Backbone-free duplex-stacked monomer nucleic acids exhibiting Watson-Crick selectivity.

We demonstrate that nucleic acid (NA) mononucleotide triphosphates (dNTPs and rNTPs), at sufficiently high concentration and low temperature in aqueous solution, can exhibit a phase transition in which chromonic columnar liquid crystal ordering spontaneously appears. Remarkably, this polymer-free state exhibits, in a self-assembly of NA monomers, the key structural elements of biological nucleic acids, including: long-ranged duplex stacking of base pairs, complementarity-dependent partitioning of molecules, and Watson-Crick selectivity, such that, among all solutions of adenosine, cytosine, guanine, and thymine NTPs and their binary mixtures, duplex columnar ordering is most stable in the A-T and C-G combinations

Supernova 2008bk and Its Red Supergiant Progenitor

We have obtained limited photometric and spectroscopic data for supernova (SN) 2008bk in NGC 7793, primarily at ≳ 150 days after explosion. We find that it is a Type II-Plateau (II-P) SN that most closely resembles the low-luminosity SN 1999br in NGC 4900. Given the overall similarity between the observed light curves and colors of SNe 2008bk and 1999br, we infer that the total visual extinction to SN 2008bk (A_V = 0.065 mag) must be almost entirely due to the Galactic foreground, similar to what has been assumed for SN 1999br. We confirm the identification of the putative red supergiant (RSG) progenitor star of the SN in high-quality g'r'i' images we had obtained in 2007 at the Gemini-South 8 m telescope. Little ambiguity exists in this progenitor identification, qualifying it as the best example to date, next to the identification of the star Sk –69°202 as the progenitor of SN 1987A. From a combination of photometry of the Gemini images with that of archival, pre-SN, Very Large Telescope JHK_s images, we derive an accurate observed spectral energy distribution (SED) for the progenitor. We find from nebular strong-intensity emission-line indices for several H II regions near the SN that the metallicity in the environment is likely subsolar (Z ≈ 0.6 Z_☉). The observed SED of the star agrees quite well with synthetic SEDs obtained from model RSG atmospheres with effective temperature T_(eff) = 3600 ± 50 K. We find, therefore, that the star had a bolometric luminosity with respect to the Sun of log (L_(bol)/L_☉) = 4.57 ± 0.06 and radius R* = 496 ± 34 R_☉ at ~6 months prior to explosion. Comparing the progenitor's properties with theoretical massive-star evolutionary models, we conclude that the RSG progenitor had an initial mass in the range of 8-8.5 M_☉. This mass is consistent with, albeit at the low end of, the inferred range of initial masses for SN II-P progenitors. It is also consistent with the estimated upper limit on the initial mass of the progenitor of SN 1999br, and it agrees with the low initial masses found for the RSG progenitors of other low-luminosity SNe II-P

Students Studying Students and Reasoning about Reasoning: A Qualitative Analysis

In this work, a faculty member takes a journey along with students as they enhance their understanding of how people solve mathematical problems through a mainly qualitative statistical project. Student authors of this paper registered for a problem solving seminar led by the faculty author, and then created and analyzed self-built assessment tools to explore problem solving techniques. Here we share our findings and recommendations, which we hope will inspire others to explore novel pedagogical techniques in the teaching of mathematical problem solving. We incorporate into our presentation ur voices, reflecting on how we and others solve problems

SN 2009bb: a Peculiar Broad-Lined Type Ic Supernova

Ultraviolet, optical, and near-infrared photometry and optical spectroscopy of the broad-lined Type Ic supernova (SN) 2009bb are presented, following the flux evolution from -10 to +285 days past B-band maximum. Thanks to the very early discovery, it is possible to place tight constraints on the SN explosion epoch. The expansion velocities measured from near maximum spectra are found to be only slightly smaller than those measured from spectra of the prototype broad-lined SN 1998bw associated with GRB 980425. Fitting an analytical model to the pseudo-bolometric light curve of SN 2009bb suggests that 4.1+-1.9 Msun of material was ejected with 0.22 +-0.06 Msun of it being 56Ni. The resulting kinetic energy is 1.8+-0.7x10^52 erg. This, together with an absolute peak magnitude of MB=-18.36+-0.44, places SN 2009bb on the energetic and luminous end of the broad-lined Type Ic (SN Ic) sequence. Detection of helium in the early time optical spectra accompanied with strong radio emission, and high metallicity of its environment makes SN 2009bb a peculiar object. Similar to the case for GRBs, we find that the bulk explosion parameters of SN 2009bb cannot account for the copious energy coupled to relativistic ejecta, and conclude that another energy reservoir (a central engine) is required to power the radio emission. Nevertheless, the analysis of the SN 2009bb nebular spectrum suggests that the failed GRB detection is not imputable to a large angle between the line-of-sight and the GRB beamed radiation. Therefore, if a GRB was produced during the SN 2009bb explosion, it was below the threshold of the current generation of gamma-ray instruments.Comment: Accepted for publication in Ap

