The Pim kinases control rapamycin-resistant T cell survival and activation

Although Pim-1 or Pim-2 can contribute to lymphoid transformation when overexpressed, the physiologic role of these kinases in the immune response is uncertain. We now report that T cells from Pim-1−/−Pim-2−/− animals display an unexpected sensitivity to the immunosuppressant rapamycin. Cytokine-induced Pim-1 and Pim-2 promote the rapamycin-resistant survival of lymphocytes. The endogenous function of the Pim kinases was not restricted to the regulation of cell survival. Like the rapamycin target TOR, the Pim kinases also contribute to the regulation of lymphocyte growth and proliferation. Although rapamycin has a minimal effect on wild-type T cell expansion in vitro and in vivo, it completely suppresses the response of Pim-1−/−Pim-2−/− cells. Thus, endogenous levels of the Pim kinases are required for T cells to mount an immune response in the presence of rapamycin. The existence of a rapamycin-insensitive pathway that regulates T cell growth and survival has important implications for understanding how rapamycin functions as an immunomodulatory drug and for the development of complementary immunotherapeutics

Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis

Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer’s disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease

An intron variant of the GLI family zinc finger 3 (GLI3) gene differentiates resistance training-induced muscle fiber hypertrophy in younger men

We examined the association between genotype and resistance training-induced changes (12 wk) in dual x-ray energy absorptiometry (DXA)-derived lean soft tissue mass (LSTM) as well as muscle fiber cross-sectional area (fCSA; vastus lateralis; n = 109; age = 22 ± 2 y, BMI = 24.7 ± 3.1 kg/m2). Over 315 000 genetic polymorphisms were interrogated from muscle using DNA microarrays. First, a targeted investigation was performed where single nucleotide polymorphisms (SNP) identified from a systematic literature review were related to changes in LSTM and fCSA. Next, genome-wide association (GWA) studies were performed to reveal associations between novel SNP targets with pre- to post-training change scores in mean fCSA and LSTM. Our targeted investigation revealed no genotype-by-time interactions for 12 common polymorphisms regarding the change in mean fCSA or change in LSTM. Our first GWA study indicated no SNP were associated with the change in LSTM. However, the second GWA study indicated two SNP exceeded the significance level with the change in mean fCSA (P = 6.9 × 10–7 for rs4675569, 1.7 × 10–6 for rs10263647). While the former target is not annotated (chr2:205936846 (GRCh38.p12)), the latter target (chr7:41971865 (GRCh38.p12)) is an intron variant of the GLI Family Zinc Finger 3 (GLI3) gene. Follow-up analyses indicated fCSA increases were greater in the T/C and C/C GLI3 genotypes than the T/T GLI3 genotype (P \u3c.05). Data from the Auburn cohort also revealed participants with the T/C and C/C genotypes exhibited increases in satellite cell number with training (P \u3c.05), whereas T/T participants did not. Additionally, those with the T/C and C/C genotypes achieved myonuclear addition in response to training (P \u3c.05), whereas the T/T participants did not. In summary, this is the first GWA study to examine how polymorphisms associate with the change in hypertrophy measures following resistance training. Future studies are needed to determine if the GLI3 variant differentiates hypertrophic responses to resistance training given the potential link between this gene and satellite cell physiology

The UK Centre for Astrobiology:A Virtual Astrobiology Centre. Accomplishments and Lessons Learned, 2011-2016

