Kooperativer Bibliotheksverbund

In: Functional Ecology, Wiley, Vol. 37, No. 4 ( 2023-04), p. 1055-1066

Abstract: Warmer winters with less snowfall are increasing the frequency of soil freeze–thaw cycles across temperate regions. Soil microbial responses to freeze–thaw cycles vary and some of this variation may be explained by microbial conditioning to prior winter conditions, yet such linkages remain largely unexplored. We investigated how differences in temperature history influenced microbial community composition and activity in response to freeze–thaw cycles. We collected soil microbial communities that developed under colder (high elevation) and warmer (low elevation) temperature regimes in spruce‐fir forests, then added each of these soil microbial communities to a sterile bulk‐soil in a laboratory microcosm experiment. The inoculated high‐elevation cold and low‐elevation warm microcosms were subjected to diurnal freeze–thaw cycles or constant above‐freezing temperature for 9 days. Then, all microcosms were subjected to a 7‐day above‐freezing recovery period. Overall, we found that the high‐elevation cold community had, relative to the low‐elevation warm community, a smaller reduction in microbial respiration (CO 2 flux) during freeze–thaw cycles. Further, the high‐elevation cold community, on average, experienced lower freeze–thaw‐induced bacterial mortality than the warm community and may have partly acclimated to freeze–thaw cycles via increased lipid membrane fluidity. Respiration of both microbial communities quickly recovered following the end of the freeze–thaw treatment period and there were no changes in soil extractable carbon or nitrogen. Our results provide evidence that past soil temperature conditions may influence the responses of soil microbial communities to freeze–thaw cycles. The microbial community that developed under a colder temperature regime was more tolerant of freeze–thaw cycles than the community that developed under a warmer temperature regime, although both communities displayed some level of resilience. Taken together, our data suggest that microbial communities conditioned to less extreme winter soil temperatures may be most vulnerable to rapid changes in freeze–thaw regimes as winters warm, but they also may be able to quickly recover if mortality is low. Read the free Plain Language Summary for this article on the Journal blog.

Type of Medium: Online Resource

ISSN: 0269-8463 , 1365-2435

URL: Issue

URL: Article

DOI: 10.1111/fec.v37.4

DOI: 10.1111/1365-2435.14273

Language: English

Publisher: Wiley

Publication Date: 2023

detail.hit.zdb_id: 2020307-X

detail.hit.zdb_id: 619313-4

SSG: 12

In: Haematologica, Ferrata Storti Foundation (Haematologica), Vol. 104, No. 2 ( 2019-02), p. e51-e53

Type of Medium: Online Resource

ISSN: 0390-6078 , 1592-8721

URL: Article

DOI: 10.3324/haematol.2018.196295

Language: English

Publisher: Ferrata Storti Foundation (Haematologica)