Potential improvements in global carbon flux estimates from a network of laser heterodyne radiometer measurements of column carbon dioxide

We present observing system simulation experiments (OSSEs) to evaluate the impact of a proposed network of ground-based miniaturized laser heterodyne radiometer (mini-LHR) instruments that measure atmospheric column-averaged carbon dioxide (XCO2) with a 1 ppm precision. A particular strength of this passive measurement approach is its insensitivity to clouds and aerosols due to its direct sun pointing and narrow field of view (0.2). Developed at the NASA Goddard Space Flight Center (GSFC), these portable, low-cost mini-LHR instruments were designed to operate in tandem with the sun photometers used by the AErosol RObotic NETwork (AERONET). This partnership allows us to leverage the existing framework of AERONET's global ground network of more than 500 sites as well as providing simultaneous measurements of aerosols that are known to be a major source of error in retrievals of XCO2 from passive nadir-viewing satellite observations. We show, using the global 3-D GEOS-Chem chemistry transport model, that a deployment of 50 mini-LHRs at strategic (but not optimized) AERONET sites significantly improves our knowledge of global and regional land-based CO2 fluxes. This improvement varies seasonally and ranges 58%81% over southern lands, 47%76% over tropical lands, 71%92% over northern lands, and 64%91% globally. We also show significant added value from combining mini-LHR instruments with the existing ground-based NOAA flask network. Collectively, these data result in improved a posteriori CO2 flux estimates on spatial scales of 10 km2, especially over North America and Europe, where the ground-based networks are densest. Our studies suggest that the mini-LHR network could also play a substantive role in reducing carbon flux uncertainty in Arctic and tropical systems by filling in geographical gaps in measurements left by ground-based networks and space-based observations. A realized network would also provide necessary data for the quinquennial global stock takes that form part of the Paris Agreement

A MISSING-LINK IN THE SUPERNOVA-GRB CONNECTION: THE CASE OF SN 2012ap

Gamma Ray Bursts (GRBs) are characterized by ultra-relativistic outflows, while supernovae are generally characterized by non-relativistic ejecta. GRB afterglows decelerate rapidly usually within days, because their low-mass ejecta rapidly sweep up a comparatively larger mass of circumstellar material. However supernovae, with heavy ejecta, can be in nearly free expansion for centuries. Supernovae were thought to have non-relativistic outflows except for few relativistic ones accompanied by GRBs. This clear division was blurred by SN 2009bb, the first supernova with a relativistic outflow without an observed GRB. Yet the ejecta from SN 2009bb was baryon loaded, and in nearly-free expansion for a year, unlike GRBs. We report the first supernova discovered without a GRB, but with rapidly decelerating mildly relativistic ejecta, SN 2012ap. We discovered a bright and rapidly evolving radio counterpart driven by the circumstellar interaction of the relativistic ejecta. However, we did not find any coincident GRB with an isotropic fluence of more than a sixth of the fluence from GRB 980425. This shows for the first time that central engines in type Ic supernovae, even without an observed GRB, can produce both relativistic and rapidly decelerating outflows like GRBs.Comment: 8 pages, 5 figures, 1 table, accepted for publication in Ap

A systematic review of progranulin concentrations in biofluids in over 7,000 people—assessing the pathogenicity of GRN mutations and other influencing factors

