We present Hubble Space Telescope (HST) photometry of a selected sample of 50 long-period, low-extinction Milky Way Cepheids measured on the same WFC3 F555W-, F814W-, and F160W-band photometric ...system as extragalactic Cepheids in Type Ia supernova host galaxies. These bright Cepheids were observed with the WFC3 spatial scanning mode in the optical and near-infrared to mitigate saturation and reduce pixel-to-pixel calibration errors to reach a mean photometric error of 5 mmag per observation. We use the new Gaia DR2 parallaxes and HST photometry to simultaneously constrain the cosmic distance scale and to measure the DR2 parallax zeropoint offset appropriate for Cepheids. We find the latter to be −46 13 as or 6 as for a fixed distance scale, higher than found from quasars, as expected for these brighter and redder sources. The precision of the distance scale from DR2 has been reduced by a factor of 2.5 because of the need to independently determine the parallax offset. The best-fit distance scale is 1.006 0.033, relative to the scale from Riess et al. with H0 = 73.24 km s−1 Mpc−1 used to predict the parallaxes photometrically, and is inconsistent with the scale needed to match the Planck 2016 cosmic microwave background data combined with ΛCDM at the 2.9 confidence level (99.6%). At 96.5% confidence we find that the formal DR2 errors may be underestimated as indicated. We identify additional errors associated with the use of augmented Cepheid samples utilizing ground-based photometry and discuss their likely origins. Including the DR2 parallaxes with all prior distance-ladder data raises the current tension between the late and early universe route to the Hubble constant to 3.8 (99.99%). With the final expected precision from Gaia, the sample of 50 Cepheids with HST photometry will limit to 0.5% the contribution of the first rung of the distance ladder to the uncertainty in H0.
A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic ...variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1-15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident.
Closed-loop systems that automate insulin delivery may improve glycemic outcomes in patients with type 1 diabetes.
In this 6-month randomized, multicenter trial, patients with type 1 diabetes were ...assigned in a 2:1 ratio to receive treatment with a closed-loop system (closed-loop group) or a sensor-augmented pump (control group). The primary outcome was the percentage of time that the blood glucose level was within the target range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter), as measured by continuous glucose monitoring.
A total of 168 patients underwent randomization; 112 were assigned to the closed-loop group, and 56 were assigned to the control group. The age range of the patients was 14 to 71 years, and the glycated hemoglobin level ranged from 5.4 to 10.6%. All 168 patients completed the trial. The mean (±SD) percentage of time that the glucose level was within the target range increased in the closed-loop group from 61±17% at baseline to 71±12% during the 6 months and remained unchanged at 59±14% in the control group (mean adjusted difference, 11 percentage points; 95% confidence interval CI, 9 to 14; P<0.001). The results with regard to the main secondary outcomes (percentage of time that the glucose level was >180 mg per deciliter, mean glucose level, glycated hemoglobin level, and percentage of time that the glucose level was <70 mg per deciliter or <54 mg per deciliter 3.0 mmol per liter) all met the prespecified hierarchical criterion for significance, favoring the closed-loop system. The mean difference (closed loop minus control) in the percentage of time that the blood glucose level was lower than 70 mg per deciliter was -0.88 percentage points (95% CI, -1.19 to -0.57; P<0.001). The mean adjusted difference in glycated hemoglobin level after 6 months was -0.33 percentage points (95% CI, -0.53 to -0.13; P = 0.001). In the closed-loop group, the median percentage of time that the system was in closed-loop mode was 90% over 6 months. No serious hypoglycemic events occurred in either group; one episode of diabetic ketoacidosis occurred in the closed-loop group.
In this 6-month trial involving patients with type 1 diabetes, the use of a closed-loop system was associated with a greater percentage of time spent in a target glycemic range than the use of a sensor-augmented insulin pump. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; iDCL ClinicalTrials.gov number, NCT03563313.).
