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The impact of Quaternary Ice Ages on mammalian evolution.

The Quaternary was a time of extensive evolution among mammals. Most living species arose at this time, and many of them show adaptations to peculiarly Quaternary environments. The latter include continental northern steppe and tundra, and the formation of lakes and offshore islands. Although some species evolved fixed adaptations to specialist habitats, others developed flexible adaptations enabling them to inhabit broad niches and to survive major environmental changes. Adaptation to short-term (migratory and seasonal) habitat change probably played a part in pre-adapting mammal species to the longer-term cyclical changes of the Quaternary. Fossil evidence indicates that environmental changes of the order of thousands of years have been sufficient to produce subspeciation, but speciation has typically required one hundred thousand to a few hundred thousand years, although there are both shorter and longer exceptions. The persistence of taxa in environments imposing strong selective regimes may have been important in forcing major adaptive change. Individual Milankovitch cycles are not necessarily implicated in this process, but nor did they generally inhibit evolutionary change among mammals: many evolutionary divergences built over multiple climatic cycles. Deduction of speciation timing requires input from fossils and modern phenotypic and breeding data, to complement and constrain mitochondrial DNA coalescence dates which appear commonly to overestimate taxic divergence dates and durations of speciation. Migrational and evolutionary responses to climate change are not mutually exclusive but, on the contrary, may be synergistic. Finally, preliminary analysis suggests that faunal turnover, including an important element of speciation, was elevated in the Quaternary compared with the Neogene, at least in some biomes. Macroevolutionary species selection or sorting has apparently resulted in a modern mammalian fauna enriched with fast-reproducing and/or adaptively generalist species.

Adaptation, Biological↗

VEGF-induced HUVEC migration and proliferation are decreased by PDE2 and PDE4 inhibitors.

Migration and proliferation of endothelial cells in response to VEGF play an important role in angiogenesis associated to pathologies such as atherosclerosis, diabetes and tumor development. Elevation of cAMP in endothelial cells has been shown to inhibit growth factor-induced proliferation. Our hypothesis was that inactivation of cAMP-specific phosphodiesterases (PDEs) would inhibit angiogenesis. The purpose of this study was to evaluate the effect of PDE inhibitors on in vitro and in vivo angiogenesis, using human umbilical vein endothelial cell (HUVEC) and chick chorioallantoic membrane (CAM) models respectively. Here, we report that: 1) PDE2, PDE3, PDE4 and PDE5 are expressed in HUVEC; 2) EHNA (20 microM), PDE2 selective inhibitor, and RP73401 (10 microM), PDE4 selective inhibitor, are able to increase the intracellular cAMP level in HUVEC; 3) EHNA and RP73401 are able to inhibit proliferation, cell cycle progression and migration of HUVEC stimulated by VEGF; 4) these in vitro effects can be mimic by treating HUVEC with the cAMP analogue, 8-Br-cAMP (600 microM); 5) only the association of EHNA and RP73401 inhibits in vivo angiogenesis, indicating that both migration and proliferation must be inhibited. These data strongly suggest that PDE2 and PDE4 represent new potential therapeutic targets in pathological angiogenesis.

3',5'-Cyclic-AMP Phosphodiesterases↗

Recombinant Ascaris 16-Kilodalton protein-induced protection against Ascaris suum larval migration after intranasal vaccination in pigs.