Background: Pathogenic heterozygous mutations in the progranulin gene (GRN) are a key cause of frontotemporal dementia (FTD), leading to significantly reduced biofluid concentrations of the progranulin protein (PGRN). This has led to a number of ongoing therapeutic trials aiming to treat this form of FTD by increasing PGRN levels in mutation carriers. However, we currently lack a complete understanding of factors that affect PGRN levels and potential variation in measurement methods. Here, we aimed to address this gap in knowledge by systematically reviewing published literature on biofluid PGRN concentrations. Methods: Published data including biofluid PGRN concentration, age, sex, diagnosis and GRN mutation were collected for 7071 individuals from 75 publications. The majority of analyses (72%) had focused on plasma PGRN concentrations, with many of these (56%) measured with a single assay type (Adipogen) and so the influence of mutation type, age at onset, sex, and diagnosis were investigated in this subset of the data. Results: We established a plasma PGRN concentration cut-off between pathogenic mutation carriers and non-carriers of 74.8 ng/mL using the Adipogen assay based on 3301 individuals, with a CSF concentration cut-off of 3.43 ng/mL. Plasma PGRN concentration varied by GRN mutation type as well as by clinical diagnosis in those without a GRN mutation. Plasma PGRN concentration was significantly higher in women than men in GRN mutation carriers (p = 0.007) with a trend in non-carriers (p = 0.062), and there was a significant but weak positive correlation with age in both GRN mutation carriers and non-carriers. No significant association was seen with weight or with TMEM106B rs1990622 genotype. However, higher plasma PGRN levels were seen in those with the GRN rs5848 CC genotype in both GRN mutation carriers and non-carriers. Conclusions: These results further support the usefulness of PGRN concentration for the identification of the large majority of pathogenic mutations in the GRN gene. Furthermore, these results highlight the importance of considering additional factors, such as mutation type, sex and age when interpreting PGRN concentrations. This will be particularly important as we enter the era of trials for progranulin-associated FTD.</p

Special Low Protein Foods Prescribed in England for PKU Patients: An Analysis of Prescribing Patterns and Cost.

Patients with phenylketonuria (PKU) are reliant on special low protein foods (SLPFs) as part of their dietary treatment. In England, several issues regarding the accessibility of SLPFs through the national prescribing system have been highlighted. Therefore, prescribing patterns and expenditure on all SLPFs available on prescription in England (n = 142) were examined. Their costs in comparison to regular protein-containing (n = 182) and 'free-from' products (n = 135) were also analysed. Similar foods were grouped into subgroups (n = 40). The number of units and costs of SLPFs prescribed in total and per subgroup from January to December 2020 were calculated using National Health Service (NHS) Business Service Authority (NHSBSA) ePACT2 (electronic Prescribing Analysis and Cost Tool) for England. Monthly patient SLPF units prescribed were calculated using patient numbers with PKU and non-PKU inherited metabolic disorders (IMD) consuming SLPFs. This was compared to the National Society for PKU (NSPKU) prescribing guidance. Ninety-eight percent of SLPF subgroups (n = 39/40) were more expensive than regular and 'free-from' food subgroups. However, costs to prescribe SLPFs are significantly less than theoretical calculations. From January to December 2020, 208,932 units of SLPFs were prescribed (excluding milk replacers), costing the NHS £2,151,973 (including milk replacers). This equates to £962 per patient annually, and prescribed amounts are well below the upper limits suggested by the NSPKU, indicating under prescribing of SLPFs. It is recommended that a simpler and improved system should be implemented. Ideally, specialist metabolic dietitians should have responsibility for prescribing SLPFs. This would ensure that patients with PKU have the necessary access to their essential dietary treatment, which, in turn, should help promote dietary adherence and improve metabolic control

Altered plasma protein profiles in genetic FTD – a GENFI study

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Methods: Blood samples from 693 participants in the GENetic Frontotemporal Dementia Initiative study were analysed using a multiplexed antibody array targeting 158 proteins. Results: We found 13 elevated proteins in symptomatic mutation carriers, when comparing plasma levels from people diagnosed with genetic FTD to healthy non-mutation controls and 10 proteins that were elevated compared to presymptomatic mutation carriers. Conclusion: We identified plasma proteins with altered levels in symptomatic mutation carriers compared to non-carrier controls as well as to presymptomatic mutation carriers. Further investigations are needed to elucidate their potential as fluid biomarkers of the disease process.Open access funding provided by Karolinska Institute. C.G. received funding from EU Joint Programme—Neurodegenerative Disease Research -Prefrontals Vetenskapsrådet Dnr 529–2014-7504, Vetenskapsrådet 2015–02926, Vetenskapsrådet 2018–02754, the Swedish FTD Inititative-Schörling Foundation, Alzheimer Foundation, Brain Foundation, Dementia Foundation and Region Stockholm ALF-project. PN received funding from KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, the Swedish FTD Inititative-Schörling Foundation and Åhlén foundation. D.G. received support from the EU Joint Programme—Neurodegenerative Disease Research and the Italian Ministry of Health (PreFrontALS) grant 733051042. E.F. has received funding from a Canadian Institute of Health Research grant #327387. F.M. received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease. J.B.R. has received funding from the Welcome Trust (103838) and is supported by the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (SUAG/051 G101400) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215–20014). J.C.V.S. was supported by the Dioraphte Foundation grant 09–02-03–00, Association for Frontotemporal Dementias Research Grant 2009, Netherlands Organization for Scientific Research grant HCMI 056–13-018, ZonMw Memorabel (Deltaplan Dementie, project number 733 051 042), Alzheimer Nederland and the Bluefield Project. J.D.R. is supported by the Bluefield Project and the National Institute for Health and Care Research University College London Hospitals Biomedical Research Centre, and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and a Miriam Marks Brain Research UK Senior Fellowship. M.M. has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and Ontario Brain Institute. M.O. has received funding from Germany’s Federal Ministry of Education and Research (BMBF). R.S-V. is supported by Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2) and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). R.V. has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. This work was also supported by the EU Joint Programme—Neurodegenerative Disease Research GENFI-PROX grant [2019–02248; to J.D.R., M.O., B.B., C.G., J.C.V.S. and M.S.info:eu-repo/semantics/publishedVersio

