In EVEREST II (Endovascular Valve Edge-to-Edge Repair Study), treatment of mitral regurgitation (MR) with a novel percutaneous device showed superior safety compared with surgery, but less effective ...reduction in MR at 1 year.
This study sought to evaluate the final 5-year clinical outcomes and durability of percutaneous mitral valve (MV) repair with the MitraClip device compared with conventional MV surgery.
Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the device or conventional MV surgery in a 2:1 ratio (178:80). Patients prospectively consented to 5 years of follow-up.
At 5 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the as-treated population was 44.2% versus 64.3% in the percutaneous repair and surgical groups, respectively (p = 0.01). The difference was driven by increased rates of 3+ to 4+ MR (12.3% vs. 1.8%; p = 0.02) and surgery (27.9% vs. 8.9%; p = 0.003) with percutaneous repair. After percutaneous repair, 78% of surgeries occurred within the first 6 months. Beyond 6 months, rates of surgery and moderate-to-severe MR were comparable between groups. Five-year mortality rates were 20.8% and 26.8% (p = 0.4) for percutaneous repair and surgery, respectively. In multivariable analysis, treatment strategy was not associated with survival.
Patients treated with percutaneous repair more commonly required surgery for residual MR during the first year after treatment, but between 1- and 5-year follow-up, comparably low rates of surgery for MV dysfunction with either percutaneous or surgical therapy endorse the durability of MR reduction with both repair techniques. (EVEREST II Pivotal Study High Risk Registry; NCT00209274).
Because tenofovir alafenamide (TAF) leads to significantly lower plasma tenofovir concentrations than tenofovir disoproxil fumarate (TDF) and is a stronger substrate for P-glycoprotein (P-gp) than ...TDF, TAF could lead to decreased central nervous system (CNS) tenofovir exposure than TDF. We aimed to determine if switching from TDF to TAF increases the risk of neuronal injury, by quantifying plasma levels of neurofilament light protein (NfL), a sensitive marker of neuronal injury in HIV CNS infection.
Plasma NfL concentration was measured at baseline, week 24, and week 84 in stored plasma samples from 416 participants (272 switching to elvitegravir (E)/cobicistat (C)/emtricitabine (F)/TAF and 144 continuing E/C/F/TDF) enrolled in the randomized, active-controlled, multicenter, open-label, noninferiority Gilead GS-US-292-0109 trial.
While plasma NfL levels in both groups were within the normal range, we found a small but significant decrease in the E/C/F/TAF arm after 84 weeks from a geometric mean of 9.3 to 8.8 pg/mL (5.4% decline, 95% CI 2.0-8.4, p = 0.002). This change was significantly different (p = 0.001) from that of the E/C/F/TDF arm, in which plasma NfL concentration changed from 9.7 pg/mL at baseline to 10.2 pg/mL at week 84 (5.8% increase, 95% CI -0.8-12.9, p = 0.085). This increase is in line with what could be expected in normal ageing. Plasma NfL concentrations significantly correlated with age. No correlation was found between plasma NfL and serum creatinine.
We found no biomarker evidence of CNS injury when switching from TDF to TAF. It is unclear whether the small decrease in plasma NfL found after switch to TAF is of any clinical relevance, particularly with plasma NfL levels in both arms remaining within the limits found in HIV-negative controls. These results indicate that switching from TDF to TAF appears safe with regard to neuronal injury.
Tryptophan C-mannosylation is an unusual co-translational protein modification performed by metazoans and apicomplexan protists. The prevalence and biological functions of this modification are ...poorly understood, with progress in the field hampered by a dearth of convenient tools for installing and detecting the modification. Here, we engineer a yeast system to produce a diverse array of proteins with and without tryptophan C-mannosylation and interrogate the modification's influence on protein stability and function. This system also enabled mutagenesis studies to identify residues of the glycosyltransferase and its protein substrates that are crucial for catalysis. The collection of modified proteins accrued during this work facilitated the generation and thorough characterization of monoclonal antibodies against tryptophan C-mannosylation. These antibodies empowered proteomic analyses of the brain C-glycome by enriching for peptides possessing tryptophan C-mannosylation. This study revealed many new modification sites on proteins throughout the secretory pathway with both conventional and non-canonical consensus sequences.
