APOBEC3 proteins (A3s) are enzymes that catalyze the deamination of cytidine to uridine in single-stranded DNA (ssDNA) substrates, thus playing a key role in innate antiviral immunity. However, ...the APOBEC3 family has also been linked to many mutational signatures in cancer cells, which has led to an intense interest to develop inhibitors of A3's catalytic activity as therapeutics as well as tools to study A3's biochemistry, structure, and cellular function. Recent studies have shown that ssDNA containing 2'-deoxy-zebularine (dZ-ssDNA) is an inhibitor of A3s such as A3A, A3B, and A3G, although the atomic determinants of this activity have remained unknown. To fill this knowledge gap, we determined a 1.5 Å resolution structure of a dZ-ssDNA inhibitor bound to active A3G. The crystal structure revealed that the activated dZ-H
O mimics the transition state by coordinating the active site Zn
and engaging in additional stabilizing interactions, such as the one with the catalytic residue E259. Therefore, this structure allowed us to capture a snapshot of the A3's transition state and suggests that developing transition-state mimicking inhibitors may provide a new opportunity to design more targeted molecules for A3s in the future.
Background:The aim of this study was to assess the echocardiographic characteristics of chronic hemodialysis (HD) patients with end-stage renal disease (ESRD) in a multicenter prospective cohort ...study.Methods and Results:Three hundred and fifteen patients with ESRD (67.9±10.6 years, 47.6% male) on chronic HD for ≥1 year were examined on transthoracic echocardiography, including Doppler-derived aortic valve area (AVA) measurement. Only 11.5% and 3.4% of all patients had normal left ventricular (LV) geometry and normal LV filling pattern, respectively. The majority of patients had aortic and mitral valvular calcification, and approximately 50% of all 315 patients had aortic valve narrowing with AVA <2.0 cm2. Patients were divided into 3 groups according to AVA index tertile: group 1, highest tertile; group 2, middle tertile; and group 3, lowest tertile. Group 3 was older, had a greater cardiothoracic ratio on chest X-ray, higher plasma brain natriuretic peptide and total LV afterload, and lower stroke volume index than the other 2 groups. Age and intact parathyroid hormone (PTH) level were independently associated with low AVA index.Conclusions:Patients with ESRD on chronic HD have a high prevalence of cardiac structural and functional abnormalities including calcified aortic sclerosis. High age and PTH were associated with aortic valve narrowing in these patients.
The human APOBEC3G (A3G) DNA cytosine deaminase restricts and hypermutates DNA-based parasites including HIV-1. The viral infectivity factor (Vif) prevents restriction by triggering A3G degradation. ...Although the structure of the A3G catalytic domain is known, the structure of the N-terminal Vif-binding domain has proven more elusive. Here, we used evolution- and structure-guided mutagenesis to solubilize the Vif-binding domain of A3G, thus permitting structural determination by NMR spectroscopy. A smaller zinc-coordinating pocket and altered helical packing distinguish the structure from previous catalytic-domain structures and help to explain the reported inactivity of this domain. This soluble A3G N-terminal domain is bound by Vif; this enabled mutagenesis and biochemical experiments, which identified a unique Vif-interacting surface formed by the α1-β1, β2-α2 and β4-α4 loops. This structure sheds new light on the Vif-A3G interaction and provides critical information for future drug development.
The concept of network functions virtualization (NFV) has been embodied in commercial networks over the past years. Software-based virtual network functions have forwarding performance concerns in ...general, and various acceleration technologies have been developed so far, such as DPDK and vhost-user. Existence of several alternatives requires network engineers or operators to select appropriate technologies; however, no pragmatic criterion exists for constructing high-performance NFV-nodes. From their points of view, a lack of common benchmark and understanding of performance characteristics makes it difficult to predict hop-by-hop performance in a service chain, which results in prevention of NFV deployment in mission-critical networks. In this paper, we clarify performance characteristics of packet forwarding in NFV nodes focusing on three types of acceleration technologies; packet I/O architecture, virtual network I/O, and forwarding engine in a practical stage. We examined three packet I/O architectures (NAPI, netmap, and DPDK), three virtual I/O mechanisms (vhost-net, vhost-user, and SR-IOV), and four practical forwarding programs (Open vSwitch, OVS-DPDK, xDPd-DPDK, and Lagopus) with three referential programs (Linux Bridge, VALE, and L2FWD-DPDK). The experiment was conducted on a 40 GbE environment and we examined two device-under-test machines having different CPU performance. We argue performance characteristics of each technology and give quantitative analyses of the result. The key findings are: 1) CPU core speed has impact on both throughput and latency/jitter; 2) DPDK can allow performance prediction; 3) vhost-user is appropriate for real environment; and 4) OVS-DPDK provides a good combination of performance and functionality.