We recently cloned a protective antigen that is commonly expressed in Ascaris species that infect humans and pigs. We evaluated the vaccinal effects of this 16-kilodalton protein (As16) in pigs, the natural host of Ascaris suum, by intranasal immunization. Pigs that received Escherichia coli-expressed recombinant As16 (rAs16) coupled with cholera toxin (CT) had significantly elevated levels of rAs16-specific serum immunoglobulin G (IgG) and mucosal-associated IgA antibodies. rAs16 evoked a type II immune response characterized by elevated levels of interleukin-4 and -10 in the culture supernatants of peripheral blood mononuclear cells of the vaccinated pigs. An increased level of rAs16-specific serum IgG1 was also detected. Pigs vaccinated with rAs16-CT were protected from migration of A. suum larvae through the lungs, as indicated by a 58% reduction in the recovery of lung-stage third-stage larvae (L3), compared with that in nonvaccinated controls. Purified immunoglobulin from rAs16-CT-vaccinated pigs inhibited survival of infective L3 and interrupted the molting of lung-stage L3. Immunofluorescence studies revealed that this immunoglobulin bound to the digestive tracts of L3, suggesting that it might inactivate functions of the gut tissues of Ascaris species. We conclude that rAs16 is a promising mucosal vaccine candidate for pig and human ascariasis.

Adjuvants, Immunologic↗

Association of elevated levels of hyaluronidase, a matrix-degrading enzyme, with prostate cancer progression.

Components of extracellular matrix and the matrix-degrading enzymes are some of the key regulators of tumor metastasis and angiogenesis. Hyaluronic acid (HA), a matrix glycosaminoglycan, is known to promote tumor cell adhesion and migration, and its small fragments are angiogenic. We have compared levels of hyaluronidase, an enzyme that degrades HA, in normal adult prostate (NAP), benign prostate hyperplasia (BPH) and prostate cancer (CaP) tissues and in conditioned media from epithelial explant cultures, using a sensitive substrate(HA)-gel assay and an ELISA-like assay. The results show a significant elevation (3-10-fold) of this enzyme in tumor tissues compared to that in NAP and BPH tissues. Furthermore, the hyaluronidase levels in tissues correlates well with the tumor grade. For example, the concentrations in a locally extended CaP lesion (191 +/- 7.9 milliunits/mg protein), and low-grade tumors (9.4 +/- 1.4 milliunits/mg protein), respectively. Among the primary epithelial explant cultures, CaP cultures secrete at least 10-fold higher levels of hyaluronidase that those secreted by NAP and BPH cultures. Furthermore, among the established prostate cancer cell lines, DU145, an androgen-unresponsive metastatic line, secretes 4-fold more hyaluronidase than LNCaP, an androgen-responsive and relatively well-differentiated cell line. We also show that prostatic hyaluronidase has an apparent M(r) approximate to 55,000, a pH optimum of 4.6, and is distinct from other well-characterized hyaluronidases.

Adult↗

Endothelial microparticles (EMP) bind and activate monocytes: elevated EMP-monocyte conjugates in multiple sclerosis.

Elevated plasma endothelial microparticles (EMP) have been documented in MS during exacerbation. However, the role of EMP in pathogenesis of MS remains unclear. We investigated the formation of EMP-monocyte conjugates (EMP-MoC) and their potential role in transendothelial migration of inflammatory cells in MS. EMP-MoC were assayed in 30 MS patients in exacerbation, 20 in remission and in 35 controls. EMP-leukocyte conjugation was investigated flowcytometrically by employing alpha-CD54 or alpha-CD62E for EMP, and alpha-CD45 for leukocytes. EMP-MoC were characterized by identifying adhesion molecules involved and their effect on monocyte function. In vivo (clinical): EMP-MoC were markedly elevated in exacerbation vs. remission and controls, correlating with presence of GD+ MRI lesions. Free CD54+ EMP were not elevated but free CD62E+ EMP were. In vitro: EMP bound preferentially to monocytes, less to neutrophils, but little to lymphocytes. Bound EMP activated monocytes: CD11b expression increased 50% and migration through cerebral endothelial cell layer increased 2.6-fold. Blockade of CD54 reduced binding by 80%. Most CD54+ EMP bound to monocytes, leaving little free EMP, while CD62+ EMP were found both free and bound. These results demonstrated that phenotypic subsets of EMP interacted differently with monocytes. Based on our observations, EMP may enhance inflammation and increase transendothelial migration of monocytes in MS by binding to and activating monocytes through CD54. EMP-MoC were markedly increased in MS patients in exacerbation compared to remission and may serve as a sensitive marker of MS disease activity.