For the past half-century, the study of organizations has been an active area within sociology. I provide an overview of the emergence of this specialty during the second half of the twentieth ...century, its relation to the larger field of organization studies, and the important theoretical advances associated with the adoption of an open system framework during the 1960s. Among the recent trends I describe are changes in our conceptions of organization boundaries, strategies, and controls, and the beginning of a shift from an entity-based to a process-based view of organization. Evidence of success—the number of sociologists now employed in professional schools—simultaneously raises concerns about the source of future organizational sociologists.
Leveraging observations by two NASA missions—GOLD (Global‐scale Observations of the Limb and Disk) and ICON (Ionospheric Connection Explorer), we investigate concurrent responses of thermospheric ...composition, temperatures, and neutral winds to the geomagnetic storm on 3–4 November 2021, as well as their interplay at low and middle latitudes. The synergetic observations reveal remarkable depletions up to 60%–70% in GOLD O/N2, along with large enhancements in GOLD temperatures poleward of 30° in the middle thermosphere. Meridional winds from ICON observations are altered by ∼100 m/s equatorward of 25°N latitude and at 250 km, characterized by a reversal of prevailing northward winds to geomagnetic storm‐driven southward winds. This study fills a need, after a decade‐long gap, for observing concurrent and co‐located responses of composition, temperatures, and neutral winds in the thermosphere to geomagnetic storms.
Plain Language Summary
Geomagnetic storms, arising from solar wind shocks emitted from the Sun, deposit a large portion of the absorbed solar energy into the Earth's high‐latitude atmosphere through Joule heating and high energy particle heating. Accurate prediction of the responses to geomagnetic storms in the thermosphere‐ionosphere is one of the core scientific objectives of space weather. The recently launched Global‐scale Observations of the Limb and Disk (GOLD) and Ionospheric Connection Explorer (ICON) missions provides an unparalleled opportunity to assess storm‐induced concurrent changes in multiple key parameters. During a G3 geomagnetic storm on 3 November 2021, GOLD observed the substantial changes of 60%–70% in thermosphere column density ratios of atomic oxygen to molecular nitrogen and temperatures. Exceptional meridional winds of 100–200 m/s were also seen by ICON over a broad altitude range. Such observations fill a decades‐long need for simultaneous observations of the key variables in the ionosphere‐thermosphere system.
Key Points
Remarkable depletions in O/N2 and enhancements in temperature, up to 60%–70%, are seen by Global‐scale Observations of the Limb and Disk during the geomagnetic storm
Averaged southward wind deviations of ∼100 m/s are observed by Ionospheric Connection Explorer, coincident with the largest gradient in O/N2 depletions
Both O/N2 and temperatures recover rapidly from the disturbed states to pre‐storm states
Topoisomerase poisons are chemotherapeutic agents that are used extensively for treating human malignancies. These drugs can be highly effective, yet tumors are frequently refractory to treatment or ...become resistant upon tumor relapse. Using a pool-based RNAi screening approach and a well characterized mouse model of lymphoma, we explored the genetic basis for heterogeneous responses to topoisomerase poisons in vitro and in vivo. These experiments identified Top2A expression levels as major determinants of response to the topoisomerase 2 poison doxorubicin and showed that suppression of Top2A produces resistance to doxorubicin in vitro and in vivo. Analogously, using a targeted RNAi approach, we demonstrated that suppression of Top1 produces resistance to the topoisomerase 1 poison camptothecin yet hypersensitizes cancer cells to doxorubicin. Importantly, lymphomas relapsing after treatment display spontaneous changes in topoisomerase levels as predicted by in vitro gene knockdown studies. These results highlight the utility of pooled shRNA screens for identifying genetic determinants of chemotherapy response and suggest strategies for improving the effectiveness of topoisomerase poisons in the clinic.
