Ligand Binding Pathways and Conformational Transitions of the HIV Protease

It is important to determine the binding pathways and mechanisms of ligand molecules to target proteins to effectively design therapeutic drugs. Molecular dynamics (MD) is a promising computational tool that allows us to simulate protein–drug binding at an atomistic level. However, the gap between the time scales of current simulations and those of many drug binding processes has limited the usage of conventional MD, which has been reflected in studies of the HIV protease. Here, we have applied a robust enhanced simulation method, Gaussian accelerated molecular dynamics (GaMD), to sample binding pathways of the XK263 ligand and associated protein conformational changes in the HIV protease. During two of 10 independent GaMD simulations performed over 500–2500 ns, the ligand was observed to successfully bind to the protein active site. Although GaMD-derived free energy profiles were not fully converged because of insufficient sampling of the complex system, the simulations still allowed us to identify relatively low-energy intermediate conformational states during binding of the ligand to the HIV protease. Relative to the X-ray crystal structure, the XK263 ligand reached a minimum root-mean-square deviation (RMSD) of 2.26 Å during 2.5 μs of GaMD simulation. In comparison, the ligand RMSD reached a minimum of only ~5.73 Å during an earlier 14 μs conventional MD simulation. This work highlights the enhanced sampling power of the GaMD approach and demonstrates its wide applicability to studies of drug–receptor interactions for the HIV protease and by extension many other target proteins

Contribution of the Oral and Gastrointestinal Microbiomes to Bloodstream Infections in Leukemia Patients

Bloodstream infections (BSIs) pose a significant mortality risk for acute myeloid leukemia (AML) patients. It has been previously reported that intestinal domination (\u3e30% relative abundance [RA] attributed to a single taxon) with the infecting taxa often precedes BSI in stem cell transplant patients. Using 16S rRNA amplicon sequencing, we analyzed oral and stool samples from 63 AML patients with BSIs to determine the correlation between the infectious agent and microbiome composition. Whole-genome sequencing and antimicrobial susceptibilities were performed on all BSI isolates. Species-level detection of the infectious agent and presence of antibiotic resistance determinants in the stool

Transit Hunt for Young and Maturing Exoplanets (THYME). VIII. A Pleiades-age Association Harboring Two Transiting Planetary Systems from Kepler

Young planets provide a window into the early stages and evolution of planetary systems. Ideal planets for such research are in coeval associations, where the parent population can precisely determine their ages. We describe a young association (MELANGE-3) in the Kepler field, which harbors two transiting planetary systems (KOI-3876 and Kepler-970). We identify MELANGE-3 by searching for kinematic and spatial overdensities around Kepler planet hosts with high levels of lithium. To determine the age and membership of MELANGE-3, we combine new high-resolution spectra with archival light curves, velocities, and astrometry of stars near KOI-3876 spatially and kinematically. We use the resulting rotation sequence, lithium levels, and color-magnitude diagram of candidate members to confirm the presence of a coeval 105 ± 10 Myr population. MELANGE-3 may be part of the recently identified Theia 316 stream. For the two exoplanet systems, we revise the stellar and planetary parameters, taking into account the newly determined age. Fitting the 4.5 yr Kepler light curves, we find that KOI-3876b is a 2.0 ± 0.1 R⊕ planet on a 19.58 day orbit, while Kepler-970 b is a 2.8 ± 0.2 R⊕ planet on a 16.73 day orbit. KOI-3876 was previously flagged as an eclipsing binary, which we rule out using radial velocities from APOGEE and statistically validate the signal as planetary in origin. Given its overlap with the Kepler field, MELANGE-3 is valuable for studies of spot evolution on year timescales, and both planets contribute to the growing work on transiting planets in young stellar associations

Hazy with a chance of star spots: constraining the atmosphere of the young planet, K2-33b

Although all-sky surveys have led to the discovery of dozens of young planets, little is known about their atmospheres. Here, we present multi-wavelength transit data for the super Neptune-sized exoplanet, K2-33b -- the youngest (~10 Myr) transiting exoplanet to-date. We combined photometric observations of K2-33 covering a total of 33 transits spanning >2 years, taken from K2, MEarth, Hubble, and Spitzer. The transit photometry spanned from the optical to the near-infrared (0.6-4.5$\mu$m), enabling us to construct a transmission spectrum of the planet. We find that the optical transit depths are nearly a factor of two deeper than those from the near-infrared. This difference holds across multiple datasets taken over years, ruling out issues of data analysis and unconstrained systematics. Surface inhomogeneities on the young star can reproduce some of the difference, but required spot coverage fractions (>60%) are ruled out by the observed stellar spectrum(<20%). We find a better fit to the transmission spectrum using photochemical hazes, which were predicted to be strong in young, moderate-temperature, and large-radius planets like K2-33b. A tholin haze with CO as the dominant gaseous carbon carrier in the atmosphere can reasonably reproduce the data with small or no stellar surface inhomogeneities, consistent with the stellar spectrum. The HST data quality is insufficient for the detection of any molecular features. More observations would be required to fully characterize the hazes and spot properties and confirm the presence of CO suggested by current data.Comment: Accepted to AJ. 26 pages, 14 figures, 6 table

