Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To ...investigate the importance of miRNAs in mouse insulin secreting β-cells, we have generated mice with a β-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Δ/wt)), RIP-Cre(+/-)Dicer1(flox/flox) mice (RIP-Cre Dicer1(Δ/Δ)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased β-cell mass, reduced numbers of granules within the β-cells and reduced granule docking in adult RIP-Cre Dicer1(Δ/Δ) mice. β-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal β-cell development as 2-week old RIP-Cre Dicer1(Δ/Δ) mice showed ultrastructurally normal β-cells and intact insulin secretion. In conclusion, we have demonstrated that a β-cell specific disruption of the miRNAs network, although allowing for apparently normal β-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.
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The widespread occurrence and significance of chiral compounds does not only require new methods for their enantioselective synthesis but also efficient tools that allow rapid determination of the ...absolute configuration, enantiomeric composition and overall concentration of nonracemic mixtures. Although chiral analysis is a frequently encountered challenge in the chemical, environmental, materials and health sciences it is typically addressed with slow and laborious chromatographic or NMR spectroscopic techniques. We now show with almost 40 analytes representing 5 different compound classes, including mono-alcohols which are particularly challenging sensing targets, that this task can be solved very quickly by chiroptical sensing with a single, readily available arylisocyanate probe. The probe reacts smoothly and irreversibly with amino and alcohol groups when an organocatalyst is used at room temperature toward urea or carbamate products exhibiting characteristic UV and CD signals above 300 nm. The UV signal induction is not enantioselective and correlated to the total concentration of both enantiomers, the concomitant generation of a CD band allows determination of the enantiomeric composition from the same sample, and the sense of the induced Cotton effect reveals the absolute configuration by comparison with a reference. This approach eliminates complications that can arise when enantiomerically impure NMR derivatizing agents are used and it outperforms time-consuming HPLC protocols. The generation of distinct UV and CD signals at high wavelengths overcomes issues with insufficient resolution of overlapping signals often encountered with chiral NMR solvating agents that rely on weak binding forces. The broad solvent compatibility is another noteworthy and important characteristic of this assay. It addresses frequently encountered problems with insufficient solubility of polar analytes, for example pharmaceuticals, in standard mobile phase mixtures required for chiral HPLC analysis. We anticipate that the broad application spectrum, ruggedness and practicality of organocatalytic chiroptical sensing with aryliso(thio)cyanate probes together with the availability of automated CD multi-well plate readers carry exceptional promise to accelerate chiral compound development projects at reduced cost and with less waste production.
Organocatalysis with a simple arylisocyanate probe enables accelerated optical concentration and enantiomeric ratio determination of a large variety of chiral compounds based on straightforward UV/CD analysis.
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IJS, KILJ, NUK, UL, UM, UPUK
Norovirus genogroup II genotype 4 (GII.4) has been the predominant cause of viral gastroenteritis since 1996. Here we show that during the winter of 2014-2015, an emergent variant of a previously ...rare norovirus GII.17 genotype, Kawasaki 2014, predominated in Hong Kong and outcompeted contemporary GII.4 Sydney 2012 in hospitalized cases. GII.17 cases were significantly older than GII.4 cases. Root-to-tip and Bayesian BEAST analyses estimate GII.17 viral protein 1 (VP1) evolves one order of magnitude faster than GII.4 VP1. Residue substitutions and insertion occur in four of five inferred antigenic epitopes, suggesting immune evasion. Sequential GII.4-GII.17 infections are noted, implicating a lack of cross-protection. Virus bound to saliva of secretor histo-blood groups A, B and O, indicating broad susceptibility. This fast-evolving, broadly recognizing and probably immune-escaped emergent GII.17 variant causes severe gastroenteritis and hospitalization across all age groups, including populations who were previously less vulnerable to GII.4 variants; therefore, the global spread of GII.17 Kawasaki 2014 needs to be monitored.
