Renormalization group running of neutrino parameters in the inverse seesaw model

We perform a detailed study of the renormalization group equations in the inverse seesaw model. Especially, we derive compact analytical formulas for the running of the neutrino parameters in the standard model and the minimal supersymmetric standard model, and illustrate that, due to large Yukawa coupling corrections, significant running effects on the leptonic mixing angles can be naturally obtained in the proximity of the electroweak scale, perhaps even within the reach of the LHC. In general, if the mass spectrum of the light neutrinos is nearly degenerate, the running effects are enhanced to experimentally accessible levels, well suitable for the investigation of the underlying dynamics behind the neutrino mass generation and the lepton flavor structure. In addition, the effects of the seesaw thresholds are discussed, and a brief comparison to other seesaw models is carried out.Comment: 30 pages, 7 figures. Final version published in Phys. Rev. D. v3: Typo in Eq. (33) correcte

Liraglutide and renal outcomes in type 2 diabetes

In a randomized, controlled trial that compared liraglutide, a glucagon-like peptide 1 analogue, with placebo in patients with type 2 diabetes and high cardiovascular risk who were receiving usual care, we found that liraglutide resulted in lower risks of the primary end point (nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes) and death. However, the long-term effects of liraglutide on renal outcomes in patients with type 2 diabetes are unknown

The structural biology of patellamide biosynthesis

This work was supported by grants from the ERC339367 (JHN and MJ) and BBSRCBB/K015508/1 (JHN and MJ).The biosynthetic pathways for patellamide and related natural products have recently been studied by structural biology. These pathways produce molecules that have a complex framework and exhibit a diverse array of activity due to the variability of the amino acids that are found in them. As these molecules are difficult to synthesize chemically, exploitation of their properties has been modest. The patellamide pathway involves amino acid heterocyclization, peptide cleavage, peptide macrocyclization, heterocycle oxidation and epimerization; closely related products are also prenylated. Enzyme activities have been identified for all these transformations except epimerization, which may be spontaneous. This review highlights the recent structural and mechanistic work on amino acid heterocyclization, peptide cleavage and peptide macrocyclization. This work should help in using the enzymes to produce novel analogs of the natural products enabling an exploitation of their properties.Peer reviewe

Welche Rolle spielen Kinder in Schulen und Kindertagesstätten bei der Übertragung von SARS-CoV-2? – Eine evidenzbasierte Perspektive

Are children and adolescents relevant disease vectors when it comes to the transmission of SARS-CoV-2? Moreover, do they play a role as relevant disease vectors in a~school or kindergarten setting? These questions could not be sufficiently answered at the beginning of the pandemic. Consequently, schools and childcare facilities were closed to stop the spread of SARS-CoV\hbox-2. Over the past few months, researchers have gained a~more detailed understanding of the overall pandemic situation. The SARS-CoV\hbox-2 infection rate in children below 10~years of age in 2020 has been substantially lower than in adults. In addition, it showed that children had a~milder course of disease.Although a~majority of the analyses performed in schools and childcare facilities revealed that the virus is transmitted in these facilities, these transmissions did not, however, have a~considerable influence on the overall rate of new infections. Despite these findings, German politicians continue to advocate for the closure of childcare facilities, including schools, to fight the pandemic, whereas many specialist societies such as the German Society for Pediatric Infectious Diseases (DGPI) have emphasized that such closures should be the measure of last resort in combating the pandemic. The same message is also conveyed by a~German evidence-based S3~guideline established by an interdisciplinary expert group that had already put forward clear recommendations for high incidences in the general population at the beginning of February 2021, indicating that school closures were only required in exceptional cases.In this article, we would like to outline the situation based on the currently available data, try to predict the future, and discuss the circumstances necessary to realize normal classroom teaching without accepting the risk of an uncontrolled spread of SARS-CoV\hbox-2. ZUSAMMENFASSUNG Sind Kinder und Jugendliche relevante Vektoren für die Übertragung von SARS-CoV-2? Und welche Rolle spielt es, wenn sie eine Schule oder Kindertagesstätte besuchen? Diese Fragen konnten zu Beginn der Pandemie nur unzureichend beantwortet werden. So wurden weltweit Schulen und Kinderbetreuungseinrichtungen geschlossen, um die Verbreitung von SARS-CoV\hbox-2 einzudämmen. Inzwischen ist die Rolle von Kindern im Gesamtgeschehen der Pandemie jedoch klarer. Die Rate von SARS-CoV-2-Infektionen bei Kindern unter 10~Jahren war im Jahr 2020 deutlich niedriger als die bei Erwachsenen. Zudem zeigte sich bei Kindern ein deutlich milderer Verlauf der Erkrankung.Analysen zu Ausbrüchen an Schulen und Kinderbetreuungseinrichtungen kamen mehrheitlich zu dem Ergebnis, dass die Weitergabe des Virus in den Einrichtungen zwar stattfindet, jedoch das Infektionsgeschehen insgesamt nicht maßgeblich beeinflusst. Trotz dieser Erkenntnisse hält die deutsche Politik Schulschließungen weiterhin für einen integralen Baustein der Pandemiebekämpfung, wohingegen viele Fachgesellschaften, wie die Deutsche Gesellschaft für Pädiatrische Infektiologie e. V. (DGPI), betonen, dass es sich um das letzte Mittel in der Bekämpfung der Pandemie handeln sollte. Diese Botschaft hat auch eine evidenzbasierte und auf interdisziplinärem Expertenkonsens aufgebaute S3-Leitlinie, die bereits Anfang Februar 2021 klare Empfehlungen für Zeiten hoher Inzidenzen in der Gesamtbevölkerung ausgesprochen hat, die Schulschließungen nur noch in Ausnahmefällen für notwendig erachten.In diesem Artikel möchten wir die Datenlage mit Stand Juni 2021 zu diesem Thema darlegen, einen Blick in die Zukunft wagen und diskutieren, unter welchen Umständen ein regulärer Präsenzunterricht gelingen kann, ohne das Risiko einer unkontrollierten Ausbreitung von SARS-CoV\hbox-2 in Kauf nehmen zu müssen