Adult↗

Pharmacological profile of rat pleurisy induced by Bothrops jararaca venom.

Bothrops jararaca venom (30 micrograms/site) triggered a marked inflammatory reaction in the pleural cavity that was long-lasting and reproducible. In the first 1 h after pleurisy induction, a significant decrease of total and differential cell count was observed in comparison with control values, despite the gradual enhancement of fluid leakage. A significant increase of cell migration was observed after 3 h of pleurisy induction, due to mononuclear and neutrophil cells that peaked 8 h later and this was followed by a gradual decrease, remaining elevated up to 24 h. In parallel with cell influx, a significant increase of fluid leakage that peaked between 1 and 8 h was observed, being completely abolished after 12 h following pleurisy induction. This inflammatory response was not associated in parallel with significant changes in circulating leucocyte cells and it was significantly inhibited by compound 48/80, cyproheptadine, pyrilamine, dexamethasone, indomethacin and phenidone. Preheating of the venom (100 degrees C) caused a significant decrease of both leakage of fluid and cell migration in the pleural cavity 8 h after pleurisy induction. Previous exposure to the venom (30 micrograms/site, 5 days before) produced a significant decrease of both cell migration and fluid leakage 4 h after triggering pleurisy with the same dose of the venom. Otherwise, prior daily treatment with the venom (10 micrograms/site, 4 days) resulted only in marked fluid leakage reduction 1 h after treating the animals with BJV (30 micrograms/site). These results show that the venom elicits pro-inflammatory effects in the rat pleural cavity which involve the participation of several mediators, including histamine, 5-hydroxytryptamine and products of arachidonic pathways.

Animals↗

Aberrant N-glycosylation of beta1 integrin causes reduced alpha5beta1 integrin clustering and stimulates cell migration.

Altered expression of cell surface N-linked oligosaccharides is associatedwith the oncogenic transformation of many types of animal cells. One of the most common forms of glycosylation in transformed cells and human tumors is the highly elevated beta1,6 branching of N-linked oligosaccharides caused by increased transcription of N-acetylglucosaminyltransferase V (GnT-V). To characterize the effects of increased beta1,6 branching on cell-matrix adhesion-mediated phenotypes, human fibrosarcoma HT1080 cells were transfected with retroviral systems encoding GnT-V that used both noninducible and tetracycline-inducible promoters. Increased GnT-V expression resulted in a >25% inhibition of cell attachment to and a >50% inhibition of cell spreading on fibronectin. Both cell adhesion and spreading were suppressed by function-blocking antibodies specific for the alpha(5) and beta(1) integrin subunits of the fibronectin receptor. Cell migration toward fibronectin and invasion through Matrigel were both substantially stimulated in cells with induced expression of GnT-V. Induction of GnT-V had no effect on the level of cell surface expression of alpha(5) and beta(1) integrin subunits but did result in a more diffuse staining of the alpha(5) and beta(1) integrin subunits on the cell surface, suggesting that inhibition of integrin clustering may be causing these cells to be less adhesive and more motile. Surprisingly, there was no detectable expression of N-linked beta1,6 branching on the alpha(5) subunit purified from HT1080 cells before and after induction of GnT-V; by contrast, however, the beta(1) subunit showed a basal level of beta1,6 branching that was greatly increased after induction of GnT-V. These results suggest that changes in N-linked beta1,6 branching that occur during oncogenesis alter cell-matrix adhesion and migration by modulating integrin clustering and subsequent signal transduction pathways. These effects most likely result from altered N-linked carbohydrate expression on the beta(1) integrin subunit.

Actins↗

Mechanism of action of the migration stimulating factor produced by fetal and cancer patient fibroblasts: effect on hyaluronic and synthesis.

