up how we can see?If there is any problem with this item you will have 30 days to return it and claim a refund. Refund can only be arranged if there is a problem. CDs must be returned prior to refund being issued. We will try our best to resolve any problem ASAP.
For file manage function, it run too bad. In my oponion, its just suitable for gallery, not for file management !
I have this amazing photo gallery on my Homepage. I havent seen anything better then TWG ever, the instructions are very good, and the best is - its easy to make the gallery for ur wish, it has everything u need, it cant fail. And also the Author is soo nice, he helps in everything ;).
After been searching for hours to find a easy to use gallery which also looks great i found TinyWebGallery. This was perfect for my website. Now i don't have to make my own thumbnails anymore, and i can select passwords for different folders. I can even with a click on my mouse send a notification to all the registred person when i upload new pictures. Beside that the gallery is perfect for me, TWG gives greate suport too. Additional to what i wrote it has much more exstras. Thanks to TWG
Hi, It's a gallery - not a file management tool. The file management is simply a nice addon for users that cannot handle or don't have FTP.


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Today, I posted this on Instagram.
I am trying to be kind with myself and love who I am in the moment.
I am 43.
There are thousands, if not tens of thousands or even more, women of that age who look far better than me. Can I get better?
I have, and I will again.
However, I am okay with where I am at the moment.
I yo-yo with motivation and discipline...and food. It's life, but I keep on trying.
A little progress is still progress.
I will never be perfect, and I have to stop getting upset with myself when I screw up.
I'm telling the negative talk in my head to fuck off more, and it's making me happier.
And this is probably meant to be a spoof, but eff it doesn't make me feel better and smile every single time that I listen to it.