In Europe, herbal medicinal products containing horse chestnut seed extract as an active ingredient are widely used in patients with chronic venous insufficiency (CVI). In Japan, however, no clinical ...evidence for this drug has been established, and it has not been approved as a drug for CVI in Japan. Accordingly, we conducted a multicenter, open-label, single-arm study to confirm the efficacy and safety of ZO-SA0 (Belfemin) containing horse chestnut seed extract in seventy Japanese patients with mild CVI. After 12 weeks of treatment with the drug, a decrease in lower leg volume and improvement in subjective symptoms were suggested, as in overseas clinical studies, and no safety problems were observed.
RX J1347.5-1145 (z = 0.451) is one of the most luminous X-ray galaxy clusters; it hosts a prominent cool core and exhibits a signature of a major merger. We present the first direct observational ...evidence for the subsonic nature of the sloshing motion of the cool core. We find that a residual X-ray image from the Chandra X-ray Observatory after removing the global emission shows a clear dipolar pattern characteristic of gas sloshing, whereas we find no significant residual in the Sunyaev-Zel'dovich effect (SZE) image from the Atacama Large Millimeter/submillimeter Array (ALMA). We estimate the equation of state of perturbations in the gas from the X-ray and SZE residual images. The inferred velocity is km s−1, which is much lower than the adiabatic sound speed of the intracluster medium in the core. We thus conclude that the perturbation is nearly isobaric, and the gas sloshing motion is consistent with being in pressure equilibrium. Next, we report evidence for gas stripping of an infalling subcluster, which likely shock-heats the gas to a temperature well in excess of 20 keV. Using the mass distribution inferred from strong lensing images of the Hubble Space Telescope (HST), we find that the mass peak is located away from the peak position of the stripped gas with a statistical significance of >5 . Unlike for the gas sloshing, the velocity inferred from the equation of state of the excess hot gas is comparable to the adiabatic sound speed expected for the 20 keV intracluster medium. All of the results support that the southeast substructure is created by a merger. On the other hand, the positional offset between the mass and the gas limits the self-interaction cross section of dark matter to be less than 3.7 h−1 cm2 g−1 (95% CL).
For astronomical observation at terahertz frequencies, a variety of cryogenic detector technologies are being developed to achieve background-limited observation from space, where a noise equivalent ...power (NEP) of less than
10
-
18
W/Hz
0.5
is often required. When each photon signal is resolved in time, the requirements on NEP are reduced and 1 ns time resolution corresponds to an NEP of approximately
10
-
17
W/Hz
0.5
at THz frequencies. Furthermore, fast photon counting detectors have a high dynamic range to observe bright terahertz sources such as stars and active galactic nuclei. Applications of photon counting detector are discussed for cosmic microwave background and photon counting terahertz interferometry.
The small Ultra-Red Fluorescent Protein (smURFP) represents a new class of fluorescent protein with exceptional photostability and brightness derived from allophycocyanin in a previous directed ...evolution. Here, we report the smURFP crystal structure to better understand properties and enable further engineering of improved variants. We compare this structure to the structures of allophycocyanin and smURFP mutants to identify the structural origins of the molecular brightness. We then use a structure-guided approach to develop monomeric smURFP variants that fluoresce with phycocyanobilin but not biliverdin. Furthermore, we measure smURFP photophysical properties necessary for advanced imaging modalities, such as those relevant for two-photon, fluorescence lifetime, and single-molecule imaging. We observe that smURFP has the largest two-photon cross-section measured for a fluorescent protein, and that it produces more photons than organic dyes. Altogether, this study expands our understanding of the smURFP, which will inform future engineering toward optimal FPs compatible with whole organism studies.
We present the results of a blind millimeter line emitter search using ALMA Band 6 data with a single-frequency tuning toward four gravitational lensing clusters (RXJ1347.5−1145, Abell S0592, MACS ...J0416.1−2403, and Abell 2744). We construct 3D signal-to-noise ratio (S/N) cubes with 60 and 100 MHz binning, and search for millimeter line emitters. We do not detect any line emitters with a peak S/N > 5, although we do find a line emitter candidate with a peak S/N 4.5. These results provide upper limits to the CO(3−2), CO(4−3), CO(5−4), and C ii luminosity functions at z 0.3, 0.7, 1.2, and 6, respectively. Because of the magnification effect of gravitational lensing clusters, the new data provide the first constraints on the CO and C ii luminosity functions at unprecedentedly low luminosity levels, i.e., down to 10−3 - 10−1 Mpc−3 dex−1 at K km s−1 pc2 and 10−3-10−2 Mpc−3 dex−1 at , respectively. Although the constraints to date are not yet stringent, we find that the evolution of the CO and C ii luminosity functions are broadly consistent with the predictions of semi-analytical models. This study demonstrates that the wide observations with a single-frequency tuning toward gravitational lensing clusters are promising for constraining the CO and C ii luminosity functions.
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