We have previously demonstrated that confluent fetal fibroblasts migrate into three-dimensional collagen gels to a significantly greater extent than their normal adult counterparts. Recent studies have revealed that this behavioral difference results from the secretion by fetal fibroblasts of a soluble migration-stimulating factor (MSF) which acts on these cells in an autocrine fashion. Adult fibroblasts do not produce MSF but remain responsive to it. Skin fibroblasts from cancer patients resemble fetal fibroblasts (rather than normal adult cells) with respect to their migratory behavior on collagen gels and continued production of MSF. This communication is concerned with elucidating the biochemical basis of MSF activity. Data are presented indicating that a) hyaluronic acid is required for the elevated migratory activity displayed by confluent fetal and breast cancer patient skin fibroblast; b) adult fibroblasts exhibit a bell-shaped dose-response to MSF, with maximal stimulation of migration observed at a concentration of 10 ng/ml; c) the migratory activity of adult fibroblasts pre-incubated with MSF remains high in the absence of additional factor: and d) MSF affects both the quantity and size class distribution of hyaluronic acid synthesized by adult fibroblasts. We have previously speculated that the persistent fetal-like fibroblasts of breast cancer patients play a direct role in disease pathogenesis by perturbing normal epithelial-mesenchymal interactions. The observations reported here suggest that MSF-induced alterations in hyaluronic acid synthesis may contribute to the molecular basis of such perturbations.

Cell Line↗

Inflammation in chronic venous insufficiency. Is the problem insurmountable?

One of the hallmarks of venous insufficiency is an elevated venous pressure. While a number of mechanisms have been proposed for vascular and parenchymal cell damage following venous pressure elevation, such as white cell infiltration, a key question remains as to what degree venous occlusion and flow interruption per se may constitute a risk factor in venous disease. To gain an insight into this mechanism, we examined the effect of venous occlusion followed by reperfusion. A draining venule (circa 50 micrometer) in the rat mesentery was occluded with a micropipette (1 h) followed by reperfusion (1 h). The procedure serves to raise the microvascular pressure to about 31 mm Hg during the occlusion while the flow is completely stopped in the local venous and capillary network. Parenchymal cell death in the mesentery was monitored by propidium iodide (PI) labeling. The number of PI-positive cells significantly increased predominantly during reperfusion. A 1-week treatment with a micronized purified flavonoid fraction (100 mg/kg/day) served to significantly reduce parenchymal cell death as well as leukocyte rolling, adhesion to postcapillary venule, and migration into the tissue both during occlusion and reperfusion. The results indicate, that even in an initially symptomless tissue, flow reduction combined with microvascular pressure elevation during venous occlusion results in tissue damage not only during reperfusion (as in arterial occlusion) but also during occlusion.

Animals↗

The functional competence of uterine-derived polymorphonuclear neutrophils (PMN) from mares resistant and susceptible to chronic uterine infection: a sequential migration analysis.

The functional competence of uterine-derived polymorphonuclear neutrophils (PMNs) from 28 mares was measured for migration responsiveness by use of a chamber (filter) assay. Uterine infection was induced with Streptococcus zooepidemicus in mares considered resistant to chronic uterine infection (Grade I). In sequential analysis of uterine flushings obtained from these mares 5, 12, 15, 20, and 25 h after infection was induced, PMNs showed an initial rise at 12 h (from 5), then a general decline in migration response and in concentration of cells per ml from 12 through 25 h post-inoculation. In contrast, PMNs obtained from the uterine flushings from mares considered susceptible to chronic uterine infection (Grade III) demonstrated premature migration dysfunction 12 h after infection. Subsequent increases in functional competence of the PMNs were demonstrated at 15 and again at 25 h after induced infection. The concentration of uterine PMNs per ml from mares considered susceptible to chronic endometritis remained elevated from 12 through 25 h after inoculation, which suggests a possible continued recruitment of new PMNs from the peripheral circulation. The results of this study suggest that uterine-derived PMNs obtained from mares susceptible to chronic uterine infection have a compromised ability to migrate. This dysfunction may play an important role in rendering the endometrium (uterus) susceptible to chronic endometritis.