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Reinhardt Guide: Strategy & Gameplay "Crusader online!"
Table of Contents
- 1. Strengths
- 2. Weaknesses
- +3. Strategy
- 4. ChangeLog
This guide takes an in-depth look at how to play Reinhardt in Overwatch. We look at the strengths and weaknesses of the hero, and we go over mechanics, recommended strategies, and things to beware of.
The guide has been written based on our extensive experience playing the game since before the Closed Beta began, and it relies on our decades-long FPS experience. That said, our aim is to keep the guide relatively brief and easy to understand, making it accessible to veterans and new players alike.
If you have any comment on the guide's content or structure, please let us know in the comments! :)
Stamp of Approval
This guide has been reviewed and approved by michr, formerly one of the best Day of Defeat players in Europe, who now plays Overwatch for OWKings. He also writes for Gosu Gamers.
1. Strengths
- Can reliably protect his team from high amounts of damage
- Deals extremely high melee damage
- Very good at initiating fights
- Earthshatter (ultimate) has great team-wiping potential
- Viable on both Attack and Defense
2. Weaknesses
- Low mobility
- Very low damage outside of melee range
- Cannot perform any actions while protecting his team with Barrier Field
- Needs his teammates for protection and support
3. Strategy
In this section, we will briefly go over the main strategies you should employ as Reinhardt. We will begin with an Overview, and then we will go in depth more about each ability that Reinhardt has.
3.1. Overview
Reinhardt is perhaps the most iconic tank in Overwatch. His most recognisable state is protecting his team with his massive Barrier Field. In addition to his Barrier Field, Reinhardt has very high melee range damage (and his melee range is greater than that of other heroes), while his Charge gives him the potential to break up an enemy team and get a nearly-guaranteed kill.
Reinhardt's Earthshatter ultimate is in the category of ultimates that are a nice perk on top of an already-powerful hero. Making frequent use of it is not required; instead, we will advise you to save it for opportune moments.
Despite this high damage and killing potential, Reinhardt should spend most of the game trying to protect his team from damage, since he excels at this. The protection that Reinhardt's shield offers gives his team a lot of momentum (provided that they carefully take cover behind the shield), allowing them to progress very quickly.
Reinhardt has low mobility, and he is vulnerable to heroes that can stay out of his range; this means that he should not wander off on his own. He does best when he is together with his team.
3.2. Abilities
3.2.1. Rocket Hammer
Devastating melee weapon.
The Rocket Hammer is Reinhardt's only way of dealing damage without a cooldown. It is a melee only weapon that Reinhardt can swing freely. It deals 75 damage to all enemies in a wide arc in front of Reinhardt and knocks them back slightly. Reinhardt has no other melee attacks, making him the only hero in the game not to have an attack bound to V by default.
It is important to note that Reinhardt can animation cancel his attacks using Right Mouse Button during his swing animation. Doing so will instantly stop the attack, allowing Reinhardt to then attack again sooner than he would have been able to do if he had let the whole swing animation finish. The drawback to this is that the cancelled swing will only damage those enemies that had been hit before the animation was canceled (possibly reducing or even removing the AoE component of the swing, depending how many enemies had been hit when it was canceled). This technique is especially useful for increasing Reinhardt's DPS against immobile or very large targets (such as other tanks) who are close to him.
The very high damage of Rocket Hammer, coupled with its relative ease of use make Reinhardt a very dangerous hero in melee range. As such, if you are engaged by other heroes, hitting them with your hammer gives you a solid chance of killing them or forcing them to run away. We advise this course of action any time you run into enemies in confined spaces, unless you are keeping your shield up to protect teammates that are with you (who can then do the killing themselves).
That said, there are a few fights from which even Reinhardt should run away. McCree and Reaper can both kill you in melee range. McCree's Flashbang, if you do not block it with your shield, almost guarantees your death. Even without Flashbang, however, McCree is capable of extreme burst damage. Reaper's shotguns will also make quick work of your large model. In short, against these two heroes in particular you should avoid confrontation and look to retreat.
A more advanced technique is to have a Lúcio use Crossfade (Speed Boost) to increase Reinhardt's movement speed so that enemies cannot run away from his Rocket Hammer swings, thus almost ensuring that they will die.
3.2.2. Barrier Field
Hold to deploy a frontal energy barrier.
Barrier Field is a large shield that is activated while you hold down your Right Mouse Button. It absorbs up to 2000 damage (from most sources, as we will see below), most notably blocking enemy fire.
2 seconds after the shield is no longer active, it will begin regenerating 225 points per second. If the shield is destroyed (due to absorbing its maximum damage), it cannot be activated again for 5 seconds (and it must still recharge based on the 225/second rate).
Before we discuss recommended usage of Barrier Field, we must look at some notable things that it does and does not block.
Barrier Field blocks:
- all pistol, rifle, and rocket projectiles;
- damage from Symmetra's Sentry Turrets, and Junkrat's Rip-Tire (if the tire explodes in front of the barrier);
- damage from Zarya's weapon;
- Roadhog's Chain Hook and Reinhardt's Earthshatter.
Barrier Field does NOT block:
- melee attacks;
- channeled weapons (Winston's and Symmetra's);
- Symmetra's Photon Projector orbs and Reinhardt's Fire Strike;
- AoE effects (Hanzo's Dragonstrike, Mei's Blizzard, etc.);
- player models (including Junkrat's Rip Tire).
To understand how to use Barrier Field, you must understand its strengths and weaknesses. It is most useful when you have teammates around you, and when they are taking enemy fire. Your entire game plan for Barrier Field should be ensuring that it is charged up for these moments.
If there are no enemies around, having your barrier active serves no purpose and simply slows you down. If there are no teammates around to take advantage of your barrier, then the enemies will simply shoot at it until it is depleted. This is a problem because the barrier will then not be available for some time, and you might need it to protect teammates who join you during this time.
The only reason you might want to use Barrier Field when you are alone is to keep yourself safe from ranged enemies (while you are perhaps pushing a Payload by yourself against an enemy Widowmaker or Pharah), or to cover your retreat.
So, your ideal way of playing is being on or near the map's objective, having your teammates behind you, and having your Barrier Field active and protecting them.
While Barrier Field is active, your positioning is extremely important, as this directly affects how the barrier is positioned and what areas it is protecting. You will want to rotate around so that you protect yourself and as much of your team as possible from the most dangerous of opponents.
Particularly, Barrier Field is great at stopping the damage of such powerful enemy abilities as Pharah's Barrage, Reaper's Death Blossom, D.Va's Self-Destruct, or Soldier: 76's Tactical Visor. Whenever these heroes are in the game and alive, be prepared to use your barrier against them.