BackgroundThe goal of this study was to characterize viral loads and factors affecting viral clearance in persons with severe influenza MethodsThis was a 1-year prospective, observational study ...involving consecutive adults hospitalized with influenza. Nasal and throat swabs were collected at presentation, then daily until 1 week after symptom onset. Real-time reverse-transcriptase polymerase chain reaction to determine viral RNA concentration and virus isolation were performed. Viral RNA concentration was analyzed using multiple linear or logistic regressions or mixed-effect models ResultsOne hundred forty-seven inpatients with influenza A (H3N2) infection were studied (mean age ± standard deviation, 72±16 years). Viral RNA concentration at presentation positively correlated with symptom scores and was significantly higher than that among time-matched outpatients (control subjects). Patients with major comorbidities had high viral RNA concentration even when presenting >2 days after symptom onset (mean ± standard deviation, 5.06±1.85 vs 3.62±2.13 log10 copies/mL; P=.005; β, +0.86 95% confidence interval, +0.03 to +1.68). Viral RNA concentration demonstrated a nonlinear decrease with time; 26% of oseltamivir-treated and 57% of untreated patients had RNA detected at 1 week after symptom onset. Oseltamivir started on or before symptom day 4 was independently associated with an accelerated decrease in viral RNA concentration (mean β standard error, −1.19 0.43 and −0.68 0.33 log10 copies/mL for patients treated on day 1 and days 2–3, respectively; P<.05) and viral RNA clearance at 1 week (odds ratio, 0.10 95% confidence interval, 0.03–0.35 and 0.30 0.10–0.90 for patients treated on day 1–2 and day 3–4, respectively). Conversely, major comorbidities and systemic corticosteroid use for asthma or chronic obstructive pulmonary disease exacerbations were associated with slower viral clearance. Viral RNA clearance was associated with a shorter hospital stay (7.0 vs 13.5 days; P=.001) ConclusionPatients hospitalized with severe influenza have more active and prolonged viral replication. Weakened host defenses slow viral clearance, whereas antivirals started within the first 4 days of illness enhance viral clearance
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We make publicly available a catalog of calibrated environmental measures for galaxies in the five 3D-Hubble Space Telescope (HST)/CANDELS deep fields. Leveraging the spectroscopic and grism ...redshifts from the 3D-HST survey, multiwavelength photometry from CANDELS, and wider field public data for edge corrections, we derive densities in fixed apertures to characterize the environment of galaxies brighter than mag in the redshift range . By linking observed galaxies to a mock sample, selected to reproduce the 3D-HST sample selection and redshift accuracy, each 3D-HST galaxy is assigned a probability density function of the host halo mass, and a probability that it is a central or a satellite galaxy. The same procedure is applied to a z = 0 sample selected from Sloan Digital Sky Survey. We compute the fraction of passive central and satellite galaxies as a function of stellar and halo mass, and redshift, and then derive the fraction of galaxies that were quenched by environment specific processes. Using the mock sample, we estimate that the timescale for satellite quenching is it is longer at lower stellar mass or lower redshift, but remarkably independent of halo mass. This indicates that, in the range of environments commonly found within the 3D-HST sample ( ), satellites are quenched by exhaustion of their gas reservoir in the absence of cosmological accretion. We find that the quenching times can be separated into a delay phase, during which satellite galaxies behave similarly to centrals at fixed stellar mass, and a phase where the star formation rate drops rapidly ( Gyr), as shown previously at z = 0. We conclude that this scenario requires satellite galaxies to retain a large reservoir of multi-phase gas upon accretion, even at high redshift, and that this gas sustains star formation for the long quenching times observed.
Recent advances are enabling delivery of precision genomic medicine to cancer clinics. While the majority of approaches profile panels of selected genes or hotspot regions, comprehensive data ...provided by whole genome and transcriptome sequencing and analysis (WGTA) presents an opportunity to align a much larger proportion of patients to therapies.
Samples from 570 patients with advanced or metastatic cancer of diverse types enrolled in the Personalized OncoGenomics (POG) program underwent WGTA. DNA-based data, including mutations, copy number, and mutation signatures, were combined with RNA-based data, including gene expression and fusions, to generate comprehensive WGTA profiles. A multidisciplinary molecular tumour board used WGTA profiles to identify and prioritize clinically actionable alterations and inform therapy. Patient responses to WGTA-informed therapies were collected.
Clinically actionable targets were identified for 83% of patients, 37% of whom received WGTA-informed treatments. RNA expression data were particularly informative, contributing to 67% of WGTA-informed treatments; 25% of treatments were informed by RNA expression alone. Of a total 248 WGTA-informed treatments, 46% resulted in clinical benefit. RNA expression data were comparable to DNA-based mutation and copy number data in aligning to clinically beneficial treatments. Genome signatures also guided therapeutics including platinum, PARP inhibitors, and immunotherapies. Patients accessed WGTA-informed treatments through clinical trials (19%), off-label use (35%), and as standard therapies (46%) including those which would not otherwise have been the next choice of therapy, demonstrating the utility of genomic information to direct use of chemotherapies as well as targeted therapies.
Integrating RNA expression and genome data illuminated treatment options that resulted in 46% of treated patients experiencing positive clinical benefit, supporting the use of comprehensive WGTA profiling in clinical cancer care.