Animals↗

Tes regulates neural crest migration and axial elongation in Xenopus.

Tes is a member of an emerging family of proteins sharing a set of protein motifs referred to as PET-LIM domains. PET-LIM proteins such as Prickle regulate cell behavior during gastrulation in Xenopus and zebrafish, and to ask whether Tes is also involved in controlling cell behavior, we isolated its Xenopus orthologue. Xtes is expressed as a maternal transcript that is maintained at low levels until neurula stages when expression is elevated in the head and axial structures. Depletion of Xtes leads to a foreshortened head and severe defects in axis elongation. The anterior defect is due in part to the inhibition of cranial neural crest migration while the defects in elongation may be due to perturbation of expression of XFGF8, Xdelta-1 and Xcad-3 and thereby to disruption of posterior somitogenesis. Finally, we note that simultaneous depletion of Xtes and Xenopus Prickle results in axial defects that are more severe than those resulting from depletion of Xtes alone, suggesting that the two proteins act together to control axial elongation.

Amino Acid Sequence↗

NFS1 activates PI3K/AKT/mTOR signaling to upregulate GPX4 expression and enhance ferroptosis resistance in osteosarcoma.

Osteosarcoma continues to exhibit poor survival outcomes due to chemoresistance and metastasis, with metabolic reprogramming and ferroptosis resistance being key features of tumor heterogeneity, yet their upstream regulators remain poorly defined. NFS1, a cysteine desulfurase essential for iron-sulfur cluster biogenesis, protects multiple cancers from ferroptosis, but its role in osteosarcoma is unknown. In this study, we performed a transcriptomic meta-analysis and found that NFS1 expression was significantly upregulated in osteosarcoma tissues, with further elevation in metastatic lesions, and high NFS1 expression correlated with poor overall survival. Genome‑wide CRISPR screening data revealed a marked NFS1 dependency in osteosarcoma cell lines. Functionally, NFS1 promoted cell proliferation, migration, and invasion, whereas its knockdown suppressed these phenotypes. Using single‑cell RNA sequencing data from 27 osteosarcoma specimens, we applied a multi‑algorithm glycolytic scoring framework and observed NFS1 enrichment in highly glycolytic malignant cells, along with an association with PI3K/AKT/mTOR pathway activation. Mechanistically, NFS1 selectively enhanced PI3K, AKT, and mTOR phosphorylation without altering total protein levels, and upregulated GPX4, a central ferroptosis suppressor, leading to elevated ferroptosis resistance scores in NFS1‑high malignant cells. Collectively, these findings identify a previously unrecognized NFS1-PI3K/AKT/mTOR-GPX4 regulatory axis in osteosarcoma, linking metabolic reprogramming to ferroptosis resistance, and suggest that NFS1 functions as an oncogenic driver, as well as a promising prognostic biomarker and therapeutic target in osteosarcoma.

Humans↗

Identification of membrane calcium channels essential for cytoplasmic and nuclear calcium elevations induced by vascular endothelial growth factor in human endothelial cells.