Naturally, a great part of your barrier being useful comes from how well your teammates utilise it. Less experienced players will not always take advantage of it, instead straying off to the side, or even running out in front of it. Unfortunately, given your low movement speed while the barrier is active, there is not much you can do to protect these players. Instead, we recommend that you communicate with your team (ideally by voice) to remind them to take cover behind the safety of your barrier.
If your barrier is broken by having taken its maximum amount of damage, you and your team are very vulnerable. You should take cover and let your barrier regenerate, but more than this, you should do your best to avoid the situation in the first place. This means you must be very careful when using your barrier, and do not hesitate to deactivate it when you feel it is simply taking damage while not providing anything in return (such as if a Torbjörn turret is damaging it while it is not protecting anyone except you).
3.2.3. Charge
- Cooldown: 10 seconds
Charge forward and smash an enemy against a wall.
Charge causes Reinhardt to charge forward in a straight line until he hits an obstacle or until the maximum charge distance is reached (this is very long, so this hardly ever happens).
The first enemy that Reinhardt comes in contact with is picked up and taken along for the remainder of the charge. This deals 50 damage to that hero, and if Reinhardt then hits an obstacle, this further deals 300 damage to that hero. Any other heroes that Reinhardt comes in contact with after the first target are knocked back and take 50 damage.
Reinhardt himself does not take any damage from hitting obstacles while charging, but he also cannot cancel the charge or perform any other actions while charging, except to very slightly alter the charge trajectory. Lastly, if two enemy charging Reinhardts collide with each other, both of them will be stunned and knocked down. This happens to be a good way to counter an enemy Reinhardt that is Charging into your team.
Generally, when faced with a choice between keeping up your Barrier Field and using Charge, you should use your Barrier Field. This is especially true when your team is located behind your Barrier Field; the damage you expose them to while Charging is probably not worth the damage you do with your Charge. That said, Charge has great offensive potential, as any non-tank that you manage to pin with it will die as a result, and even tanks will take great amounts of damage (on which you can then follow up with your Rocket Hammer).
If your Barrier Field is depleted, or if there is no one to protect (either because you are alone, or because your teammates are spread out), then it is perfectly viable to Charge the enemy, although you must also decide whether it is better to Charge or to use your melee attacks.
In general, using your Rocket Hammer during a fight is better than using Charge, due to its superior damage output. The only exception is when your Charge can take out a particularly important enemy hero, such as a tank or support (killing a Mercy or Lúcio is extremely valuable). Even in these cases, only Charge when the enemy damage dealers are engaged in a fight with your own team, as otherwise you will be an easy target.
When using Charge, there are two dangers to be mindful of.
- You cannot stop Charge if it becomes a bad idea; this means you risk charging into more enemies than you had wanted, or charging off the map to your death.
- Your speed while charging is not very high, meaning that alert enemies will be able to avoid it, rendering it useless.
One especially important use of Charge is to use it against an enemy Reinhardt who has his Barrier Field active. Reinhardt will Charge directly through the shield (since it does not block players), taking out the enemy Reinhardt and his shield. This is an excellent initiation move.
3.2.4. Fire Strike
- Cooldown: 6 seconds
Launch a fiery projectile.
Fire Strike is Reinhardt's only means of dealing damage outside the range of his Rocket Hammer. Fire Strike deals 100 damage to every enemy in its path (going through enemies and shields), the only other ability to work this way being Symmetra's Photon Projector orbs. Keep in mind that Fire Strike does not go through either of Zarya's shields.
Fire Strike is a great way of charging up your ultimate, unless you are taking part in a proper fight (when its damage component is also very important). In fact, outside of a fight, dealing damage with Fire Strike should only be done it if it also charges your ultimate; otherwise (if your Earthshatter is available), Fire Strike will simply result in damage that the enemy healers have a chance to heal up, granting them ultimate charge in return. Keep in mind that using Fire Strike deactivates your Barrier Field for a few seconds, which can mean that you and your team will take a lot of damage in that time.
Another thing to consider is that Fire Strike has travel time, and while it is quite fast, it is still possible for your enemies to avoid it.
3.2.5. Earthshatter
- Ultimate
Knock down all enemies in front of you.
Earthshatter is a frontal cone-shaped AoE ability that damages all affected enemies for a low amount (50 damage) and stuns them for 2.5 seconds.
As an AoE stun of such great length, Earthshatter is a tremendously powerful ability. The ideal usage is, of course, against a group of 5 or 6 stacked enemies, but this requires set-up and coordination with your team to perform. The other team will be very wary of you using this ability in the first place, so any time you are seen running up to the other team, they will disperse to avoid it. This is not a bad thing, however, since splitting up the enemies to make them easier to pick off is advantageous to your team. Having a Lúcio use Amp It Up/ Crossfade (Speed Boost) to help you get close to your enemies quickly and surprise them is a good idea.
As tempting as getting a 5 or 6-man Earthshatter is (and if you see an opportunity for it, by all means take it), we feel that Earthshatter is better used in a more modest but reliable fashion. Even using it to stun 2 enemies can be very powerful, and it is much easier to achieve. Moreover, you can even use it against a single opponent, if it means you will get the kill on them, or especially avoid dying yourself (such as if you run into McCree).
After using Earthshatter, you should follow up with a guaranteed hit of Fire Strike against the stationary targets, after which time you should keep hitting them with your Rocket Hammer. This will result in the most damage output (which will also charge up your next Earthshatter), and it is superior to using Charge to follow up on Earthshatter. This last technique should only be employed if you want to Charge an enemy hero that you know has their ultimate ready and whom you want to kill at all costs (such as Mercy and her Resurrect).
Finally, note that Earthshatter has a short casting time of 0.5 seconds, so take that into account when planning its usage.
4. ChangeLog+ show all entries - show only 10 entries
- 21 May 2016: Updated the guide following review.
- Added Strength that Reinhardt is a good initiator.
- Added Weakness that Reinhardt relies on help from teammates.
- Added information about Rocket Hammer animation canceling.
- Improved Charge section with better recommendations for when to use it, as well as mentioning what happens when two enemy Reinhardts charge one another.
- Changed Fire Strike recommendations to only using it when it will charge your ultimate or when its damage is efficient (such as during a proper fight).
- Revamped Earthshatter recommendations.
- 04 May 2016: Guide added.
- Overwatch Doomfist
- Overwatch Orisa
- Overwatch Animated Short - The Last Bastion
- Overwatch Reaper
- Overwatch Payload
- Dance with me baby
- Sorry Sombra
- Overwatch D.Va