Abstract
We present second observations by K2 of OJ 287 and seven other
γ
-ray active galactic nuclei (AGNs) obtained in 2017–2018, second and third observations of the lobe-dominated, steep-spectrum ...quasar 3C 207, and observations of nine additional blazars not previously observed with K2. The AGNs were observed simultaneously with K2 and the Fermi Large Area Telescope for 51–81 days. Our full sample, observed in 2014–2018, contained 16 BL Lacertae objects (BL Lacs), nine flat-spectrum radio quasars (FSRQs), and four other
γ
-ray AGNs. Twelve BL Lacs and seven FSRQs exhibited fast, jagged light curves, while four BL Lacs and two FSRQs had slow, smooth light curves. Some objects changed their red-noise character significantly between repeated K2 observations. The optical characteristics of OJ 287 derived from the short-cadence K2 light curves changed between observations made before and after the predicted passage of the suspected secondary supermassive black hole through the accretion disk of the primary supermassive black hole. The average slopes of the periodogram power spectral densities of the BL Lacs’ and FSRQs’ light curves differed significantly, by ≈12%, with the BL Lac slopes being steeper, and a Kolmogorov–Smirnov test with a
p
-value of 0.039 indicates that these samples probably come from different populations; however, this result is not as strongly supported by power spectral response (PSRESP) analyses. Differences in the origin of the jets from the ergosphere or accretion disk in these two classes could produce such a disparity, as could different sizes or locations of emission regions within the jets.
The emergence of drug-resistant bacteria has compromised the use of many conventional antibiotics, leading to heightened interest in a variety of antimicrobial peptides. Although these peptides have ...attractive potential as antibiotics, their size, stability, tissue distribution, and toxicity have hampered attempts to harness these capabilities. To address such issues, we have developed small (molecular mass < 1,000 Da) arylamide foldamers that mimic antimicrobial peptides. Hydrogen-bonded restraints in the arylamide template rigidity the conformation via hydrogen bond formation and increase activity toward Staphylococcus aureus and Escherichia coli. The designed foldamers are highly active against S. aureus in an animal model. These results demonstrate the application of foldamer templates as therapeutics.
While antimicrobial peptides (AMPs) have been widely investigated as potential therapeutics, high-resolution structures obtained under biologically relevant conditions are lacking. Here, the ...high-resolution structures of the homologous 22-residue long AMPs piscidin 1 (p1) and piscidin 3 (p3) are determined in fluid-phase 3:1 phosphatidylcholine/phosphatidylglycerol (PC/PG) and 1:1 phosphatidylethanolamine/phosphatidylglycerol (PE/PG) bilayers to identify molecular features important for membrane destabilization in bacterial cell membrane mimics. Structural refinement of 1H–15N dipolar couplings and 15N chemical shifts measured by oriented sample solid-state NMR and all-atom molecular dynamics (MD) simulations provide structural and orientational information of high precision and accuracy about these interfacially bound α-helical peptides. The tilt of the helical axis, τ, is between 83° and 93° with respect to the bilayer normal for all systems and analysis methods. The average azimuthal rotation, ρ, is 235°, which results in burial of hydrophobic residues in the bilayer. The refined NMR and MD structures reveal a slight kink at G13 that delineates two helical segments characterized by a small difference in their τ angles (<10°) and significant difference in their ρ angles (∼25°). Remarkably, the kink, at the end of a G(X)4G motif highly conserved among members of the piscidin family, allows p1 and p3 to adopt ρ angles that maximize their hydrophobic moments. Two structural features differentiate the more potent p1 from p3: p1 has a larger ρ angle and less N-terminal fraying. The peptides have comparable depths of insertion in PC/PG, but p3 is 1.2 Å more deeply inserted than p1 in PE/PG. In contrast to the ideal α-helical structures typically assumed in mechanistic models of AMPs, p1 and p3 adopt disrupted α-helical backbones that correct for differences in the amphipathicity of their N- and C-ends, and their centers of mass lie ∼1.2–3.6 Å below the plane defined by the C2 atoms of the lipid acyl chains.
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