Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes.

AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations.

Emission of methane from plants.

It has been proposed that plants are capable of producing methane by a novel and unidentified biochemical pathway. Emission of methane with an apparently biological origin was recorded from both whole plants and detached leaves. This was the first report of methanogenesis in an aerobic setting, and was estimated to account for 10-45 per cent of the global methane source. Here, we show that plants do not contain a known biochemical pathway to synthesize methane. However, under high UV stress conditions, there may be spontaneous breakdown of plant material, which releases methane. In addition, plants take up and transpire water containing dissolved methane, leading to the observation that methane is released. Together with a new analysis of global methane levels from satellite retrievals, we conclude that plants are not a major source of the global methane production.

Rates of cesarean section and perinatal outcome: stillbirths.

Based on their yearly clinical statistics for 1983-1989, the cesarean section and stillbirth rates at National Maternity Hospital (Dublin), where the patients are generally white, and University Hospital (Newark), where the patients are predominantly black, were compared. After adjusting for confounding factors, such as unregistered mothers admitted subsequent to fetal demise, differing rates of < 2500 g births and lethal congenital defects, the overall rates of intrauterine fetal demise were identical. When analyzed according to birth weights, in all weight groups, the stillbirth rates were significantly lower in Newark than in Dublin. However, for every 1000 births, more < or = 2500 g fetuses died in utero in Newark than in Dublin. This trend was reversed in the > 2500 g group, where the respective rate at National Maternity Hospital exceeded that of University Hospital more than twice. The latter result largely derived from an almost 7-fold higher rate of intrapartum deaths in the > 2500 g weight group at National Maternity Hospital as compared to University Hospital. When projected against prevailing American statistics, which reflect a stillbirth rate about twice as high among blacks than among whites, the results suggest that the management patterns favored in Newark, including a relatively liberal cesarean section rate (17.5% versus 5.8%), affected the rate of in utero losses favorably.

Ultrasonographic diagnosis of unruptured interstitial pregnancy. A case report.

Ultrasonography is frequently useful in the differential diagnosis of ectopic pregnancy. It proved to be valuable in the diagnosis of an interstitial ectopic pregnancy.

Factors affecting perinatal mortality in an urban center.

In the Division of Obstetrics of the Statewide Perinatal Center, Newark, NJ, the rate of perinatal mortality fell from 51 in 1000, to 15 in 1000, between 1971 and 1986, and increased thereafter to 28 in 1000 by 1988. This development is analyzed against the background of changes in the environment and inside the Center. It is noted that during 2 study years (1983 and 1986) in our extremely high-risk patient population, the perinatal mortality rate was kept at, or under, the national average. It appears, therefore, that with well-coordinated management and optimum use of resources, marked nationwide differences in mortality rates between white and non-white populations can be greatly reduced or eliminated. An inverse relationship between the rates of caesarean section and perinatal mortality was documented, as the former increased from 4.5% to 17%. Paradoxically, a further increase of caesarean section rates was accompanied by a parallel increase of intrauterine fetal and neonatal losses.

Effect of level of dietary calcium-phosphorus during growth and gestation on calcium-phosphorus balance and reproductive performance of first-litter sows.

Twenty-four bred gilts were used in a Ca-P metabolism trial. Twelve gilts were fed gestation treatment A (13 g Ca, 10 g/day), while the other 12 were fed gestation treatment B (19.5 g Ca. 15 g P/day). One-half of the gilts in each treatment group were fed .65% Ca, .50% P from 7 to 94 kg, and half were fed .975% Ca, .75% P for the same period. Treatment B gilts excreted more (P less than .005) fecal and urinary P. Twenty-four first litter sows fed the same treatment diets during growth and gestation and given .75% Ca, .50% P during lactation were used in a Ca and P balance trial conducted from day 38 to 42 of lactation. No difference in fecal, urinary or milk Ca or P were noted between sows fed the different diets during growth or gestation. A higher (P less than .05) value for Ca balance during lactation was observed for sows fed treatment diet B during gestation than for those fed gestation diet A. There were growth treatment x gestation treatment interactions (P less than .05) for both Ca and P balance. No differences were noted in total pigs farrowed, total pigs farrowed alive, average weaning weight or number of pigs weaned. Birth weights were higher (P less than .05) for pigs from sows fed diet B during gestation than for pigs from sows fed diet. A. Pre- and postfarrowing weights, weaned sow weight and lactation gain were similar regardless of treatment fed during growth or gestation.

Effect of maternal dietary energy source on glucose homeostasis, liver glycogen and carcass lipid in the neonatal pig.