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Located in Palu, Swiss-Belhotel Silae Palu is by the ocean and convenient to Palu Bridge and Baiturrahman Grand Mosque. This 4-star hotel is within the vicinity of Point Break-Tatura Mall.
Make yourself at home in one of the 126 air-conditioned rooms featuring refrigerators and minibars. Satellite television is provided for your entertainment. Bathrooms have complimentary toiletries and hair dryers. Conveniences include safes and coffee/tea makers.
Be sure to enjoy recreational amenities including an outdoor pool and a fitness center. This hotel also features complimentary wireless Internet access, concierge services, and wedding services.
Enjoy a meal at one of the hotel's dining establishments, which include 8 restaurants and a coffee shop/café. From your room, you can also access 24-hour room service. Quench your thirst with your favorite drink at a bar/lounge.
Business, Other Amenities
Featured amenities include a business center, dry cleaning/laundry services, and a safe deposit box at the front desk.


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Rocks and Landform Research Project
Metamorphic Rocks
A metamorphic rock is a result of a transformation of a pre-existing rock. The original rock is subjected to very high heat and pressure, which cause obvious physical and chemical changes.
- Schist is a coarse-grained metamorphic rock that consists of layers of different minerals and can be split into thin irregular plates
- Hornfels is a dark, fine-grained metamorphic rock.
- Slate is a fine-grained gray, green, or bluish metamorphic rock easily split into smooth, flat pieces.
- Soapstone is a soft rock consisting largely of talc.
- Marble is a hard metamorphic form of limestone, typically white with mottlings or streaks of color, that is capable of taking a polish and is used in sculpture and architecture.
Igneous rocks
- Andesite is a dark, fine-grained, brown or grayish volcanic rock that is intermediate in composition between rhyolite and basalt.
- Basalt is a dark, fine-grained volcanic rock that sometimes displays a columnar structure. It is typically composed largely of plagioclase with pyroxene and olivine.
- Diorite is a speckled, coarse-grained igneous rock.
- Scoria is a basalt lava rock that has a bubbly texture.
- Granite is a very hard igneous rock and is often used as a building stone.
An igneous rock is formed through the cooling and solidification of magma or lava.
Sedimentary rocks
- Limestone is a hard sedimentary rock, composed mainly of calcium carbonate or dolomite, used as building material and in the making of cement.
- Coal is a combustible black or brownish-black sedimentary rock usually occurring in rock strata in layers or veins called coal beds or coal seams.
- Rock Salt is a common salt occurring naturally as a mineral; halite.
- Sand Stone rock is a sedimentary rock consisting of sand or quartz grains cemented together, typically red, yellow, or brown in color.
- Flint Rock isa hard stone, a form of silica resembling chalcedony but more opaque, less pure, and less lustrous.
A sedimentary rocks are types of rocks that are formed by the deposition of material at the Earth's surface and within bodies of water.


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Don't Blink - Kenny Chesney (w lyrics).flv MP3
Don't Blink - Kenny Chesney Lyrics MP3
Lyrics To The Song Don't Blink By Kenny Chesney. I do not own any of the songs used. Disclaimer.
Kenny Chesney - Don't Blink MP3
Kenny Chesney's official music video for 'Don't Blink'. Click to listen to Kenny Chesney on Spotify: http://smarturl.it/KChSpotify?IQid=KChDB As featured on Just ...
Don't Blink
Kenny ChesneyI turned on the evenin' news Saw an old man being interviewed Turnin' a hundred and two today They asked him what's the secret to life He looked up from his ol' pipe Laughed and said, 'All I can say is' Don't blink Just like that You're six years old and you take a nap And you wake up and you're [...]
Kenny Chesney- Don't Blink lyrics MP3
lyrics for kenny's song don't blink. i dont own the song or lyrics.
Relient K - Don't Blink - Lyric Video MP3
Pre-order now at iTunes http://bit.ly/rkclpreit Lyric video directed by Nathan Henry. Music produced by Paul Moak and mixed by J.R. McNeely. Written by Matthew ...
Kenny Chesney Don't Blink Lyrics MP3
All rights reserved. :)
Chameleon Circuit - Blink *Lyrics* MP3
Kenny Chesney Don't Blink With Lyrics On Screen HQ MP3
I turned on the evening news Saw an old man being interviewed Turning a hundred and two today Asked him what's the secret to life He looked up from his old ...
Don't Blink - Relient K (with lyrics) MP3
Track 1 *** I OWN NOTHING *** lyrics: Don't know where to go from here My thoughts are tangled, twisted fears Been waitin' a while now on the dawn Seems ...
Kenny Chesney -Don't Blink Lyrics MP3
this is Don't Blink by Kenny Chesney comment,like,subscribe,and most of all enjoy. Here are the lyrics: I turned on the evening news Saw an old man being ...
Relient K: Don't Blink (lyrics) MP3
Relient K: Don't Blink (lyrics) Facebook: https://www.facebook.com/relientk Twitter: https://twitter.com/relientK Tumblr: (FanMade) http://fyeahrelientk.tumblr.com/ ...
Blink 182 Don't Lyrics MP3
Last song on blinks 3rd demo Buddha... ill probably do there 2nd demo (untitled) after this.
Don't Tell Me It's Over - Blink 182 (Lyrics) MP3
CB5105 02 05 Chesney, Kenny Don't Blink [Karaoke] MP3
Blink 182 - Don't Leave Me lyrics MP3
The second track of Enema of the State Sorry if the quality sucks.
Blink 182 - Don't Leave Me MP3
Blink 182 don't leave me with lyrics on screen. All rights goes to them for lyrics ans music.
Don't Blink Kenny Chesney lyrics MP3
i do not own this song or anything but i made lyrics for it, thank you for watchin plase subscribe and leave comments.
Kenny Chesney, Don't Blink (Lyrics) - Everyday life in Athens, Greece MP3
Don't blink Greece, keep on fighting for Democracy, Transparency, Growth, Human Rights & Human Develpoment, in the Country, in EU and in the World.
Don't Leave Me by Blink 182 w/lyrics MP3
All rights go to MCA Records© and BLink 182© and anyone involved with this album and song! I DO NOT OWN THIS! Artist:Blink 182 Song:Don't Leave Me ...
Blink-182 Hold On / Don't tell me that it's over Lyrics MP3