Publication Date: 2019

detail.hit.zdb_id: 2186022-1

detail.hit.zdb_id: 2030158-3

detail.hit.zdb_id: 2805244-4

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4807-4807

Abstract: Background: Pyruvate Kinase (PK) deficiency is the most common enzyme defect of the glycolytic pathway causing hereditary non-spherocytic hemolytic anemia. Patients have a broad phenotypic spectrum, ranging from mild anemia to transfusion dependence, and there is wide variation in transfusion practices and decisions about splenectomy. No prior studies have reported on the use of validated health related quality of life (HRQoL) measures in this population. Aim: To describe patient reported outcomes including general HRQoL and fatigue in adults with PK deficiency and the correlation with clinical and laboratory features. Methods: Patients were enrolled on the PK Deficiency Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PK deficiency. Adults (n=132), ages ≥18 years, completed the EuroQol-5D (high index equivalent to better QoL), PROMIS Fatigue Short Form 7a (high scores equivalent to higher fatigue), and the Functional Assessment of Cancer Therapy-Anemia (FACT-An, high scores equivalent to less fatigue) surveys at enrollment and annually. Timing of administration was convenience based. Survey data were analyzed according to proprietary scoring guidelines. Tests of association were performed using Fisher's exact test (categorical) and Wilcoxon rank sum test (continuous). Regular transfusions were defined as ≥6 transfusions in 12 months. Genotypes were grouped as two missense mutations (M/M), one missense/one non-missense (M/NM), or two non-missense mutations (NM/NM)); non-missense included deletions or other drastic variants. The minimal important difference (MID) for the FACT-An has been reported as 7 points (Cella et al, J Pain Symptom Manage 2002). P-values 〈 0.05 were considered statistically significant. Results: At enrollment, 128 adults completed the FACT-An with a median total score of 156 (IQR 122-190). Patients receiving regular transfusions reported significantly lower FACT-An scores than those who were not regularly transfused (median 129 vs 156, p=0.004) with significantly lower scores for physical, emotional, and functional well-being and anemia sub-scores (Table). This difference also surpassed the MID. However, non- regularly transfused patients with hemoglobin (Hb) 〈 8 g/dl did not report significantly different scores than those with Hb≥ 8 g/dl (p=0.75). There were also no significant differences in FACT-An scores by splenectomy status or age. The FACT-An score differences were greater than the MID for patients with iron overload (ferritin 〉 1000 ng/dL or chelation), higher number of lifetime transfusions, and two missense mutations. Females reported significantly lower scores than males (median 143 vs. 160, p=0.006) with significantly lower anemia sub-scores (p=0.0009). FACT-An surveys completed at the one year follow-up time point validated these findings. EuroQol-5D scores (n=124) at enrollment were similar to the healthy population (median PK deficiency index score 0.88; healthy population index mean 0.88, Shaw et al, Medical Care 2005). No significant differences were found by Hb level, splenectomy status, transfusion status, or genotype group. The median PROMIS fatigue T score (n=66) was 52.1 (IQR 40.5-63.7). Similar to the FACT-An survey data, PROMIS fatigue scores were significantly worse in patients who were regularly transfused (67.0 vs 52.4, p=0.02). PROMIS fatigue scores were also significantly worse in patients ≥40 years old (p=0.05) and females (p=0.01). Conclusions: Using the FACT-An and PROMIS Fatigue measures, patients with PK deficiency who are regularly transfused report significantly more fatigue and worse HRQoL compared with those who are not transfused. Important differences were also seen by iron status and mutation group using the FACT-An. Patients report similar fatigue levels regardless of Hb level, which suggests that symptoms, rather than Hb value alone, should be factored into clinical decision making. In contrast to anemia related HRQoL scores, overall HRQoL scores using validated generic measures in patients with PK deficiency show no differences compared with the healthy population, suggesting that disease-specific measures may better detect the effects of PK deficiency on HRQoL. Disclosures Van Beers: Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Glader:Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Despotovic:AmGen: Research Funding; Novartis: Research Funding; Sanofi: Consultancy. Kwiatkowski:bluebird bio: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Research Funding; Novartis: Research Funding; Apopharma: Research Funding; Terumo: Research Funding. Thompson:La Jolla Pharmaceutical: Research Funding; Baxalta/Shire: Research Funding; Novartis: Research Funding; Celgene: Research Funding; bluebird bio: Consultancy, Research Funding; Biomarin: Research Funding; Amgen: Research Funding. Newburger:TransCytos LLC: Consultancy; Janssen Research & Development, LLC: Consultancy, Honoraria; X4 Pharmaceutics: Consultancy, Honoraria. Ravindranath:AGIOS: Other: Site Investigator for Pyruvate Kinase Deficiency. Sheth:Terumo Corporation: Research Funding; Novartis: Research Funding; La Jolla Pharmaceutical Company: Research Funding; Celgene Corporation: Consultancy, Research Funding; Bluebird Bio: Consultancy. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-113206