Two experiments were conducted to determine the effects of supplementary dietary energy (carbohydrate versus fat) fed to sows during late gestation on energy storage and glucose homeostasis in neonatal pigs. In the first experiment, 28 crossbred sows received one of two dietary treatments that were initiated on day 100 of gestation. The control group was fed daily 1.82 kg of a corn-soybean meal-based diet plus an additional .18 kg of cornstarch. Their counterparts were fed 1.82 kg of a corn-soybean meal diet containing 8% bleachable fancy tallow. The effect of maternal dietary energy source during late gestation on glucose homeostasis was evaluated by fasting pigs from birth (t0), whereas the gestation-lactation effect was evaluated by fasting pigs after they had nursed the sow for 24 hr (t24). Pigs on the tallow treatment responded differently to the t0 fast, as determined by the patterns of plasma glucose (treatment x time, P less than .05) and free fatty acids (treatment x time, P less than .10). The tallow group maintained a slightly higher glucose concentration during the initial 24 hr, after which no difference was observed. Control pigs reached a peak free fatty acid (FFA) concentration by 12 hr, whereas the tallow group reached a maximum by 24 hr, which corresponded with declining glucose concentration. Pigs on the t24 tallow treatment maintained a slightly higher plasma glucose concentration during the initial 24 hr of fasting (12 hr - 68.3 vs 63.2 mg/100 ml; 24 hr - 67.1 vs 56.3 mg/100 ml); however, no significant treatment effect or treatment x time interaction was observed. Pigs on the tallow treatment maintained a higher, although not significantly different, plasma FFA concentration during the fast (144 mueq/liter) than pigs in the control group (126 mueq/liter). In the second experiment, progeny of 12 sows were sacrificed immediately after birth. The respective carcass lipid (percentage) and liver glycogen (milligrams/gram) concentrations for pigs from sows fed the control and tallow diets were 1.48, 229.1 vs 1.50, 234.9. The liver glycogen to body weight ratio (milligrams:gram) was 7.1 and 7.8 for the control and tallow groups, respectively.

Effect of virginiamycin on the apparent ileal digestibility of amino acids by growing pigs.

The objective of this experiment was to measure the influence of virginiamycin on the apparent ileal digestibility (AID) of AA by growing pigs. Fifteen barrows were surgically equipped with a T-cannula in the distal ileum and used in the experiment (initial BW = 35.0 +/- 2.7 kg). Animals were randomly allotted to 3 dietary treatments with 5 pigs per treatment during a 6-wk experiment. Dietary treatments included 1) a basal corn-soybean meal diet, 2) the basal diet supplemented with 11 mg/kg of virginiamycin, and 3) the basal diet supplemented with 22 mg/kg of virginiamycin. Pigs were fed their respective treatment diets during wk 2, 3, and 4, but during wk 1, 5, and 6, all pigs were fed the basal diet. Ileal samples were collected on d 6 and 7 of each week. Results showed that the AID of all indispensable AA, except Arg, His, and Ile, increased (P < 0.05) during wk 2, 3, and 4 compared with wk 1 in pigs fed the diet containing 11 mg/kg of virginiamycin. Pigs fed 22 mg/kg of virginiamycin during wk 2, 3, and 4 had increased (P < 0.05) AID of Trp and Val during these weeks compared with the AID in wk 1. However, the increased AID of AA did not carry over to wk 5 and 6, when virginiamycin was withdrawn from the diet, regardless of the inclusion rate. In pooled data from wk 2, 3, and 4, the AID of CP, the mean of all indispensable AA, and Ile, Leu, Met, Phe, Trp, and Val increased (linear, P < 0.05) as virginiamycin was added to the diets, whereas a tendency (P < 0.10) for a linear or quadratic increase was observed for His, Lys, and Thr. These results indicate that addition of virginiamycin to corn-soybean meal diets fed to growing pigs increases the AID of AA, but this effect is not maintained after the removal of virginiamycin from the diet.

Virginiamycin improves phosphorus digestibility and utilization by growing-finishing pigs fed a phosphorus-deficient, corn-soybean meal diet.

Evaluations of the nutritional effect of antibiotics have largely centered on effects related to the digestibility and utilization of protein and energy. The current study evaluated the potential effect of virginiamycin (VIR) on P digestibility in swine. A total of 70 barrows (mean initial BW = 51 to 64 kg) were used in 4 nutrient-balance experiments. A basal, corn-soybean meal diet that was not supplemented with any inorganic source of P was used in each experiment. In Exp. 1, two diets were tested: basal vs. basal plus 11 mg/kg of VIR. In Exp. 2, four diets were used with a 2 x 2 factorial arrangement of 0 and 11 mg/kg of VIR and 0 and 750 phytase (PHY) units/kg of diet (PU/kg). Experiments 3 and 4 were the same as Exp. 2, except PHY was reduced to 300 PU/kg. For all experiments, VIR improved P digestibility (32.71 to 37.72%, P < 0.001) and Ca digestibility (54.99 to 58.30%, P = 0.002). The addition of PHY improved both P and Ca digestibility (P < 0.001); 750 PU/kg increased P digestibility 27.3% (from 34.6 to 61.9%, P < 0.001), whereas 300 PU increased it 13.8% (from 33.4 to 47.2%, P < 0.001). In an experiment conducted to evaluate the long-term effects of VIR on gut microbial profile, pigs (24 gilts and 8 barrows; mean BW = 29.1 +/- 0.50 kg) were fed a simple corn-soybean meal diet for 16 wk with a 2 x 2 factorial arrangement of VIR (0 and 11 mg/kg) addition and 0.15% dicalcium phosphate deletion. The long-term feeding of VIR in both the control diet and the diet with a marginally reduced P level resulted in a change in ileal microbial profile. A positive numerical increment in the number of phytate-utilizing bacteria was observed in both the normal and P-deleted diets (log unit increments of 12.4 and 17.2% over the respective controls, P = 0.13) when VIR was added. The addition of VIR also tended to affect lactobacilli populations (main effect, P = 0.11; interaction, P = 0.02); VIR decreased lactobacilli in the normal-P diet but did not affect this bacterial population in the P-deleted diet. In conclusion, the antibiotic VIR improves both Ca and P digestibility in pigs. The increase in digestibility is not as great as that provided by PHY, but because the potential mechanism of action (altered microbial populations) differs from that of PHY (direct addition of an enzyme), there can be a degree of additivity in P digestibility improvement when both products are used.