Prediction of the Effects of Liraglutide on Kidney and Cardiovascular Outcomes Based on Short-Term Changes in Multiple Risk Markers

Aims: The LEADER trial demonstrated that the glucagon-like peptide-1 receptor agonist (GLP1-RA) liraglutide reduces kidney and cardiovascular (CV) risk in patients with type 2 diabetes. We previously developed a Parameter Response Efficacy (PRE) score that translates multiple short-term risk marker changes, from baseline to first available follow-up measurement, into a predicted long-term drug effect on clinical outcomes. The objective of this study was to assess the accuracy of the PRE score in predicting the efficacy of liraglutide in reducing the risk of kidney and CV outcomes. Methods: Short-term changes in glycated hemoglobin (HbA1c), systolic blood pressure (BP), urinary-albumin-creatinine-ratio (UACR), hemoglobin, body weight, high-density-lipoprotein (HDL) cholesterol, low-density-lipoprotein (LDL) cholesterol, and potassium were monitored in the LEADER trial. Associations between risk markers and kidney or CV outcomes were established using a multivariable Cox proportional hazards model in a separate pooled database of 6,355 patients with type 2 diabetes. The regression coefficients were then applied to the short-term risk markers in the LEADER trial to predict the effects of liraglutide on kidney (defined as a composite of doubling of serum creatinine or end-stage kidney disease) and CV (defined as a composite of non-fatal myocardial infarction, non-fatal stroke, and CV death) outcomes. Results: Liraglutide compared to placebo reduced HbA1c (1.4%), systolic BP (3.0 mmHg), UACR (13.2%), body weight (2.3 kg), hemoglobin (2.6 g/L), and increased HDL-cholesterol (0.01 mmol/L) (all p-values <0.01). Integrating multiple risk marker changes in the PRE score resulted in a predicted relative risk reduction (RRR) of 16.2% (95% CI 13.7–18.6) on kidney outcomes which was close to the observed RRR of 15.5% (95% CI -9.0–34.6). For the CV outcome, the PRE score predicted a 7.6% (95% CI 6.8–8.3) RRR, which was less than the observed 13.2% (95% CI 3.2–22.2) RRR. Conclusion: Integrating multiple short-term risk markers using the PRE score adequately predicted the effect of liraglutide on the composite kidney outcome. However, the PRE score underestimated the effect of liraglutide for the composite CV outcome, suggesting that the risk markers included in the PRE score do not fully capture the CV benefit of liraglutide

Expression, regulation and function of phosphofructo-kinase/fructose-biphosphatases (PFKFBs) in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia cells

