| 1. |
|
|
| 2. |
- Klonoff, D. C., et al.
(författare)
-
A Glycemia Risk Index (GRI) of Hypoglycemia and Hyperglycemia for Continuous Glucose Monitoring Validated by Clinician Ratings
- 2022
-
Ingår i: Journal of Diabetes Science and Technology. - : SAGE Publications. - 1932-2968.
-
Tidskriftsartikel (refereegranskat)abstract
- Background: A composite metric for the quality of glycemia from continuous glucose monitor (CGM) tracings could be useful for assisting with basic clinical interpretation of CGM data. Methods: We assembled a data set of 14-day CGM tracings from 225 insulin-treated adults with diabetes. Using a balanced incomplete block design, 330 clinicians who were highly experienced with CGM analysis and interpretation ranked the CGM tracings from best to worst quality of glycemia. We used principal component analysis and multiple regressions to develop a model to predict the clinician ranking based on seven standard metrics in an Ambulatory Glucose Profile: very low–glucose and low-glucose hypoglycemia; very high–glucose and high-glucose hyperglycemia; time in range; mean glucose; and coefficient of variation. Results: The analysis showed that clinician rankings depend on two components, one related to hypoglycemia that gives more weight to very low-glucose than to low-glucose and the other related to hyperglycemia that likewise gives greater weight to very high-glucose than to high-glucose. These two components should be calculated and displayed separately, but they can also be combined into a single Glycemia Risk Index (GRI) that corresponds closely to the clinician rankings of the overall quality of glycemia (r = 0.95). The GRI can be displayed graphically on a GRI Grid with the hypoglycemia component on the horizontal axis and the hyperglycemia component on the vertical axis. Diagonal lines divide the graph into five zones (quintiles) corresponding to the best (0th to 20th percentile) to worst (81st to 100th percentile) overall quality of glycemia. The GRI Grid enables users to track sequential changes within an individual over time and compare groups of individuals. Conclusion: The GRI is a single-number summary of the quality of glycemia. Its hypoglycemia and hyperglycemia components provide actionable scores and a graphical display (the GRI Grid) that can be used by clinicians and researchers to determine the glycemic effects of prescribed and investigational treatments.
|
|
| 3. |
|
|
| 4. |
- Minikel, EV, et al.
(författare)
-
Quantifying prion disease penetrance using large population control cohorts
- 2016
-
Ingår i: Science translational medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 8:322, s. 322ra9-
-
Tidskriftsartikel (refereegranskat)abstract
- Large genomic reference data sets reveal a spectrum of pathogenicity in the prion protein gene and provide genetic validation for a therapeutic strategy in prion disease.
|
|
| 5. |
- Hicks, KG, et al.
(författare)
-
Protein-metabolite interactomics of carbohydrate metabolism reveal regulation of lactate dehydrogenase
- 2023
-
Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 379:6636, s. 996-1003
-
Tidskriftsartikel (refereegranskat)abstract
- Metabolic networks are interconnected and influence diverse cellular processes. The protein-metabolite interactions that mediate these networks are frequently low affinity and challenging to systematically discover. We developed mass spectrometry integrated with equilibrium dialysis for the discovery of allostery systematically (MIDAS) to identify such interactions. Analysis of 33 enzymes from human carbohydrate metabolism identified 830 protein-metabolite interactions, including known regulators, substrates, and products as well as previously unreported interactions. We functionally validated a subset of interactions, including the isoform-specific inhibition of lactate dehydrogenase by long-chain acyl–coenzyme A. Cell treatment with fatty acids caused a loss of pyruvate-lactate interconversion dependent on lactate dehydrogenase isoform expression. These protein-metabolite interactions may contribute to the dynamic, tissue-specific metabolic flexibility that enables growth and survival in an ever-changing nutrient environment.
|
|
| 6. |
|
|
| 7. |
- Kappos, Ludwig, et al.