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2175-2175

Abstract: Introduction: Pyruvate kinase (PK) deficiency causes a defect in the glycolytic pathway, leading to a hereditary hemolytic anemia. Management is supportive and consists of splenectomy, transfusions, and chelation therapy. Aim: To better understand the comorbidity and complication profile of adults with PK deficiency, and the extent to which transfusion frequency contributes, the objectives of this study were to (1) quantify the prevalence of comorbidities and complications according to transfusion history and (2) compare the types and rates of select comorbidities and complications with the general population. Methods: Data were obtained from the enrollment survey of the PK Deficiency Natural History Study (NHS), a longitudinal, retrospective and prospective cohort study in which clinical, laboratory, transfusion, and radiologic data were collected; all participants were confirmed to have 2 mutations in the PKLR gene. Patients (n=122) were eligible for this analysis if they were ≥18 years of age and had sufficient data on transfusion history to enable classification into 1 of 3 cohorts: "Ever Regularly Transfused" (ERT, defined as ≥6 transfusions in any 12-month period), "Never Regularly Transfused" (NRT, defined as having ≥1 lifetime transfusion but never having 〉 4 transfusions in any 12-month period), or "Never Transfused" (NT). To contextualize the findings, the frequencies of select conditions were compared with an age- and gender-matched cohort of individuals from the insured, general US population who did not have any hemolytic anemia diagnoses and had ≥5 years of continuous enrollment in the Truven MarketScan administrative claims database. The NHS reported lifetime prevalence rates, whereas rates obtained from the MarketScan data were based on diagnosis and procedure codes over varying look-back periods; therefore, to minimize bias, we limited PK deficiency vs. general population comparisons to (1) chronic conditions that require lifetime management and would thus still be recorded in claims data years after initial diagnosis, and/or (2) conditions for which a diagnosis/procedure date was available in the NHS and could be matched in time to the average 8-year look-back period for the general population. Frequencies were compared across mutually exclusive cohorts using Fisher's exact 2-tailed tests of significance. Results: ERT (n=65), NRT (n=30), and NT patients (n=27) had a mean age of 34.2, 39.5, and 37.2 years at enrollment, respectively (not significant [ns]), with 46.2%, 56.7%, and 59.3%, respectively, being male (ns). ERT patients trended toward being more likely than NT patients to be Amish and have the homozygous R479H splice variant (30.8% vs 11.1% [p=0.064] ) but were significantly less likely to have a missense/missense PKLR genotype (32.3% vs 70.4% [p=0.001]). Compared with the general population, patients with PK deficiency had significantly higher rates of splenectomy, cholecystectomy, osteoporosis, liver cirrhosis, pulmonary hypertension, and current prophylactic antibiotic and anticoagulant use (Table). Rates of splenectomy, cholecystectomy, and osteoporosis were significantly higher in patients with PK deficiency, regardless of transfusion cohort, and both ERT and NRT patients had significantly higher rates of liver cirrhosis than individuals from the general population. A gradient was seen across transfusion cohorts for other conditions. Notably, 83.1% of ERT patients, 50.0% of NRT patients, and 25.9% of NT patients had a history of liver iron overload. ERT patients were also significantly more likely than NRT and NT patients to have had a splenectomy, cholecystectomy, and/or thrombosis, and to currently use prophylactic antibiotics. Findings were consistent when the analysis was restricted to non-Amish patients with PK deficiency. Conclusions: Patients with PK deficiency have higher rates of select comorbidities and complications than age- and gender-matched individuals who do not have PK deficiency. Even patients with PK deficiency who have never been transfused are at increased risk of complications of the disease and its treatment. Disclosures Boscoe: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Agios Pharmaceuticals, Inc.: Consultancy. Hedgeman:IBM Watson Health: Employment. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Al-Samkari:Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Moderna: Consultancy. Barcellini:Incyte: Consultancy; Alexion: Consultancy, Speakers Bureau; Agios Pharmaceuticals, Inc.: Consultancy; Novartis: Speakers Bureau; Apellis: Consultancy; bioverativ: Consultancy. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Rothman:Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Kwiatkowski:Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Terumo: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored). Holzhauer:Agios Pharmaceuticals, Inc.: Consultancy. Verhovsek:Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy; CRSPR/Vertex: Other: Clinical Trial Steering committee. Despotovic:Novartis: Research Funding; Dova: Honoraria. Grace:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-123069