Vascular endothelial growth factor (VEGF) is mitogenic for endothelial cells and has been shown to induce angiogenesis and endothelial cell migration through stimulation of endothelial tyrosine-kinase receptors. Here, using confocal microscopy and the patch-clamp technique on endothelial cells, membrane permeability to calcium as well as cytoplasmic and nuclear free calcium levels have been investigated in the first stages of tyrosine-kinase receptor activation by VEGF. VEGF (0.5nM) as well as inositol trisphosphate (IP3) induced an activation of membrane calcium-permeable channels exhibiting a similar low conductance in the range of 10 pS. The VEGF-triggered activation of these calcium channels, mediated by IP3 and involving the intracellular calcium stores, results in an increase in both cytoplasmic and nuclear calcium levels in endothelial cells, potentially modulating gene expression. Finally, the effect of Ni2+, a calcium channel blocker, on endothelial cell proliferation has been studied. The results show that inhibition of extracellular calcium influx significantly inhibits VEGF-induced cell proliferation. In the process of cell stimulation by VEGF, and possibly by other growth factors, activation of calcium channels could then be a key step in calcium-regulated gene expression and cell activation. These results suggest that the use of calcium channel blockers could be a novel way of prevention or reversion of VEGF-induced tumoral angiogenesis.

Calcium↗

[Serum amyloid protein A (SAA) and HDL. Clinical implication and surgical resuscitation].

The variation of Apo SAA has been studied in parallel with HDL disturbances in septic patients to try to define the role of SAA in these lipoproteins abnormalities. 14 septic patients hospitalized in a surgical intensive care unit have been studied. In these patients, the determination of cholesterol, HDL-cholesterol, Apo AI, Apo B, Apo SAA and CRP and lipoprotein electrophoresis have been made between the 4th and the 7th day after admission in the unit. A control group includes 10 patients undergoing an elective knee surgery. Our results show that SAA elevation (480 +/- 250 mg/l) are much greater than CRP ones (137 +/- 38 mg/l) with no correlation between the 2 proteins specially in patients with hepatic failure. As reported by others, we find a diminution of total cholesterol (3.0 +/- 1.2 mmol in our series) and HDL-cholesterol (0.39 +/- 0.18 mmol). Apo AI is dramatically decreased (0.50 +/- 0.29 g/l) such as a negative acute phase protein. The polyacrylamide gel electrophoresis of lipoproteins confirms the HDL decrease and reveals an abnormal migration of this class of lipoprotein in 8 cases/14 cases (4 accelerations and 4 double-bands). From the results, this HDL modification does not seem to correlate with SAA elevation; immunoblotting experiments lead to the same conclusion. The data are discussed and compared to other findings of the literature.

Adult↗

Amelioration of dextran sulfate sodium-induced colitis by anti-macrophage migration inhibitory factor antibody in mice.

BACKGROUND & AIMS: We investigated the effects of macrophage migration inhibitory factor (MIF) antibodies in experimental colitis-induced dextran sulfate sodium (DSS) and trinitrobenzenesulfonic acid (TNBS) and examined whether plasma levels of MIF were elevated in patients with inflammatory bowel disease (IBD). METHODS: BALB/c or C57BL/6 mice were fed 4% DSS in their drinking water for up to 7 days with and without administration of an anti-MIF antibody every 2 days. The severity of inflammation in the cecum and colon was assessed by clinical signs and histologic scoring. Tissue levels of MIF, tumor necrosis factor (TNF)-alpha, interferon gamma (IFN-gamma), interleukin (IL)-4, and matrix metalloproteinase (MMP)-13 messenger RNA (mRNA) were measured. The effects of anti-MIF antibody on chronic colitis induced by TNBS was assessed in BALB/c mice. Plasma MIF concentrations were assayed in patients with Crohn's disease, ulcerative colitis, and healthy controls. RESULTS: During DSS-induced colitis, colonic MIF mRNA expression was increased. Clinical signs and histopathologic features were significantly improved in animals given anti-MIF antibody. DSS-induced up-regulation of colonic TNF-alpha and IFN-gamma were significantly suppressed in animals given the anti-MIF antibody. Colonic IL-4 was decreased during DSS but restored to baseline by the anti-MIF antibody. The anti-MIF antibody prevented MMP-13 up-regulation by DSS and ameliorated TNBS colitis. Plasma MIF was elevated in patients with Crohn's disease or ulcerative colitis compared with healthy controls. CONCLUSIONS: We conclude that anti-MIF antibodies reduce the severity of experimental colitis and limit the up-regulation of Th1-type cytokines. Anti-MIF antibodies are of potential therapeutic use in IBD.