Authors thank all those individuals, UK research councils, funding agencies, nonprofit organisations, companies and corporations and UK and non-UK government agencies, who have so generously supported our aspirations and hopes over the last 5 years and supported UKCA projects. They include the STFC, the Engineering and Physical Sciences Research Council (EPSRC), the Natural Environmental Research Council (NERC), the EU, the UK Space Agency, NASA, the European Space Agency (ESA), The Crown Estate, Cleveland Potash and others. The Astrobiology Academy has been supported by the UK Space Agency (UKSA), National Space Centre, the Science and Technology Facilities Council (STFC), Dynamic Earth, The Royal Astronomical Society, The Rotary Club (Shetlands) and the NASA Astrobiology Institute.The UK Centre for Astrobiology (UKCA) was set up in 2011 as a virtual center to contribute to astrobiology research, education, and outreach. After 5 years, we describe this center and its work in each of these areas. Its research has focused on studying life in extreme environments, the limits of life on Earth, and implications for habitability elsewhere. Among its research infrastructure projects, UKCA has assembled an underground astrobiology laboratory that has hosted a deep subsurface planetary analog program, and it has developed new flow-through systems to study extraterrestrial aqueous environments. UKCA has used this research backdrop to develop education programs in astrobiology, including a massive open online course in astrobiology that has attracted over 120,000 students, a teacher training program, and an initiative to take astrobiology into prisons. In this paper, we review these activities and others with a particular focus on providing lessons to others who may consider setting up an astrobiology center, institute, or science facility. We discuss experience in integrating astrobiology research into teaching and education activities.Publisher PDFPeer reviewe

Improved Measurement of the Partial-Rate CP Asymmetry in B+ -> K0pi+ and B- -> K0bar pi- Decays

We report an improved measurement of the partial-rate CP asymmetry in B+ => K0pi+ and B- => K0bar pi- decays. The analysis is based on a data sample of 85 million BBbar pairs collected at the Upsilon(4S) resonance with the Belle detector at the KEKB e+ e- storage ring. We measure Acp(K0pi+-) = 0.07^{+0.09 +0.01}_{-0.08 -0.03}, where the first and second errors are statistical and systematic, respectively; the corresponding 90% confidence-level interval is -0.10 < Acp(K0pi+-) < 0.22 .Comment: 7 pages, 8 figures, submitted to Phys. Rev.

Improved Measurements of Branching Fractions for B->Kpi, pipi and KK Decays

We report improved measurements of branching fractions for $B\to K\pi$, $\pi^+\pi^-$, $\pi^+\pi^0$ and $K\bar{K}$ decays based on a data sample of 85.0 million $B\bar{B}$ pairs collected at the $\Upsilon (4S)$ resonance with the Belle detector at the KEKB $e^+e^-$ storage ring. This data sample is almost three times larger than the sample previously used. We observe clear signals for $B\to K\pi$, $\pi^+\pi^-$ and $\pi^+\pi^0$ decays and set upper limits on $B\to K\bar{K}$ decays. The results can be used to give model-dependent constraints on the CKM angle $\phi_3$, as well as limits on the hadronic uncertainty in the time-dependent analysis of the angle $\phi_2$.Comment: 10 pages, 1 figure, 4 tables. Submitted to Phys. Rev. D Rapid Communications. Several corrections were mad

Measurement of branching fraction ratios and CP asymmetries in B±→DCPK±B^{\pm} \to D_{CP}K^{\pm}

We report results on the decay $B^{-} \to D_{CP}K^{-}$ and its charge conjugate using a data sample of 85.4 million $B\bar{B}$ pairs recorded at the $\Upsilon(4S)$ resonance with the Belle detector at the KEKB asymmetric $e^{+}e^{-}$ storage ring. Ratios of branching fractions of Cabibbo-suppressed to Cabibbo-favored processes are determined to be ${\cal B}(B^- \to D^0 K^-)/{\cal B}(B^- \to D^0 \pi^-)= 0.077 \pm 0.005(stat) \pm 0.006(sys)$, ${\cal B}(B^- \to D_1 K^-)/{\cal B}(B^- \to D_1 \pi^-) = 0.093 \pm 0.018(stat) \pm 0.008(sys)$ and ${\cal B}(B^- \to D_2 K^-)/{\cal B}(B^- \to D_2 \pi^-) = 0.108 \pm 0.019(stat) \pm 0.007(sys)$ where the indices 1 and 2 represent the CP=+1 and CP=$-$1 eigenstates of the $D^{0}-\bar{D^{0}}$ system, respectively. We find the partial-rate charge asymmetries for $B^{-} \to D_{CP}K^{-}$ to be ${\cal{A}}_1 = 0.06 \pm 0.19(stat) \pm 0.04(sys)$ and ${\cal{A}}_2 = -0.19 \pm 0.17(stat) \pm 0.05(sys)$.Comment: 10 pages, 3 figures, submitted to Physical Review