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Product Spotlight
Featured Research
Quick Stats
You are here
Healthy Partnership Between Kellogg and Retailers Goes Nationwide
BATTLE CREEK, Mich. -- Leading CPG manufacturer Kellogg Co. here is in the midst of rolling out its Healthy Beginnings program to more than 70 grocery retailers nationwide, to help consumers better understand how to improve their health.
BATTLE CREEK, Mich. -- Leading CPG manufacturer Kellogg Co. here is in the midst of rolling out its Healthy Beginnings program to more than 70 grocery retailers nationwide, to help consumers better understand how to improve their health.
Retailers ranging from major chains such as Kroger and Albertsons, to smaller companies such as Ukrop's Super Markets and Rouses Markets, have signed on to participate. The first leg of the nationwide rollout began in February and will continue through May.
Kellogg's Healthy Beginnings was successfully pilot-tested in 2005, and has been substantially expanded to provide consumers across the country with educational information and free health screenings and assessments focused on heart health, digestive health, and weight management.
At participating stores, shoppers can:
-- Participate in a free health screening -- a $25 value that includes a cholesterol test, blood pressure check, dietary fiber intake assessment, heart health assessment, and BMI screening;
-- Receive a free booklet containing helpful information and easy-to-use health assessment tools;
-- Collect valuable coupons and product samples of Kellogg's Healthy Beginnings brands; and
-- Receive a complimentary "food ruler" with nutrition information to help consumers easily apply the new FDA Food Pyramid guidelines.
"We're pioneering this program on behalf of Kellogg's to help retailers cross-promote grocery and pharmacy," explained Daniel Moore, spokesman at Collins Youngclaus Health & Wellness Marketing, the firm that is managing the Healthy Beginnings program on behalf of Kellogg. "We believe that a better understanding of nutrition and education, along with exercise, go hand in hand in promoting healthy lives and management and prevention of disease," he told Progressive Grocer.
The Kellogg's Healthy Beginnings brands include Kellogg's Smart Start Healthy Heart, Frosted Mini-Wheats, Special K, and All-Bran.
The Kellogg's Healthy Beginnings program will be offered by major food retailers nationwide through May, with a second wave of events scheduled to take place in the fall.


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Had trouble finding someplace to stay in Farmington, NM and stumbled on this place. Huge room, very comfortable beds, large vanity, refrigerator and microwave. Bathroom included a large tub AND a separate shower! Very well maintained and super quiet in residential part of town. Loved the old style entry and fully tiled bathroom in beautiful colors. Best motel stay I've had for a long time.
- Reservation Options:
- TripAdvisor is proud to partner with Travelocity, Orbitz and Hotwire so you can book your Royal Inn reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
- Also Known As:
- Knights Inn Farmington
- Farmington Knights Inn


text:
Dec. 11, 2012
OREM, Utah - University of Wyoming 149-pound sophomore Brandon Richardson earned his first career Western Wrestling Conference Wrestler of the Week honor after upsetting sixth-ranked Nick Lester of Oklahoma over the weekend. The conference honor was announced Tuesday by the league.
After Oklahoma took a 10-3 lead after three matches on Dec. 7, Richardson gave the Cowboys a spark in the dual versus the Sooners. The Rathdrum, Idaho, native took on the sixth-ranked wrestler in the nation at 149 pounds in OU's Lester and earned the biggest win of his career by upsetting him. Richardson beat Lester for the first time ever in a gritty 4-3 decision on the road. Richardson avenged an 8-1 loss to Lester on Jan. 4, 2012.
The victory gave UW three team points in a close dual, and allowed No. 20 Wyoming to upset 10th-ranked Oklahoma, 25-13.
It was Richardson's ninth win of the year and first versus a ranked wrestler. The conference honor was also his first of the season and the first of his career.
The Western Wrestling Conference, which is in its seventh year of competition, is comprised of six schools including the Air Force Academy, North Dakota State, Northern Colorado, South Dakota State, Utah Valley and Wyoming.
2012-13 WWC Wrestlers of the Week
Nov. 6 - Alfonso Hernandez (Wyoming)
Nov. 13 - Josh Wilson (Utah Valley)
Nov. 20 - Cole VonOhlen (Air Force)
Nov. 27 - Trent Sprenkle (North Dakota State)
Dec. 4 - Steven Monk (North Dakota State)
Dec. 11 - Brandon Richardson (Wyoming)