We present new measurements of the parallax of seven long-period (≥10 days) Milky Way (MW) Cepheid variables (SS CMa, XY Car, VY Car, VX Per, WZ Sgr, X Pup, and S Vul) using one-dimensional ...astrometric measurements from spatial scanning of Wide-Field Camera 3 on the Hubble Space Telescope (HST). The observations were obtained at ∼6 month intervals over 4 years. The distances are 1.7-3.6 kpc, with a mean precision of 45 as (signal-to-noise ratio (S/N) 10) and a best precision of 29 as (S/N = 14). The accuracy of the parallaxes is demonstrated through independent analyses of >100 reference stars. This raises to 10 the number of long-period Cepheids with significant parallax measurements, 8 obtained from this program. We also present high-precision mean F555W, F814W, and F160W magnitudes of these Cepheids, allowing a direct, zeropoint-independent comparison to >1800 extragalactic Cepheids in the hosts of 19 SNe Ia. This sample addresses two outstanding systematic uncertainties affecting prior comparisons of MW and extragalactic Cepheids used to calibrate the Hubble constant (H0): their dissimilarity of periods and photometric systems. Comparing the new parallaxes to their predicted values derived from reversing the distance ladder gives a ratio (or independent scale for H0) of 1.037 0.036, consistent with no change and inconsistent at the 3.5 level with a ratio of 0.91 needed to match the value predicted by Planck cosmic microwave background data in concert with ΛCDM. Using these data instead to augment the Riess et al. measurement of H0 improves the precision to 2.3%, yielding 73.48 1.66 km s−1 Mpc−1, and the tension with Planck + ΛCDM increases to 3.7 . The future combination of Gaia parallaxes and HST spatial scanning photometry of 50 MW Cepheids can support a <1% calibration of H0.
To study virus-host protein interactions, knowledge about viral and host protein architectures and repertoires, their particular evolutionary mechanisms, and information on relevant sources of ...biological data is essential. The purpose of this review article is to provide a thorough overview about these aspects. Protein domains are basic units defining protein interactions, and the uniqueness of viral domain repertoires, their mode of evolution, and their roles during viral infection make viruses interesting models of study. Mutations at protein interfaces can reduce or increase their binding affinities by changing protein electrostatics and structural properties. During the course of a viral infection, both pathogen and cellular proteins are constantly competing for binding partners. Endogenous interfaces mediating intraspecific interactions-viral-viral or host-host interactions-are constantly targeted and inhibited by exogenous interfaces mediating viral-host interactions. From a biomedical perspective, blocking such interactions is the main mechanism underlying antiviral therapies. Some proteins are able to bind multiple partners, and their modes of interaction define how fast these "hub proteins" evolve. "Party hubs" have multiple interfaces; they establish simultaneous/stable (domain-domain) interactions, and tend to evolve slowly. On the other hand, "date hubs" have few interfaces; they establish transient/weak (domain-motif) interactions by means of short linear peptides (15 or fewer residues), and can evolve faster. Viral infections are mediated by several protein-protein interactions (PPIs), which can be represented as networks (protein interaction networks, PINs), with proteins being depicted as nodes, and their interactions as edges. It has been suggested that viral proteins tend to establish interactions with more central and highly connected host proteins. In an evolutionary arms race, viral and host proteins are constantly changing their interface residues, either to evade or to optimize their binding capabilities. Apart from gaining and losing interactions via rewiring mechanisms, virus-host PINs also evolve via gene duplication (paralogy); conservation (orthology); horizontal gene transfer (HGT) (xenology); and molecular mimicry (convergence). The last sections of this review focus on PPI experimental approaches and their limitations, and provide an overview of sources of biomolecular data for studying virus-host protein interactions.
In the small intestine, type 2 responses are regulated by a signaling circuit that involves tuft cells and group 2 innate lymphoid cells (ILC2s). Here, we identified the microbial metabolite ...succinate as an activating ligand for small intestinal (SI) tuft cells. Sequencing analyses of tuft cells isolated from the small intestine, gall bladder, colon, thymus, and trachea revealed that expression of tuft cell chemosensory receptors is tissue specific. SI tuft cells expressed the succinate receptor (SUCNR1), and providing succinate in drinking water was sufficient to induce a multifaceted type 2 immune response via the tuft-ILC2 circuit. The helminth Nippostrongylus brasiliensis and a tritrichomonad protist both secreted succinate as a metabolite. In vivo sensing of the tritrichomonad required SUCNR1, whereas N. brasiliensis was SUCNR1 independent. These findings define a paradigm wherein tuft cells monitor microbial metabolites to initiate type 2 immunity and suggest the existence of other sensing pathways triggering the response to helminths.