Elevated CSF and plasma complement proteins in genetic frontotemporal dementia: results from the GENFI study

© The Author(s) 2022 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Neuroinflammation is emerging as an important pathological process in frontotemporal dementia (FTD), but biomarkers are lacking. We aimed to determine the value of complement proteins, which are key components of innate immunity, as biomarkers in cerebrospinal fluid (CSF) and plasma of presymptomatic and symptomatic genetic FTD mutation carriers. Methods: We measured the complement proteins C1q and C3b in CSF by ELISAs in 224 presymptomatic and symptomatic GRN, C9orf72 or MAPT mutation carriers and non-carriers participating in the Genetic Frontotemporal Dementia Initiative (GENFI), a multicentre cohort study. Next, we used multiplex immunoassays to measure a panel of 14 complement proteins in plasma of 431 GENFI participants. We correlated complement protein levels with corresponding clinical and neuroimaging data, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP). Results: CSF C1q and C3b, as well as plasma C2 and C3, were elevated in symptomatic mutation carriers compared to presymptomatic carriers and non-carriers. In genetic subgroup analyses, these differences remained statistically significant for C9orf72 mutation carriers. In presymptomatic carriers, several complement proteins correlated negatively with grey matter volume of FTD-related regions and positively with NfL and GFAP. In symptomatic carriers, correlations were additionally observed with disease duration and with Mini Mental State Examination and Clinical Dementia Rating scale® plus NACC Frontotemporal lobar degeneration sum of boxes scores. Conclusions: Elevated levels of CSF C1q and C3b, as well as plasma C2 and C3, demonstrate the presence of complement activation in the symptomatic stage of genetic FTD. Intriguingly, correlations with several disease measures in presymptomatic carriers suggest that complement protein levels might increase before symptom onset. Although the overlap between groups precludes their use as diagnostic markers, further research is needed to determine their potential to monitor dysregulation of the complement system in FTD.This study was supported in the Netherlands by Memorabel grants from Deltaplan Dementie (ZonMw and Alzheimer Nederland; grant numbers 733050813, 733050103, 733050513), the Bluefield Project to Cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300), and the European Joint Programme—Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD: 733051024); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the MRC UK GENFI grant (MR/M023664/1) and the JPND GENFI-PROX grant (2019-02248); JDR is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH); ASE supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK; IJS is supported by the Alzheimer’s Association; JBR is supported by the Wellcome Trust (103838); in Spain by the Fundació Marató de TV3 (20143810 to RSV); in Germany by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy—ID 390857198) and by grant 779357 “Solve-RD” from the Horizon 2020 Research and Innovation Programme (to MS); in Sweden by grants from the Swedish FTD Initiative funded by the Schörling Foundation, grants from JPND PreFrontALS Swedish Research Council (VR) 529–2014-7504, Swedish Research Council (VR) 2015–02926, Swedish Research Council (VR) 2018–02754, Swedish Brain Foundation, Swedish Alzheimer Foundation, Stockholm County Council ALF, Swedish Demensfonden, Stohnes foundation, Gamla Tjänarinnor, Karolinska Institutet Doctoral Funding, and StratNeuro. HZ is a Wallenberg Scholar.info:eu-repo/semantics/publishedVersio