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|(L-R) 1 swipe - 3 swipes
Wednesday, September 25, 2013
Review: Canmake Clear Cream Cheeks CL01
|the Angels think :
10 comments:
Ooh, I've heard so much about this brand but never tried it. *o* I'm totally loving cream blushes, so thank you very much for the review! <3 *u*ReplyDelete
- icelacelSeptember 25, 2013 at 7:59 PM
racuunnn >,< canmake tp emg kualitasnya bagus sih yaaa :DReplyDelete
thanks for the review ^^
- Erna WijayaSeptember 26, 2013 at 8:46 AM
Cakeppppppppp banget warnanyaaa!ReplyDelete
Olin racuun :(
- SuperRach LoveSeptember 27, 2013 at 8:03 AM
great review :D i lovee the coloursReplyDelete
Please follow my blog 'Heylinni' at:
I will gladly follow you back!!! Us bloggers need to support each other
hihihi cakep kan tapi er :3ReplyDelete
XD iyaaa bagus! lol, you're welcome, selamat membeli XDReplyDelete
you're very welcome, june! should give it a try sometimes ;)ReplyDelete
Hallo :3 Aku baca bio kamu katanya mau ke uni jakarta yah? Mau kemana? Hehe :3 aku juga di jakarta hehe~ReplyDelete
Kamu cute sekali~
hello! iyaa, sepertinya mau kesana deh..70% maybe! mau ke UPH :3 hope we can meet soon~~ReplyDelete
thanksssss! *kiss
- nihonmartApril 20, 2015 at 1:30 PM
Hi dear, mau info aja kalau canmake cream cheek bisa beli online di nihonmartbeauty.comReplyDelete
Mampir-mampir ya^^


text:
Patterns Pacifica 3012; ca. early 1970s; Muu-Muu in two lengths, sleeveless, back zipper.
Links to reviews/blog postsEdit
- Resurrections
- kinseysue on etsy Uncut Sz 12 Bust 34
- One More Cup Of Tea
Add a photo to the gallery by clicking the "modify" button below.
[insert your username, and make sure your preferences allow for people to contact you via e-mail. Do not list your email address here!]


text:
Pitt was photographed with 22 year old American Maxim model, April Florio, in a Santa Monica ice cream store earlier this week
Is Pitt date April Florio? Still there hasn't an answer for that question. But, earlier this week, Pitt was photographed with the 22-year-old American Maxim model in a Santa Monica ice cream store.
Their knowing each other from Pitt Ocean Twelve co-star, George Clooney happened last summer maybe worth for just ice cream treat so far, but who knows what might happen next ???


text:
Product details
A 5 zone 90cm induction hob with 9 power levels and an electronic touch control panel. This hob features both keep warm and pause functions for cooking convenience, plus a double booster per zone for high speed heat up and reduced cooking times. Other features also include an auto safety switch and a child lock for safety.
- Colour: Black
- Material: Glass
- Effects and finish: Semi-gloss
- Features: Electronic touch control, front control, 9 power levels, booster function on 2 boost levels on each zone, keep warm function, melt function, pause/restart function, automatic heat function and easy clean surface, Residual heat indicators, LED display, safety key lock, 99 minute timer, auto safety switch off, overflow detection, overheat detection, automatic pan detection, small object detection and time limit security system.
- Guarantee: 2 year labour 5 year parts
- Dimensions: (H)5.1, (W)87, (D)51.8cm
- Weight: 20kg
- Number of burners: 5
- Power levels: 9.0
- Liquefied petroleum gas (LPG) kit included: No
- Child lock: Yes
- Residual heat indicator: Yes
- Type of controls: Touch
- Wok burner: No
- Dual zones: No
- Power supply: 48amps
- Size of cut out: (W)75, (D)49cm
- Fuel type: Electric
CDA HN9611FR Five Zone Induction Hob 380290
Select product options
CDA HN9611FR Five Zone Induction Hob
Available to order at the service desk in store for home delivery
Home delivery within 5 days
{"calculators": { "calculator": { "pimProductAttr": ["", "", "", ""], "calcType": "" } } }