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 949-949

Abstract: Background: Pyruvate kinase deficiency (PKD) is the most common cause of chronic hereditary non-spherocytic hemolytic anemia. The spectrum of disease in PKD is broad, ranging from an incidentally discovered mild anemia to a severe transfusion-dependent anemia. Splenectomy partially ameliorates the anemia and reduces the transfusion burden in the majority of patients. Because hemoglobin poorly correlates with symptoms in PKD, transfusion requirements are typically used clinically to classify disease severity with those who are regularly transfused despite splenectomy recognized as the most severely affected subgroup. Aim: To compare demographics, complications, and laboratory results between the most severely-affected PKD patients (those that are splenectomized and regularly transfused) with non-regularly transfused splenectomized PKD patients. Methods: After ethics committee approval, patients were enrolled on the PKD Natural History Study, a prospective 30 site international study. All patients had molecularly confirmed PKD. Only splenectomized patients were included in the analysis. Transfusion frequency was observed over a 3-year period. Patients were divided into two groups based on transfusion frequency: the severe phenotype group was defined as those who receive regular transfusions (≥6 discrete red cell transfusion episodes per year) and the control group did not receive regular transfusions. Phenotype stability over the 3-year period was also assessed. Results: 154 splenectomized patients with PKD were included: 30 patients in the severe PKD phenotype group and 124 patients in the comparison PKD group. Results of the analysis comparing the two groups are described in the Table. Severely affected patients were more likely to be female (77% versus 51%, p=0.013), older at the time of splenectomy (median age: 5 versus 3.6, p=0.011), have iron overload (93% vs. 51%, p & lt;0.0001), have received chelation therapy (90% vs. 42%, p & lt;0.0001), and had more lifetime transfusions (median: 77 versus 15, p & lt;0.0001). Rates of other PKD complications including pulmonary hypertension, extramedullary hematopoiesis, liver cirrhosis, endocrinopathy, and bone fracture appear similar between the two groups. Laboratory values, including hemoglobin, total bilirubin, normalized PK enzyme activity, and median absolute reticulocyte count appear similar between the two groups. The underlying genetic mutation patterns (missense mutations versus non-missense mutations) were also similar between the groups. Phenotype stability over time was highly variable: of the patients with a severe phenotype at enrollment, 62% had a severe phenotype during the first follow-up year and 39% had a severe phenotype at the second follow-up year. Conclusions: Patients with PKD who are regularly transfused despite splenectomy appeared to have similar rates of PKD-associated complications (except for iron overload) and similar relevant laboratory values and genotypes when compared to those who are not regularly transfused after splenectomy. The similarity observed between severe phenotype patients and comparison patients with PKD may result from a protective effect of transfusion (e.g. reduction of bone fractures and extramedullary hematopoiesis) or could suggest transfusion-dependence is an artificial signifier of disease severity, reflective of provider practices and patient symptoms rather than an actual distinct phenotype. Transfusion requirements in severe PKD appear to fluctuate significantly over time. Disclosures Al-Samkari: Dova: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. van Beers:RR Mechatronics: Research Funding; Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Barcellini:Agios: Consultancy, Other: Advisory board; Apellis: Consultancy; Incyte: Consultancy, Other: Advisory board; Bioverativ: Consultancy, Other: Advisory board; Novartis: Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Kuo:Pfizer: Consultancy; Novartis: Consultancy, Honoraria; Celgene: Consultancy; Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy. Despotovic:Dova: Honoraria; Novartis: Research Funding; Amgen: Research Funding. Kwiatkowski:Celgene: Consultancy; Terumo: Research Funding; Apopharma: Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Agios: Consultancy; Imara: Consultancy; Novartis: Research Funding. Thompson:Baxalta: Research Funding; Novartis: Consultancy, Research Funding; bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Rothman:Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Agios: Honoraria, Research Funding. Verhovsek:Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees; Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:CRSPR/Vertex: Other: Clinical Trial Steering committee; Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy. London:United Therapeutics: Consultancy; ArQule, Inc: Consultancy. Grace:Novartis: Research Funding; Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-125352