Hazy with a Chance of Star Spots: Constraining the Atmosphere of Young Planet K2-33b

Although all-sky surveys have led to the discovery of dozens of young planets, little is known about their atmospheres. Here, we present multiwavelength transit data for the super-Neptune sized exoplanet, K2-33b-the youngest (~10 Myr) transiting exoplanet to date. We combined photometric observations of K2-33 covering a total of 33 transits spanning >2 yr, taken from K2, MEarth, the Hubble Space Telescope (HST), and Spitzer. The transit photometry spanned from the optical to the near-infrared (0.6-4.5 μm), enabling us to construct a transmission spectrum of the planet. We find that the optical transit depths are nearly a factor of 2 deeper than those from the near-infrared. This difference holds across multiple data sets taken over years, ruling out issues of data analysis and unconstrained systematics. Surface inhomogeneities on the young star can reproduce some of the difference, but required spot coverage fractions (>60%) are ruled out by the observed stellar spectrum (<20%). We find a better fit to the transmission spectrum using photochemical hazes, which were predicted to be strong in young, moderate-temperature, and large-radius planets like K2-33b. A tholin haze with CO as the dominant gaseous carbon carrier in the atmosphere can reasonably reproduce the data with small or no stellar surface inhomogeneities, consistent with the stellar spectrum. The HST data quality is insufficient for the detection of any molecular features. More observations would be required to fully characterize the hazes and spot properties and confirm the presence of CO suggested by current data

Quantitative phosphoproteome analysis of embryonic stem cell differentiation toward blood

Murine embryonic stem (ES) cells can differentiate in vitro into three germ layers (endodermic, mesodermic, ectodermic). Studies on the differentiation of these cells to specific early differentiation stages has been aided by an ES cell line carrying the Green Fluorescent Protein (GFP) targeted to the Brachyury (Bry) locus which marks mesoderm commitment. Furthermore, expression of the Vascular Endothelial Growth Factor receptor 2 (Flk1) along with Bry defines hemangioblast commitment. Isobaric-tag for relative and absolute quantification (iTRAQTM) and phosphopeptide enrichment coupled to liquid chromatography separation and mass spectrometry allow the study of phosphorylation changes occurring at different stages of ES cell development using Bry and Flk1 expression respectively. We identified and relatively quantified 37 phosphoentities which are modulated during mesoderm-induced ES cells differentiation, comparing epiblast-like, early mesoderm and hemangioblast-enriched cells. Among the proteins differentially phosphorylated toward mesoderm differentiation were: the epigenetic regulator Dnmt3b, the protein kinase GSK3b, the chromatin remodeling factor Smarcc1, the transcription factor Utf1; as well as protein specifically related to stem cell differentiation, as Eomes, Hmga2, Ints1 and Rif1. As most key factors regulating early hematopoietic development have also been implicated in various types of leukemia, understanding the post-translational modifications driving their regulation during normal development could result in a better comprehension of their roles during abnormal hematopoiesis in leukemia

Does Physical Activity Moderate The Association Between Shorter Leukocyte Telomere Length and Incident Coronary Heart Disease? Data From 54,180 UK Biobank Participants

Telomere shortening is a biological aging hallmark. The effect of short telomere length may be targeted by increased physical activity to reduce the risk of multiple aging-related diseases, including coronary heart disease (CHD). The objective was to assess the moderation effect of accelerometer-based physical activity (aPA) on the association between shorter leukocyte telomere length (LTL) relatively in the population sample and incident CHD. Data were from the UK Biobank participants with well-calibrated accelerometer data for at least 6.5 days (n = 54,180). Relative mean LTL at baseline (5–6 years prior to aPA assessment) was measured in T/S ratio, using a multiplex quantitative polymerase chain reaction (qPCR) technology, by comparing the amount of the telomere amplification product (T) to that of a single-copy gene (S). aPA measures included total number of events (at least 10-s continued physical activity \u3e 32 milligravities [mg]), total volume, mean duration, mean intensity, and peak intensity of all events. LTL, aPA measures, and their interactions were associated with incident CHD (mean follow-up 6.8 years) using Cox proportional hazards models adjusting for covariates. Longer LTL (relative to the sample distribution) was associated with reduced incidence of CHD (adjusted hazard ratio [aHR] = 0.94 per standard deviation [SD] increase in LTL, [95% CI, 0.90 to 0.99], P = .010). Incidence of CHD was reduced by higher total volume of aPA (aHR = 0.82 per SD increase in LTL, [95% CI, 0.71 to 0.95], P = .010) but increased by higher total number of events (aHR = 1.11 per SD increase in LTL, [95% CI, 1.02 to 1.21], P = .020) after controlling for other aPA measures and covariates. However, none of the interactions between LTL and aPA measures was statistically significant (P = .171)