text:
5. Too Many Distros
4. Drivers
"WHAT THE HELL LINUX, THERE ARE NO GOOD UI'S"This is the bit where Tim shows that he isn't really a Linux user and probably never really has been. The other clue is that during his point about the number of distributions he mentions that he can name a dozen distros but his own personal favourite is "Red Hat".
"Red Hat Linux" isn't really the sort of distribution most people would run from home especially when there are free alternatives such as Fedora or CentOS.
So back to the point. Apparently there aren't any good user interfaces within Linux and it is ugly. The one that Tim has always used is "XWindows".
Now I am going to give Tim the benefit of the doubt and hope that by saying "XWindows" he maybe meant "XFCE" but it is likely he really did mean XWindows which is the graphical server that most window managers and then desktop environments are built on top of.
To answer the point however. There are no good user interfaces in Linux? If you are looking for beauty then take a look at these:
This all goes back to the choice argument. There are so many different desktop environments to choose from that you are bound to find one which you think works for you better than anything else.
The ridiculous thing about this argument is that Windows 8 can never go down as having a better GUI than either Unity, GNOME, KDE, Pantheon, Cinnamon, XFCE, MATE, Enlightenment or even LXDE,
If we are talking about usability then what about the mess that is Microsoft Office. Those ribbon bars are truly horrific.
There seems to be this impression that Microsoft does software well. Has anybody tried using Reporting Services to get a consistent report to Excel? The columns generally end up all over the place. Visual Studio 13 seems to be crashing a lot more now than it used to as well.
2. Software
1. Ease Of UseI can't believe ease of use is the number 1 reason not to use Linux.
I bet if I gave my eldest child who is 13 a Windows DVD and a Linux DVD and asked him to install one on one computer and one on the other he would find it easier to install Linux.
My wife who is not particularly computer literate quite often borrows one of my laptops running Linux and she can navigate her way around without any hassle.
How can anyone level ease of use being a problem for Linux when you now have to compare it against Windows 8 and above?
Is Unity and GNOME any harder than using the tiled Windows 8 interface? Is Cinnamon any harder to use than the Windows 7 interface?
What about software? Is Evolution any more difficult than Microsoft Outlook and can anybody honestly say that it is harder to use LibreOffice than it is Microsoft Office with the dreaded ribbons?
I mentioned earlier that it was easier to set up my printer using Linux than Windows. Using Mint, Bodhi and Ubuntu I simply had to click "Add Printer" and it found my printer and installed the driver. Within Mageia I had to download and install the driver. When I used Windows I had to insert a CD, install the driver and software and then download an update, finally followed by the obligatory reboot.
Summary2000+ people have already watched Tim's video and that is potentially 2000 people that might not use Linux based on invalid arguments.
Hopefully a few more people will read this article and therefore redress the balance somewhat.
Before I go I wanted to mention that Tim has produced his own counter argument called "5 Reasons To Use Linux". The points in that video state that Linux is multikernel, is open source, has support for many different hardware devices such as the Raspberry PI, has lots of distros (which kind of counters against point 5 in the reasons not to use Linux) and finally it is free.
If you have read this article and you are looking for a distribution why not read this guide which highlights the "5 easiest to use modern distros". It is a year old and I plan to update it but might still be good for an indication.
Thanks for reading.


text:
A statement piece designed for the woman on the go. Go instantly from day to night with this dazzling and uber-stylish accessory. Sold in Pairs.
Intricate detailing and diamante gems adorn this exquisite piece to take your look from 'now' to WOW. Sold in Pairs.
No products
No new products at this time
No best sellers at this time


text: 16 photos $891,765 447 acres Trammell Mill Road, Shiloh, GA 31826 - Harris County Annual Income in Growing County GA Harris 447 Lazer Sparks Tract Annual Income in a Growing County Located at the southern base of beautiful Pine Mountain in growing Harris County Georgia just south of quaint and historic Warm Springs, this +-447 acre productive timber property has great topography ranging from flat to rolling with awesome views of Pine Mountain. The headwaters of Lazer Creek is on the east side of the property, and tributaries to Sparks Creek are on the west side. The majority of the property is high site index loblolly pine plantations planted in 2008, 2010, and 2012. +-120 acres of the pine plantations are on old-field sites. The creek bottoms are mature hardwood and pine. The mixture of creek bottoms and ridges of level to rolling terrain g Mike Matre Matre Forestry Consulting, Inc.


text:
McCall's 2269; ©1970; Skirt Set in Two Lengths. Skirts cut in regular or mini length. (A & B) Skirt, with front inverted center and side pleats sewn to button stitched front yoke, has back darts, faced upper edge, center back zipper. (C & D) Skirt, gathered at waistline by elastic in casing, has stitch and button trimmed faced flaps and fabric bow on front. E- Darted skirt, with front inverted pleat and underlay, has fabric carriers, center back zipper. Stitch trimmed regular length skirt has flapped, button trimmed pockets, buckled fabric belt. F- Mini skirt has purchased belt. Skirts are interfaced where necessary.
Links to reviews/blog posts Edit
Roobeedoo post (view A made with Civil Defence buttons)
Sources/Vendors Edit
Gallery Edit
[insert your photos of this pattern made up]
Wishlist Edit
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text:
Choose from a selection of new introductions, exceptional values and special promotions that will add a touch of France to your dining room, kitchen, deck or patio.
Care Instructions: Just use a wet cloth to clean and wipe off the spills! Can be occasionally machine washed in cold or warm water without loosing the coating.Hang dry, iron on the reverse side only using cotton setting. Do not dry clean.Do not use bleach or a detergent with bleach additives. Do not use fabric softener. Note: Any linens containing cotton may shrink if tumble-dried on high temperature setting. We recommend not to use top loading washing machines for any of our linens.
SHOP IN PERSON: visit PARISCOPE, our retail outlet in the beautiful village of Elora, ON offering all the products seen on-line plus more.