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3607-3607

Abstract: Pyruvate kinase (PK) catalyzes the second ATP-forming step in glycolysis. Erythrocytes lack mitochondria and are dependent on glycolysis for energy. Recessively inherited mutations in the pyruvate kinase (PKLR) gene are the most common defect in the glycolytic pathway associated with chronic nonspherocytic hemolytic (CNSHA) anemia. Symptomatology is variable, ranging from well compensated anemia to severe disease with lifelong transfusion dependence. Genetic analyses of PK-deficient patients have shown most carry missense, frameshift, and nonsense mutations that lead to qualitative or quantitative defects in pyruvate kinase. We studied CNSHA PK-deficient patients from 13 kindreds with one (n=8) or no (n=5) amino acid altering mutations identified in the PKLR gene. To search for potential splicing or regulatory mutations on the other allele, or an alternate red blood cell diagnosis, whole exome sequencing (WES) or whole genome sequencing (WGS) of genomic DNA from affected patients was performed. Five patients with no PKLR coding region mutations had other rare genetic variants predicted to be damaging or previously associated with hematologic disease, including a GATA1 mutation previously associated with PK deficiency, a KIF23 mutation, and 3 with pathogenic PIEZO1 mutations. DNA of patients from 5 other kindreds with single coding region mutations; 1) R486W; 2) G319D; 3) R510Q; 4) A392T; and 5) R510Q, had WGS performed. Genomic analyses did not identify deletional or structural variants in or around the PKLR locus. Haplotyping did not reveal any common shared alleles between the 5 kindreds. Detailed sequence analysis identified unique deep intronic mutations in the PKLR gene in affected members from all 5 kindreds: 1) intron 7 G 〉 A, 2) intron 7 T 〉 G, 3) intron 9 T 〉 A, 4) intron 9 G 〉 A, and 5) exon 7/intron 7 boundary G 〉 A. Four of the 5 mutations were not found in the 1000 Genomes database, while the fifth was found at a frequency of 0.0006. The Scroogle algorithm predicted all 5 mutations would perturb normal mRNA processing; kindred 1) create a novel 3' acceptor splice site; 2) disrupt an intron splicing enhancer or create a 3' splice acceptor site, 3) and 4) create novel 5' donor splice sites, and 5) disrupt a wild type 5' donor splice site. Minigene assays were performed to examine whether these PKLR intron mutations influenced splicing in vitro. Each minigene contained the ANK1 erythroid promoter, a patient-specific PKLR fragment with a mutant intronic allele inserted into intron 2 of the HBG1 gene, and the HBG1 3'untranslated region and polyA signal. After transformation in K562 cells, minigene-specific RNA was harvested, RT-PCR performed, followed by shotgun subcloning of PKLR cDNA. Sequence analysis of plasmid DNA identified aberrant PKLR mRNA isoforms from all 5 minigenes including partial exon skipping, single or multiple exon skipping, and/or partial intron retention. Specifically, kindred 1) skip exon 8 or skip exons 7-9; 2) skip exons 7-8 or skip exons 7-9; 3) insert 38bp 5' of exon 10 or skip exon 10, 4) delete first 67bp of exon 10 or skip exon 10; 5) skip exon 7-8 or skip exon 7-9. In aggregate, these isoforms all to lead to frameshift, with premature chain termination predicted to trigger nonsense mediated decay. Splicing studies from primary patient reticulocyte RNA are ongoing. Three patients with heterozygous PKLR mutations, S8A, V134D, and V460M, had no obvious disease-associated variants detected on WGS. These variants, particularly V134D and V460M, could lead to a dominant negative phenotype. These results indicate that detailed investigation, including whole genome sequencing, lead to a specific hematologic diagnosis in most pyruvate-kinase deficient patients. They also show that in a subset of patients, intron mutations leading to aberrant splicing may be a genetic mechanism associated with pyruvate kinase deficiency. This may be an under recognized mechanism of genetic disease. Disclosures Glader: Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Grace:Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy; Agios Pharmaceuticals: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-117805

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: BioScience, Oxford University Press (OUP), Vol. 72, No. 9 ( 2022-08-29), p. 889-907

Abstract: Long-term observations and experiments in diverse drylands reveal how ecosystems and services are responding to climate change. To develop generalities about climate change impacts at dryland sites, we compared broadscale patterns in climate and synthesized primary production responses among the eight terrestrial, nonforested sites of the United States Long-Term Ecological Research (US LTER) Network located in temperate (Southwest and Midwest) and polar (Arctic and Antarctic) regions. All sites experienced warming in recent decades, whereas drought varied regionally with multidecadal phases. Multiple years of wet or dry conditions had larger effects than single years on primary production. Droughts, floods, and wildfires altered resource availability and restructured plant communities, with greater impacts on primary production than warming alone. During severe regional droughts, air pollution from wildfire and dust events peaked. Studies at US LTER drylands over more than 40 years demonstrate reciprocal links and feedbacks among dryland ecosystems, climate-driven disturbance events, and climate change.