(författare)
-
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study
- 2018
-
Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 391, s. 1263-1273
-
Tidskriftsartikel (refereegranskat)abstract
- © 2018 Elsevier Ltd Background: No treatment has consistently shown efficacy in slowing disability progression in patients with secondary progressive multiple sclerosis (SPMS). We assessed the effect of siponimod, a selective sphingosine 1-phosphate (S1P) receptor 1,5 modulator, on disability progression in patients with SPMS. Methods: This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatme nt arms, patients (age 18–60 years) with SPMS and an Expanded Disability Status Scale score of 3·0–6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. Findings: 1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65–0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. Interpretation: Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. Funding: Novartis Pharma AG.
|
|
| 8. |
- Rosen, R., et al.
(författare)
-
Identification, Location, and Emergence of the Cercaria of Leuceruthrus micropteri (Trematoda: Azygiidae) Recovered from the Snail Pleurocera semicarinata (Gastropoda: Pleuroceridae) at North Elkhorn Creek, Kentucky
- 2019
-
Ingår i: Comparative Parasitology. - : Helminthological Society. - 1525-2647. ; 86:2, s. 142-148
-
Tidskriftsartikel (refereegranskat)abstract
- We have encountered azygiid cercariae shed from the snail, Pleurocera semicarinata, at North Elkhorn Creek, Scott County, Kentucky, since 2004. Samples of these cercariae were frozen, and their DNA analyzed. The resulting alignment total length of 394 base pairs from partial 5.8S and 28S genes and the complete ribosomal internal transcribed spacer 2 (ITS2) confirmed our identification of the North Elkhorn Creek cercaria as Leuceruthrus micropteri. There was a 100% match to adult L. micropteri obtained from largemouth bass at Wheeler Reservoir, Alabama. Prevalence of infections by L. micropteri in snails was low at North Elkhorn Creek during 2004 (1.8% [7/400]) and 2017 (0.9% [4/432]). Quantitative data were obtained regarding cercarial emergence (daily and long-term patterns), site of infection of rediae, and functional morphology of the distome and tail stem. Most (96.1%) cercariae were released during the 12-hr light phase of a 12-hr light:12-hr dark cycle, and the average number of cercariae released per 7 snails per day over 21 d ranged between 0 and 2.3. Individual snails most frequently shed between 0 and 2 (range 0-6) cercariae per day. Snails shed cercariae for an average of 12.6 +/- 3.1 d of the 21-d sampling period. Histology revealed rediae in the bottom whorl of the snail within the perintestinal sinus separated from the mantle cavity and gills by a thin mantle membrane. Envelopment of the distome body by the tail stem in vitro required less than 2 min. The lip of the tail chamber moved forward over the distome body until the latter was completely enclosed.
|
|
| 9. |
- Schifferdecker, Anna, et al.
(författare)
-
Alcohol dehydrogenase gene ADH3 activates glucose alcoholic fermentation in genetically engineered Dekkera bruxellensis yeast.
- 2016
-
Ingår i: Applied Microbiology and Biotechnology. - : Springer Science and Business Media LLC. - 1432-0614 .- 0175-7598.
-
Tidskriftsartikel (refereegranskat)abstract
- Dekkera bruxellensis is a non-conventional Crabtree-positive yeast with a good ethanol production capability. Compared to Saccharomyces cerevisiae, its tolerance to acidic pH and its utilization of alternative carbon sources make it a promising organism for producing biofuel. In this study, we developed an auxotrophic transformation system and an expression vector, which enabled the manipulation of D. bruxellensis, thereby improving its fermentative performance. Its gene ADH3, coding for alcohol dehydrogenase, was cloned and overexpressed under the control of the strong and constitutive promoter TEF1. Our recombinant D. bruxellensis strain displayed 1.4 and 1.7 times faster specific glucose consumption rate during aerobic and anaerobic glucose fermentations, respectively; it yielded 1.2 times and 1.5 times more ethanol than did the parental strain under aerobic and anaerobic conditions, respectively. The overexpression of ADH3 in D. bruxellensis also reduced the inhibition of fermentation by anaerobiosis, the "Custer effect". Thus, the fermentative capacity of D. bruxellensis could be further improved by metabolic engineering.
|
|