text:
Basics of Management Studies (College Level)
Ca Raja Natarajan, Chartered Accountant
- 0.5x
- 1x (Normal)
- 1.25x
- 1.5x
- 2x
Introduction to the Course1:36
What is Managmement12:11
Effectiveness Vs Efficiency3:56
Charecteristics of Management8:49
Objectives of Management5:42
Importance of Management2:58
Nature of Management1:59
Management as an Art6:05
Management as a Science6:48
Levels of Management5:25
Functions of Management10:09
Nature of Co-ordination4:16
About This Class
Welcome to Basics of Management Studies!
Management is a very wider concept which is required in all walks of life and in Organisation for rising to top.
Successful organisation would have achieved success not by chance but only by a Process called Management.
Management is required for all kinds of organisations, whether it be small or large, manufacturing or online or elearning or trust or schools or hospitals, etc.
In this course, you will learn about the Basics of Management covering
a) Introduction to Management;
b) Concept of Management;
c) Characteristics of Management;
d) Objectives of Management;
e) Importance of Management;
f) Nature of Management;
g) Management as an Art and Science;
h) Levels of Management;
i) Functions of Management;
j) Co-ordination and its Nature.
This course is structured in self paced learning style.
Video lectures are used for delivering the course content.
Approach this course with open mind and this course will take you through academic aspects of Basics of Management.
Class Projects 1 See All
Reviews (0)
I am a Chartered Accountant with tonnes of passion for teaching.
I teach Financial Management for Chartered Accountancy and Cost and Management Accountancy students in Ernakulam,India. and I teach 100+ Finance, Accounts, Costing, Banking, Credit Analysis, Statistics, etc. in Skillshare.
I also hold
- Post Graduate Diploma in Business Administration in Finance from Symbiosis, Pune
- Bachelors in Commerce, from Loyola College, Chennai.
I worked in State Bank of India as Assistant Vice President - Credit for a period of four years after which i started my Chartered Accountancy Practice.
During the stint in State Bank of India, I worked on credit proposals of Mid Corporate Units and gained good experience in
a) Financial Analysis
b) Risk Assessment
c) Viability Study
d) Evaluating business models
e) Project Finance
f) Working Capital Management, etc.
I conduct work shops for Entrepreneurs, Chartered Accountancy / Cost and Management Accountancy Students on the topics like
a) Project Finance
b) Credit Risk Assessment
c) Entrepreneurship Development
d) Finance for Non Finance Executives
e) Burning Desire for Entrepreneurship
I love teaching and i want fundamentals of accounting and finance to reach students and so i am here.


text:
What is JotForm?
JotForm is a free online form builder which helps you create online forms without writing a single line of code. No sign-up required.
At JotForm, we want to make sure that you're getting the online form builder help that you need. Our friendly customer support team is available 24/7.
We believe that if one user has a question, there could be more users who may have the same question. This is why many of our support forum threads are public and available to be searched and viewed. If you'd like help immediately, feel free to search for a similar question, or submit your question or concern.
"Form not found" please unban.Asked by rzayevtt on August 22, 2014 at 01:42 AM
Form does not work, there is an error on the link "Form not fund." What to do? Not so long ago, the e-mail came a letter from JotForm firstname.lastname@example.com, in which it was said that I would be banned. Content of the message: Your "Video Review request is rejected by our staff for the reason given below:"
reason for rejection: This is an old video, it does not belong to user. Next time user will be banned
If you feel, there is any error on judgement, please feel free to contact us. If there were errors on the page you submitted, please fix them and
re-submit them later.
have a nice day!
However, I did not send you any video. Maybe it was a mistake.
Since I do not quite understand the English language and use an interpreter, maybe I made a mistake somewhere. Please understand and unban. Thanks in advance.
Translate translator Google, do not judge strictly
Не работает форма, по ссылке выходит ошибка "Form not фонд". Что, делать? Не так давно, на электронную почту пришло письмо от JotForm email@example.com, в котором было сказанно, что я буду забанен. Содержимое письма: Your "Video Review request is rejected by our staff for the reason given below :"
reason for rejection : This is an old video, it does not belong to user. Next time user will be banned
If you feel, there is any error on judgement, please feel free to contact us. If there were errors on the page you submitted, please fix them and
re-submit them later.
have a nice day!
Однако, я не отправлял вам никаких видео. Возможно это ошибка.
Так как я плохо понимаю английский язык и пользуюсь переводчиком, возможно я где то ошибся. Прошу понять и разбанить. Спасибо заранее.
Переводил переводчик Google , не судите строго
JotForm Support
Hello rzayevtt,
Upon checking our records, I found that your account is suspended because you keep sending the old video for "Video Review" request to increase your submission limits.
I am sending your request to my superior to review the suspension.
Thank you!
thanks) i"ll wait b))
JotForm Support Manager
Your account was banned because you sent to us an invalid video in order to get more submission limits
The type of review is : Video Review
A user (email@example.com) submitted a link for review():
" rel="nofollow noopener">https://
The video does not belong to you and is an old video.
You must be aware that we got a specialized team of people that review each request, if someone keep posting the same old video or site, the account must be banned. For now your account is back, but next time we will not reactivate it.
These are the parameters and conditions we use in order to approve any video.The video must be related to JotForm. It must not be a hacking or phishing video. The video must belong to the submitter. Date of the video should be recent
Thank you for your understanding!


text: Election Central is simply exhausted! With only four days to go, EC has yet to order an election night party platter and the liquor cabinet – well that always needs restocking! Our heroine hasn't had so much to do since she reorganized her shoe closet! And while excellently preserved, EC is not as young as the group of kids who mobilized on UC Irvine's campus to get out the vote on Proposition 77. Those youngsters have energy! And speaking of energy we have a look at Prop. 80, the electricity industry re-regulation initiative. Once you're done reveling in that, go to News 12 for the latest poll tracking Gov. Arnold Schwarzenegger's re-election chances. Ouch! Maybe he won't be back! Ciao for now.