Type of Medium: Online Resource

ISSN: 0006-3568 , 1525-3244

URL: Article

DOI: 10.1093/biosci/biab134

Language: English

Publisher: Oxford University Press (OUP)

Publication Date: 2022

detail.hit.zdb_id: 2066019-4

SSG: 12

In: Science, American Association for the Advancement of Science (AAAS), Vol. 360, No. 6386 ( 2018-04-20), p. 317-320

Abstract: Theory predicts and evidence shows that plant species that use the C 4 photosynthetic pathway (C 4 species) are less responsive to elevated carbon dioxide ( e CO 2 ) than species that use only the C 3 pathway (C 3 species). We document a reversal from this expected C 3 -C 4 contrast. Over the first 12 years of a 20-year free-air CO 2 enrichment experiment with 88 C 3 or C 4 grassland plots, we found that biomass was markedly enhanced at e CO 2 relative to ambient CO 2 in C 3 but not C 4 plots, as expected. During the subsequent 8 years, the pattern reversed: Biomass was markedly enhanced at e CO 2 relative to ambient CO 2 in C 4 but not C 3 plots. Soil net nitrogen mineralization rates, an index of soil nitrogen supply, exhibited a similar shift: e CO 2 first enhanced but later depressed rates in C 3 plots, with the opposite true in C 4 plots, partially explaining the reversal of the e CO 2 biomass response. These findings challenge the current C 3 -C 4 e CO 2 paradigm and show that even the best-supported short-term drivers of plant response to global change might not predict long-term results.

Type of Medium: Online Resource

ISSN: 0036-8075 , 1095-9203

URL: Article

DOI: 10.1126/science.aas9313

Language: English

Publisher: American Association for the Advancement of Science (AAAS)

Publication Date: 2018

detail.hit.zdb_id: 128410-1

detail.hit.zdb_id: 2066996-3

detail.hit.zdb_id: 2060783-0

SSG: 11

In: Science, American Association for the Advancement of Science (AAAS), Vol. 361, No. 6407 ( 2018-09-14)

Abstract: Nie and colleagues suggest a key role for interannual climate variation as an explanation for the temporal dynamics of an unexpected 20-year reversal of biomass responses of C 3 -C 4 grasses to elevated CO 2 . However, we had already identified some climate-dependent differences in C 3 and C 4 responses to eCO 2 and shown that these could not fully explain the temporal dynamics we observed.

Type of Medium: Online Resource

ISSN: 0036-8075 , 1095-9203

URL: Article

DOI: 10.1126/science.aau8982

Language: English

Publisher: American Association for the Advancement of Science (AAAS)

Publication Date: 2018

detail.hit.zdb_id: 128410-1

detail.hit.zdb_id: 2066996-3

detail.hit.zdb_id: 2060783-0

SSG: 11

In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 118, No. 17 ( 2021-04-27)

Abstract: Whether the terrestrial biosphere will continue to act as a net carbon (C) sink in the face of multiple global changes is questionable. A key uncertainty is whether increases in plant C fixation under elevated carbon dioxide (CO 2 ) will translate into decades-long C storage and whether this depends on other concurrently changing factors. We investigated how manipulations of CO 2 , soil nitrogen (N) supply, and plant species richness influenced total ecosystem (plant + soil to 60 cm) C storage over 19 y in a free-air CO 2 enrichment grassland experiment (BioCON) in Minnesota. On average, after 19 y of treatments, increasing species richness from 1 to 4, 9, or 16 enhanced total ecosystem C storage by 22 to 32%, whereas N addition of 4 g N m −2 ⋅ y −1 and elevated CO 2 of +180 ppm had only modest effects (increasing C stores by less than 5%). While all treatments increased net primary productivity, only increasing species richness enhanced net primary productivity sufficiently to more than offset enhanced C losses and substantially increase ecosystem C pools. Effects of the three global change treatments were generally additive, and we did not observe any interactions between CO 2 and N. Overall, our results call into question whether elevated CO 2 will increase the soil C sink in grassland ecosystems, helping to slow climate change, and suggest that losses of biodiversity may influence C storage as much as or more than increasing CO 2 or high rates of N deposition in perennial grassland systems.

Type of Medium: Online Resource

ISSN: 0027-8424 , 1091-6490

URL: Article

DOI: 10.1073/pnas.2016965118

Language: English

Publisher: Proceedings of the National Academy of Sciences

Publication Date: 2021

detail.hit.zdb_id: 209104-5

detail.hit.zdb_id: 1461794-8

SSG: 11

SSG: 12