Animals↗

In vitro guinea pig leukocyte reactions to Rickettsia rickettsii.

The presence of cell-mediated immunity in Rocky Mountain spotted fever-infected guinea pigs was determined by two in vitro assays: whole blood lymphocyte transformation (LT) and macrophage migration inhibition. Increased LT was detected as early as 1 week in guinea pigs infected with Rickettsia rickettsii and treated with oxytetracycline and was detected by two weeks in infected but untreated guinea pigs. Elevated LT was still detectable at 10 weeks postinfection. Guinea pigs vaccinated with killed rickettsiae failed to develop lymphocyte responsiveness; however, there was a rapid lymphocyte response after challenge with live organisms, suggesting potentiation by the vaccine. Vaccinated guinea pigs that were challenged and then treated with antibiotic failed to develop LT, suggesting that infection is necessary for the observed response. Macrophage migration inhibition was detected in both infected and vaccinated guinea pigs by 1 week after infection, but this response was no longer detected 4 to 5 weeks later. Antibody appeared at 2 to 3 weeks postinfection and was present at low levels through week 10. Antibody-treated rickettsiae were phagocytized and destroyed by guinea pig peritoneal macrophages, whereas normal serum-treated rickettsiae replicated and eventually destroyed the phagocytes.

Animals↗

Hereditary pyruvate kinase abnormalities associated with erythrocytosis.

A familial erythrocytosis is described. The propositus is a 52-year-old man who was found, on routine testing, to have an erythrocytosis with a Hb level of 19.8 g/dl. Physical examination and laboratory findings revealed an associated hemolysis. The P50 of the stripped hemolysis was normal. The 2,3-DPG level was reduced to 15% of normal but that of ATP was increased more than twofold. Red cell diphosphoglycerate mutase activity was normal as were the levels of all red cell glycolytic and hexose monophosphate shunt enzymes with the exception of pyruvate kinase (PK). The level of the latter was elevated to 24.5 U/g (normal: 6.2 +/- 1.1). The electrophoretic pattern of hemolysate PK was abnormal, showing three additional bands, one of these migrated as the M2 isozyme. The findings were similar in the propositus's daughter and her daughter and in one of the two brothers of the propositus. The second brother and the son of the first brother was exhibited erythrocytosis but their red cell 2,3-DPG levels were normal. In addition, the level of their RBC PK was reduced to between 50% and 60% of normal and the abnormal electrophoretic bands were absent. The erythrocytosis appears to be inherited as an autosomal-dominant trait. The relationship between the PK abnormalities appears complex.

Adenosine Triphosphate↗

Interaction of 9-(1,3-dihydroxy-2-propoxymethyl)guanine with cytosol and mitochondrial deoxyguanosine kinases: possible role in anti-cytomegalovirus activity.

The acyclic nucleoside 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG) is a potent inhibitor of human cytomegalovirus in vitro and in vivo. In order to investigate the phosphorylation of DHPG to the monophosphate and identify the enzyme responsible, attempts were made to isolate DHPG kinase from calf thymus and from human cytomegalovirus-infected lung cells. From calf thymus, a mitochondrial deoxyguanosine kinase was partially purified which co-migrated with DHPG phosphorylating activity on DEAE-cellulose, and had the same mobility by electrophoresis. DHPG triphosphate and DHPG kinase were elevated in cytomegalovirus-infected cells, but not enough enzyme activity was recovered to identify the kinase. However, DHPG was found to inhibit a cytosol deoxyguanosine kinase induced in these infected cells. The role of mitochondrial and cytosol deoxyguanosine kinases is discussed relative to the anti-cytomegalovirus activity of DHPG.

Acyclovir↗