NCT02155621
•A prospective study of 570 patients used whole genome and transcriptome analysis (WGTA) for real-time treatment options•Of 248 WGTA-informed treatments, 46% resulted in clinical benefit to the patient•RNA expression information was as valuable as DNA-based information for selecting treatments with clinical benefit•Integrated data informs selection of standard-of-care therapies, clinical trial enrollment and off-label use•This study supports the use of whole genome and transcriptome analysis in clinical cancer care
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Jupiter Energetic Particle Detector Instruments (JEDI) on the Juno Jupiter polar-orbiting, atmosphere-skimming, mission to Jupiter will coordinate with the several other space physics instruments ...on the Juno spacecraft to characterize and understand the space environment of Jupiter’s polar regions, and specifically to understand the generation of Jupiter’s powerful aurora. JEDI comprises 3 nearly-identical instruments and measures at minimum the energy, angle, and ion composition distributions of ions with energies from H:20 keV and O: 50 keV to >1 MeV, and the energy and angle distribution of electrons from <40 to >500 keV. Each JEDI instrument uses microchannel plates (MCP) and thin foils to measure the times of flight (TOF) of incoming ions and the pulse height associated with the interaction of ions with the foils, and it uses solid state detectors (SSD’s) to measure the total energy (
E
) of both the ions and the electrons. The MCP anodes and the SSD arrays are configured to determine the directions of arrivals of the incoming charged particles. The instruments also use fast triple coincidence and optimum shielding to suppress penetrating background radiation and incoming UV foreground. Here we describe the science objectives of JEDI, the science and measurement requirements, the challenges that the JEDI team had in meeting these requirements, the design and operation of the JEDI instruments, their calibrated performances, the JEDI inflight and ground operations, and the initial measurements of the JEDI instruments in interplanetary space following the Juno launch on 5 August 2011. Juno will begin its prime science operations, comprising 32 orbits with dimensions 1.1×40 RJ, in mid-2016.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The first standardized, global assessment of these fishes, using Red List criteria, reveals threatened species needing protection.
There is growing concern that in spite of the healthy status of ...several epipelagic (living near the surface) fish stocks (
1
), some scombrid (tunas, bonitos, mackerels, and Spanish mackerels) and billfish (swordfish and marlins) species are heavily overfished and that there is a lack of resolve to protect against overexploitation driven by high prices (
2
–
5
). Many populations are exploited by multinational fisheries whose regulation, from a political perspective, is exceedingly difficult. Thus, assessment and management is complicated and sometimes ineffective (
4
). Regional Fisheries Management Organizations (RFMOs) were created to manage and conserve scombrids and billfishes because of their transnational distributions and widespread economic importance (
6
). However, species-specific catch data for many scombrids and billfishes are not collected or are aggregated with other species. Even for the larger tunas, for which relatively rich data exist, population assessments and data are complex (
1
) and are difficult to combine across RFMOs, which prompts a need for alternative means of assessment.
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GABAergic circuits are critical for the synchronization and higher order function of brain networks. Defects in this circuitry are linked to neuropsychiatric diseases, including bipolar disorder, ...schizophrenia, and autism. Work in cultured neurons has shown that ankyrin-G plays a key role in the regulation of GABAergic synapses on the axon initial segment and somatodendritic domain of pyramidal neurons, where it interacts directly with the GABA
receptor-associated protein (GABARAP) to stabilize cell surface GABA
receptors. Here, we generated a knock-in mouse model expressing a mutation that abolishes the ankyrin-G/GABARAP interaction (Ank3 W1989R) to understand how ankyrin-G and GABARAP regulate GABAergic circuitry in vivo. We found that Ank3 W1989R mice exhibit a striking reduction in forebrain GABAergic synapses resulting in pyramidal cell hyperexcitability and disruptions in network synchronization. In addition, we identified changes in pyramidal cell dendritic spines and axon initial segments consistent with compensation for hyperexcitability. Finally, we identified the ANK3 W1989R variant in a family with bipolar disorder, suggesting a potential role of this variant in disease. Our results highlight the importance of ankyrin-G in regulating forebrain circuitry and provide novel insights into how ANK3 loss-of-function variants may contribute to human disease.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background. A need for quadrivalent vaccines to cover both lineages of influenza B has been raised. Information on the circulation status of influenza B lineages and the associated hospitalization ...rates is important to assist evidence-based decision making. This retrospective study revealed the situation in a subtropical city over a 10-year period. Methods. Sequences of 268 influenza B isolates were analyzed to identify the circulating pool of virus lineages for each year. Hospital records and population census data were used to estimate annual age-specific hospitalization rates. Results. Cocirculation with 2 influenza B lineages was found in 9 of the 10 years. Only in 6 of the 10 years had the vaccine strain successfully matched with the lineage that was found in >50% of the circulating pool. Six years were predominated by one lineage (occupying >80% of the circulating pool), and these years had higher (average, 1.4-fold) hospitalization rates. Matching between vaccine and circulating lineage was achieved only in 2 of the 6 "predominated years." The Yamagata lineage accounted for most (5/6) of the predominated years. Overall, 24% of influenza admissions were due to influenza B, and influenza B contributed to a higher proportion (41.9%) among children and young teenagers (5–14 years old). Conclusions. Cocirculation with 2 influenza B lineages is common in the subtropical region. To predict the next predominant lineage proves to be difficult. Influenza B accounts for a substantial fraction of influenza-associated hospitalizations, especially among children and young teenagers. Quadrivalent vaccines may improve the effectiveness of influenza vaccination programs.
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