Evidence for CP-Violating Asymmetries in B0->pi+pi- Decays and Constraints on the CKM Angle phi2

We present an improved measurement of CP-violating asymmetries in B0 -> pi+ pi- decays based on a 78 fb^-1 data sample collected at the Y(4S) resonance with the Belle detector at the KEKB asymmetric-energy e+e- collider. We reconstruct one neutral B meson as a B0 -> pi+ pi- CP eigenstate and identify the flavor of the accompanying B meson from inclusive properties of its decay products. We apply an unbinned maximum likelihood fit to the distribution of the time intervals between the two B meson decay points. The fit yields the CP-violating asymmetry amplitudes Apipi = +0.77+/-0.27(stat)+/-0.08(syst) and Spipi = -1.23+/-0.41(stat)+0.08/-0.07(syst), where the statistical uncertainties are determined from Monte Carlo pseudo-experiments. We obtain confidence intervals for CP-violating asymmetry parameters Apipi and Spipi based on a frequentist approach. We rule out the CP-conserving case, Apipi=Spipi=0, at the 99.93% confidence level. We discuss how these results constrain the value of the CKM angle phi2.Comment: 26 pages, 13 figures, submitted to Phys. Rev.

Measurement of Branching Fractions and Charge Asymmetries for Two-Body B Meson Decays with Charmonium

We report branching fractions and charge asymmetries for exclusive decays of charged and neutral B mesons to two-body final states containing a charmonium meson, J/psi or psi(2S). This result is based on a 29.4 fb^{-1} data sample collected at the Upsilon(4S) resonance with the Belle detector at the KEKB asymmetric e+e- collider.Comment: 13 pages, 5 figures, revte

Development of Risk Prediction Equations for Incident Chronic Kidney Disease

IMPORTANCE Early identification of individuals at elevated risk of developing chronic kidney disease (CKD) could improve clinical care through enhanced surveillance and better management of underlying health conditions.OBJECTIVE To develop assessment tools to identify individuals at increased risk of CKD, defined by reduced estimated glomerular filtration rate (eGFR).DESIGN, SETTING, AND PARTICIPANTS Individual-level data analysis of 34 multinational cohorts from the CKD Prognosis Consortium including 5 222 711 individuals from 28 countries. Data were collected from April 1970 through January 2017. A 2-stage analysis was performed, with each study first analyzed individually and summarized overall using a weighted average. Because clinical variables were often differentially available by diabetes status, models were developed separately for participants with diabetes and without diabetes. Discrimination and calibration were also tested in 9 external cohorts (n = 2 253 540).EXPOSURES Demographic and clinical factors.MAIN OUTCOMES AND MEASURES Incident eGFR of less than 60 mL/min/1.73 m(2).RESULTS Among 4 441 084 participants without diabetes (mean age, 54 years, 38% women), 660 856 incident cases (14.9%) of reduced eGFR occurred during a mean follow-up of 4.2 years. Of 781 627 participants with diabetes (mean age, 62 years, 13% women), 313 646 incident cases (40%) occurred during a mean follow-up of 3.9 years. Equations for the 5-year risk of reduced eGFR included age, sex, race/ethnicity, eGFR, history of cardiovascular disease, ever smoker, hypertension, body mass index, and albuminuria concentration. For participants with diabetes, the models also included diabetes medications, hemoglobin A(1c), and the interaction between the 2. The risk equations had a median C statistic for the 5-year predicted probability of 0.845 (interquartile range [IQR], 0.789-0.890) in the cohorts without diabetes and 0.801 (IQR, 0.750-0.819) in the cohorts with diabetes. Calibration analysis showed that 9 of 13 study populations (69%) had a slope of observed to predicted risk between 0.80 and 1.25. Discrimination was similar in 18 study populations in 9 external validation cohorts; calibration showed that 16 of 18 (89%) had a slope of observed to predicted risk between 0.80 and 1.25.CONCLUSIONS AND RELEVANCE Equations for predicting risk of incident chronic kidney disease developed from more than 5 million individuals from 34 multinational cohorts demonstrated high discrimination and variable calibration in diverse populations. Further study is needed to determine whether use of these equations to identify individuals at risk of developing chronic kidney disease will improve clinical care and patient outcomes.</p