JAK2V617F promotes replication fork stalling with disease-restricted impairment of the intra-S checkpoint response

Cancers result from the accumulation of genetic lesions, but the cellular consequences of driver mutations remain unclear, especially during the earliest stages of malignancy. The V617F mutation in the JAK2 non-receptor tyrosine kinase (JAK2V617F) is present as an early somatic event in most patients with myeloproliferative neoplasms (MPNs), and the study of these chronic myeloid malignancies provides an experimentally tractable approach to understanding early tumorigenesis. Introduction of exogenous JAK2V617F impairs replication fork progression and is associated with activation of the intra-S checkpoint, with both effects mediated by phosphatidylinositide 3-kinase (PI3K) signaling. Analysis of clonally derived JAK2V617F-positive erythroblasts from MPN patients also demonstrated impaired replication fork progression accompanied by increased levels of replication protein A (RPA)-containing foci. However, the associated intra-S checkpoint response was impaired in erythroblasts from polycythemia vera (PV) patients, but not in those from essential thrombocythemia (ET) patients. Moreover, inhibition of p53 in PV erythroblasts resulted in more gamma-H2Ax (γ-H2Ax)–marked double-stranded breaks compared with in like-treated ET erythroblasts, suggesting the defective intra-S checkpoint function seen in PV increases DNA damage in the context of attenuated p53 signaling. These results demonstrate oncogene-induced impairment of replication fork progression in primary cells from MPN patients, reveal unexpected disease-restricted differences in activation of the intra-S checkpoint, and have potential implications for the clonal evolution of malignancies

Use of an experimental high-magnesium tall fescue to reduce grass tetany in cattle

Grass tetany (hypomagnesemia) continues to be a problem for the livestock industry. An experimental cultivar of tall fescue (Festuca arundinacea Shreb.) selected for high Mg concentration, HiMag, was compared against four other cultivars for its ability to increase serum-Mg and reduce the risk of grass tetany. Forage from HiMag contained 22% more Mg, 183% more Ca, and 9% more P than other cultivars; K levels were not different. Regardless of cultivar, concentrations of Ca and Mg were lower while K and P were higher during the spring than the autumn. The tetany ratio IK/(Ca + Mg) on basis] was lower for HiMag than for other cultivars (1.34 vs. 1.65); all cultivars had a higher ratio during spring than autumn (1.91 vs. 1.31). In cattle (Bos taurus) grazing trials, blood serum from steers grazing HiMag contained 8% more Mg in autumn 1993 but was not different in spring 1994. Blood serum Mg was not different for cows (either dry or nursing calves) during autumn grazing, but approached significance (P = 0.09) during the spring 1995 calving season (2.32 vs. 2.07 mg/dL for HiMag vs. other cultivars). Except for differences between calves on HiMag compared with Kentucky-31 in autumn 1995 (58 vs. 43 lb, respectively), animal weight change was not affected by cultivar. Normal forage Mg concentrations (>0.20%) and tetany ratios below 2.2 for all cultivars in every season except spring 1995 may explain the lack of consistent animal response. No clinical symptoms of grass tetany were observed at any time during these studies. However, the higher Mg concentration and lower tetany ratio suggest that HiMag could provide a means of reducing the incidence of grass tetany in livestock during periods when risk of the disorder is high