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•Expression of receptors enabling chemosensing on tuft cells is tissue specific•Tuft cells in the small intestine express the succinate receptor SUCNR1•Succinate is sufficient to induce a multifaceted type 2 immune response•Immune sensing of Tritrichomonas colonization by tuft cells requires SUCNR1
Tuft cells have been proposed to act as immune sentinels in multiple tissues. Nadjsombati and McGinty et al. now show that detection of the microbial metabolite succinate by tuft cells in the small intestine is sufficient to induce a type 2 immune response, suggesting that tuft cells monitor microbial metabolites to initiate type 2 immunity.
Reservoirs of infectious HIV-1 persist despite years of combination antiretroviral therapy and make curing HIV-1 infections a major challenge. Most of the proviral DNA resides in CD4⁺T cells. Some of ...these CD4⁺T cells are clonally expanded; most of the proviruses are defective. It is not known if any of the clonally expanded cells carry replication-competent proviruses. We report that a highly expanded CD4⁺ T-cell clone contains an intact provirus. The highly expanded clone produced infectious virus that was detected as persistent plasma viremia during cART in an HIV-1–infected patient who had squamous cell cancer. Cells containing the intact provirus were widely distributed and significantly enriched in cancer metastases. These results show that clonally expanded CD4⁺T cells can be a reservoir of infectious HIV-1.
A key component of biodiversity is the number and abundance of individuals (i.e. genotypes), and yet such intraspecific diversity is rarely considered when investigating the effects of biodiversity ...of mycorrhizal plants and fungi on ecosystem processes. Within a species, individuals vary considerably in important reproductive and functional attributes, including carbon fixation, mycelial growth and nutrient utilization, but this is driven by both genetic and environmental (including climatic) factors. The interactions between individual plants and mycorrhizal fungi can have important consequences for the maintenance of biodiversity and regulation of resource transfers in ecosystems. There is also emerging evidence that assemblages of genotypes may affect ecosystem processes to a similar extent as assemblages of species. The application of whole-genome sequencing and population genomics to mycorrhizal plants and fungi will be crucial to determine the extent to which individual variation in key functional attributes is genetically based. We argue the need to unravel the importance of the diversity (especially assemblages of different evenness and richness) of individuals of both mycorrhizal plants and fungi, and the need to take a ‘community genetics’ approach to better understand the functional significance of the biodiversity of mycorrhizal symbioses.
Mitochondria are composed of many small proteins that control protein synthesis, complex assembly, metabolism, and ion and reactive oxygen species (ROS) handling. We show that a skeletal muscle- and ...heart-enriched long non-coding RNA, LINC00116, encodes a highly conserved 56-amino-acid microprotein that we named mitoregulin (Mtln). Mtln localizes to the inner mitochondrial membrane, where it binds cardiolipin and influences protein complex assembly. In cultured cells, Mtln overexpression increases mitochondrial membrane potential, respiration rates, and Ca2+ retention capacity while decreasing mitochondrial ROS and matrix-free Ca2+. Mtln-knockout mice display perturbations in mitochondrial respiratory (super)complex formation and activity, fatty acid oxidation, tricarboxylic acid (TCA) cycle enzymes, and Ca2+ retention capacity. Blue-native gel electrophoresis revealed that Mtln co-migrates alongside several complexes, including the complex I assembly module, complex V, and supercomplexes. Under denaturing conditions, Mtln remains in high-molecular-weight complexes, supporting its role as a sticky molecular tether that enhances respiratory efficiency by bolstering protein complex assembly and/or stability.
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•LINC00116 encodes a single-pass transmembrane protein known as mitoregulin (Mtln)•Mtln appears to be a sticky inner mitochondrial membrane protein that binds cardiolipin•Mtln levels influence mitochondrial respiration, ROS, and Ca2+ retention capacity•Mtln-KO mice exhibit deficiencies in FAO, mCa2+ retention, and supercomplexes
Stein et al. show that the long non-coding RNA LINC00116 encodes a highly conserved single-pass transmembrane protein named mitoregulin (Mtln). Studies in cells and mice demonstrate that Mtln localizes to inner mitochondrial membranes, where it interacts with several complexes to influence mitochondrial membrane potential, respiration, Ca2+ retention capacity, ROS, and supercomplex levels.
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