<p>Abstract</p> <p>Background</p> <p>Glucocorticoids (GCs) cause apoptosis and cell cycle arrest in lymphoid cells and constitute a central component in the therapy of lymphoid malignancies, most notably childhood acute lymphoblastic leukemia (ALL). PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-2), a kinase controlling glucose metabolism, was identified by us previously as a GC response gene in expression profiling analyses performed in children with ALL during initial systemic GC mono-therapy. Since deregulation of glucose metabolism has been implicated in apoptosis induction, this gene and its relatives, PFKFB1, 3, and 4, were further analyzed.</p> <p>Methods</p> <p>Gene expression analyses of isolated lymphoblasts were performed on Affymetrix HGU133 Plus 2.0 microarrays. GCRMA normalized microarray data were analyzed using R-Bioconductor packages version 2.5. Functional gene analyses of <it>PFKFB2-15A </it>and <it>-15B </it>isoforms were performed by conditional gene over-expression experiments in the GC-sensitive T-ALL model CCRF-CEM.</p> <p>Results</p> <p>Expression analyses in additional ALL children, non-leukemic individuals and leukemic cell lines confirmed frequent <it>PFKFB2 </it>induction by GC in most systems sensitive to GC-induced apoptosis, particularly T-ALL cells. The 3 other family members, in contrast, were either absent or only weakly expressed (<it>PFKFB1 </it>and <it>4</it>) or not induced by GC (<it>PFKFB3</it>). Conditional PFKFB2 over-expression in the CCRF-CEM T-ALL <it>in vitro </it>model revealed that its 2 splice variants (PFKFB2-15A and PFKFB2-15B) had no detectable effect on cell survival. Moreover, neither PFKFB2 splice variant significantly affected sensitivity to, or kinetics of, GC-induced apoptosis.</p> <p>Conclusions</p> <p>Our data suggest that, at least in the model system investigated, PFKFB2 is not an essential upstream regulator of the anti-leukemic effects of GC.</p

Chromatin-Remodeling Components of the BAF Complex Facilitate Reprogramming

SummaryReprogramming of somatic cells achieved by combination of the four transcription factors Oct4, Sox2, Klf4, and c-Myc has very low efficiency. To increase the reprogramming efficiency and better understand the process, we sought to identify factors that mediate reprogramming with higher efficiency. We established an assay to screen nuclear fractions from extracts of pluripotent mouse cells based on Oct4 reactivation. Using proteomics, we identified components of the ATP-dependent BAF chromatin-remodeling complex, which significantly increases reprogramming efficiency when used together with the four factors. The reprogrammed cells could transmit to the germline and exhibited pluripotency. Reprogramming remained highly efficient when c-Myc was not present but BAF components were overexpressed. BAF complex components mediate this effect by facilitating enhanced Oct4 binding to target promoters during reprogramming. Thus, somatic cell reprogramming using chromatin-remodeling molecules represents an efficient method of generating reprogrammed cells

Population-Attributable Fractions of Modifiable Lifestyle Factors for CKD and Mortality in Individuals With Type 2 Diabetes: A Cohort Study

BackgroundWe quantified the impact of lifestyle and dietary modifications on chronic kidney disease (CKD) by estimating population-attributable fractions (PAFs).Study DesignObservational cohort study.Setting & ParticipantsMiddle-aged adults with type 2 diabetes but without severe albuminuria from the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET; n=6,916).FactorsModifiable lifestyle/dietary risk factors, such as physical activity, size of social network, alcohol intake, tobacco use, diet, and intake of various food items.OutcomesThe primary outcome was CKD, ascertained as moderate to severe albuminuria or ≥5% annual decline in estimated glomerular filtration rate (eGFR) after 5.5 years. The competing risk for death was considered. PAF was defined as the proportional reduction in CKD or mortality (within 5.5 years) that would occur if exposure to a risk factor was changed to an optimal level.ResultsAt baseline, median urinary albumin-creatinine ratio and eGFR were 6.6 (IQR, 2.9-25.0) mg/mmol and 71.5 (IQR, 58.1-85.9) mL/min/1.73m2, respectively. After 5.5 years, 704 (32.5%) participants developed albuminuria, 1,194 (55.2%) had a ≥5% annual eGFR decline, 267 (12.3%) had both, and 1,022 (14.8%) had died. Being physically active every day has PAFs of 5.1% (95% CI, 0.5%-9.6%) for CKD and 12.3% (95% CI, 4.9%-19.1%) for death. Among food items, increasing vegetable intake would have the largest impact on population health. Considering diet, weight, physical activity, tobacco use, and size of social network, exposure to less than optimum levels gives PAFs of 13.3% (95% CI, 5.5%-20.9%) for CKD and 37.5% (95% CI, 27.8%-46.7%) for death. For the 17.8 million middle-aged Americans with diabetes, improving 1 of these lifestyle behaviors to the optimal range could reduce the incidence or progression of CKD after 5.5 years by 274,000 and the number of deaths within 5.5 years by 405,000.LimitationsAscertainment of changes in kidney measures does not precisely match the definitions for incidence or progression of CKD.ConclusionsHealthy lifestyle and diet are associated with less CKD and mortality and may have a substantial impact on population kidney health