Registration of HiMag Tall Fescue Germplasm

HiMag (Reg. no. GP-79, PI 615587) tall fescue (Festuca arundinacea Schreb.) was developed and released by the Missouri Agricultural Experiment Station and the USDA-ARS in 1997. HiMag has relatively high Mg and Ca concentrations and low tetany ratio [K/(Ca + Mg)] expressed as moles of charge. Parental germplasm for the Co cycle of selection for HiMag included 950 plants from 'Kenhy' (Buckner et al., 1977), 831 plants from 'Kentucky-31', and 688 plants from `Missouri-96' (Asay et al., 1979). All plants were endophyte free [ Neotyphodium coenophialum (Morgan-Jones and Gams) Glenn, Bacon, and Hanlin comb. nov.]. Parental plants were transplanted to the field near Columbia, MO, in the fall of 1983. The soil was a Mexico silt loam (a fine, montmorillonitic, mesic Udollic Ochraqualf) with a pH of 6.4. Selection was applied against crown rust (caused by Puccinia coronata Corda. var. coronata), leaving 1011 plants which were harvested in the fall of 1984 and analyzed for elemental concentrations of Mg, Ca, K, and the tetany ratio. Sixty-five plants (11 from Kentucky- 31, 54 from Missouri-96, and 0 from Kenhy) were chosen to generate the C1 cycle of selection. These 65 plants contained 5.0 to 7.0 g kg-1 Mg, 5.0 to 10.2 g kg' Ca, 20 to 33 g K, and had K/(Ca + Mg) values of 0.61 to 0.99. These were allowed to open-pollinate in the greenhouse during the winter of 1985/86. Harvested seeds were germinated in the greenhouse and seedlings were transplanted to the field in the fall of 1986. During the fall of 1987 approximately 1000 plants were analyzed from the CI cycle to determine elemental concentrations of Mg, Ca, K, and the tetany ratio. Forty-six plants chosen for the C2 contained 4.4 to 6.1 g kg -' Mg, 5.5 to 8.1 g kg-' Ca, 17.2 to 30.9 g kg' K, and had tetany ratios of 1.06 to 2.13. These were allowed to open-pollinate in the greenhouse in the winter of 1988-1989. Approximately 1000 seedlings were transplanted to the field having areas of Creldon silt loam (Mollic Fragiudalf) and Hobert silt loam (Umbric Fragiaqualf) at the Southwest Research Center, located near Mt. Vernon, MO, in the fall of 1989. In the summer of 1990, seed was harvested from these spaced plants and planted into an irrigated Portneuf silt loam soil (Durinodic Xeric Haplocalcid) to establish a seed increase block at Kimberly, ID, in April 1991. In 1992, seed from HiMag was harvested with the following characteristics: 1635 kg ha-1, 400 seeds g-1, 2.5 g 1000 seeds-1, and 302 kg m-3

Risk of End-Stage Renal Disease in HIV-Positive Potential Live Kidney Donors

New federal regulations allow HIV-positive individuals to be live kidney donors; however, potential candidacy for donation is poorly understood given the increased risk of end-stage renal disease (ESRD) associated with HIV infection. To better understand this risk, we compared the incidence of ESRD among 41 968 HIV-positive participants of North America AIDS Cohort Collaboration on Research and Design followed for a median of 5 years with the incidence of ESRD among comparable HIV-negative participants of National Health and Nutrition Examination III followed for a median of 14 years. We used risk associations from multivariable Cox proportional hazards regression to derive cumulative incidence estimates for selected HIV-positive scenarios (no history of diabetes, hypertension, AIDS, or hepatitis C virus coinfection) and compared these estimates with those from similarly selected HIV-negative scenarios. For 40-year-old HIV-positive individuals with health characteristics that were similar to those of age-matched kidney donors, viral load <400 copies/mL, and CD4+ count ≥500 cells/μL, the 9-year cumulative incidence of ESRD was higher than that of their HIV-negative peers, yet still low: 2.5 versus 1.1 per 10 000 among white women, 3.0 versus 1.3 per 10 000 among white men, 13.2 versus 3.6 per 10 000 among black women, and 15.8 versus 4.4 per 10 000 among black men. HIV-positive individuals with no comorbidities and well-controlled disease may be considered low-risk kidney donor candidates

Use of an experimental high-magnesium tall fescue to reduce grass tetany in cattle

Grass tetany (hypomagnesemia) continues to be a problem for the livestock industry. An experimental cultivar of tall fescue (Festuca arundinacea Shreb.) selected for high Mg concentration, HiMag, was compared against four other cultivars for its ability to increase serum-Mg and reduce the risk of grass tetany. Forage from HiMag contained 22% more Mg, 183% more Ca, and 9% more P than other cultivars; K levels were not different. Regardless of cultivar, concentrations of Ca and Mg were lower while K and P were higher during the spring than the autumn. The tetany ratio IK/(Ca + Mg) on basis] was lower for HiMag than for other cultivars (1.34 vs. 1.65); all cultivars had a higher ratio during spring than autumn (1.91 vs. 1.31). In cattle (Bos taurus) grazing trials, blood serum from steers grazing HiMag contained 8% more Mg in autumn 1993 but was not different in spring 1994. Blood serum Mg was not different for cows (either dry or nursing calves) during autumn grazing, but approached significance (P = 0.09) during the spring 1995 calving season (2.32 vs. 2.07 mg/dL for HiMag vs. other cultivars). Except for differences between calves on HiMag compared with Kentucky-31 in autumn 1995 (58 vs. 43 lb, respectively), animal weight change was not affected by cultivar. Normal forage Mg concentrations (>0.20%) and tetany ratios below 2.2 for all cultivars in every season except spring 1995 may explain the lack of consistent animal response. No clinical symptoms of grass tetany were observed at any time during these studies. However, the higher Mg concentration and lower tetany ratio suggest that HiMag could provide a means of reducing the incidence of grass tetany in livestock during periods when risk of the disorder is high

Registration of HiMag Tall Fescue Germplasm

HiMag (Reg. no. GP-79, PI 615587) tall fescue (Festuca arundinacea Schreb.) was developed and released by the Missouri Agricultural Experiment Station and the USDA-ARS in 1997. HiMag has relatively high Mg and Ca concentrations and low tetany ratio [K/(Ca + Mg)] expressed as moles of charge. Parental germplasm for the Co cycle of selection for HiMag included 950 plants from 'Kenhy' (Buckner et al., 1977), 831 plants from 'Kentucky-31', and 688 plants from `Missouri-96' (Asay et al., 1979). All plants were endophyte free [ Neotyphodium coenophialum (Morgan-Jones and Gams) Glenn, Bacon, and Hanlin comb. nov.]. Parental plants were transplanted to the field near Columbia, MO, in the fall of 1983. The soil was a Mexico silt loam (a fine, montmorillonitic, mesic Udollic Ochraqualf) with a pH of 6.4. Selection was applied against crown rust (caused by Puccinia coronata Corda. var. coronata), leaving 1011 plants which were harvested in the fall of 1984 and analyzed for elemental concentrations of Mg, Ca, K, and the tetany ratio. Sixty-five plants (11 from Kentucky- 31, 54 from Missouri-96, and 0 from Kenhy) were chosen to generate the C1 cycle of selection. These 65 plants contained 5.0 to 7.0 g kg-1 Mg, 5.0 to 10.2 g kg' Ca, 20 to 33 g K, and had K/(Ca + Mg) values of 0.61 to 0.99. These were allowed to open-pollinate in the greenhouse during the winter of 1985/86. Harvested seeds were germinated in the greenhouse and seedlings were transplanted to the field in the fall of 1986. During the fall of 1987 approximately 1000 plants were analyzed from the CI cycle to determine elemental concentrations of Mg, Ca, K, and the tetany ratio. Forty-six plants chosen for the C2 contained 4.4 to 6.1 g kg -' Mg, 5.5 to 8.1 g kg-' Ca, 17.2 to 30.9 g kg' K, and had tetany ratios of 1.06 to 2.13. These were allowed to open-pollinate in the greenhouse in the winter of 1988-1989. Approximately 1000 seedlings were transplanted to the field having areas of Creldon silt loam (Mollic Fragiudalf) and Hobert silt loam (Umbric Fragiaqualf) at the Southwest Research Center, located near Mt. Vernon, MO, in the fall of 1989. In the summer of 1990, seed was harvested from these spaced plants and planted into an irrigated Portneuf silt loam soil (Durinodic Xeric Haplocalcid) to establish a seed increase block at Kimberly, ID, in April 1991. In 1992, seed from HiMag was harvested with the following characteristics: 1635 kg ha-1, 400 seeds g-1, 2.5 g 1000 seeds-1, and 302 kg m-3

Nalp3 Inflammasome Activation in Neutrophilic Asthma

Introduction Non-cystic fi brosis (CF) bronchiectasis is an important cause of respiratory morbidity in both developing and developed countries. Antibiotics are considered standard therapy in the treatment of this condition. In this Cochrane review, we examined the evidence for the effi cacy of short courses (4 weeks or less) for non-CF bronchiectasis in children and adults. Methods The Cochrane Airways Group performed a literature search, in accordance with Cochrane methodology. This included the Cochrane Central Register of Controlled Trials and clinical trial registers. Inclusion criteria were randomized controlled trials (RCT) comparing outcomes with use of antibiotics (intravenous, oral or inhaled) versus placebo or usual care (control), for periods of ≤4 weeks, in non-cystic fi brosis bronchiectasis. Results 187 abstracts were reviewed. A single eligible study showed a small benefi t, when compared to placebo, of 4 weeks of inhaled antibiotic therapy in adults with bronchiectasis and pseudomonas in their sputum. There were no studies in children and no studies on oral or intravenous antibiotics. Conclusion There is insuffi cient evidence in the current literature to make reasonable conclusions about the effi cacy of short course antibiotics in the management of adults and children with non-CF bronchiectasis. Until further evidence is available, adherence to current treatment guidelines is recommended