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The HIV-1 Nef protein suppresses multiple immune surveillance mechanisms to promote viral pathogenesis and is an attractive target for the development of novel therapeutics. A key function of Nef is to remove the CD4 receptor from the cell surface by hijacking clathrin- and adaptor protein complex 2 (AP2)-dependent endocytosis. However, exactly how Nef does this has been elusive. Here, we describe the underlying mechanism as revealed by a 3.0-Å crystal structure of a fusion protein comprising Nef and the cytoplasmic domain of CD4 bound to the tetrameric AP2 complex. An intricate combination of conformational changes occurs in both Nef and AP2 to enable CD4 binding and downregulation. A pocket on Nef previously identified as crucial for recruiting class I MHC is also responsible for recruiting CD4, revealing a potential approach to inhibit two of Nef's activities and sensitize the virus to immune clearance.

The cellular protein SERINC5 inhibits the infectivity of diverse retroviruses, and its activity is counteracted by the glycosylated Gag (glycoGag) protein of murine leukemia virus (MLV), the S2 protein of equine infectious anemia virus (EIAV), and the Nef protein of human immunodeficiency virus type 1 (HIV-1). Determining the regions within SERINC5 that provide restrictive activity or Nef sensitivity should inform mechanistic models of the SERINC5/HIV-1 relationship. Here, we report that deletion of the conserved sequence EDTEE, which is located within a cytoplasmic loop of SERINC5 and which is reminiscent of an acidic-cluster membrane trafficking signal, increases the sensitivity of SERINC5 to antagonism by Nef, while it has no effect on the intrinsic activity of the protein as an inhibitor of infectivity. These effects correlated with enhanced removal of the ΔEDTEE mutant relative to that of wild-type SERINC5 from the cell surface and with enhanced exclusion of the mutant protein from virions by Nef. Mutational analysis indicated that the acidic residues, but not the threonine, within the EDTEE motif are important for the relative resistance to Nef. Deletion of the EDTEE sequence did not increase the sensitivity of SERINC5 to antagonism by the glycoGag protein of MLV, suggesting that its virologic role is Nef specific. These results are consistent with the reported mapping of the cytoplasmic loop that contains the EDTEE sequence as a general determinant of Nef responsiveness, but they further indicate that sequences inhibitory to as well as supportive of Nef activity reside in this region. We speculate that the EDTEE motif might have evolved to mediate resistance against retroviruses that use Nef-like proteins to antagonize SERINC5.IMPORTANCE Cellular membrane proteins in the SERINC family, especially SERINC5, inhibit the infectivity of retroviral virions. This inhibition is counteracted by retroviral proteins, specifically, HIV-1 Nef, MLV glycoGag, and EIAV S2. One consequence of such a host-pathogen "arms race" is a compensatory change in the host antiviral protein as it evolves to escape the effects of viral antagonists. This is often reflected in a genetic signature, positive selection, which is conspicuously missing in SERINC5 Here we show that despite this lack of genetic evidence, a sequence in SERINC5 nonetheless provides relative resistance to antagonism by HIV-1 Nef.

With the proportional reduction of metal–oxide–semiconductor field effect transistor (MOSFET) devices, the short channel effect, the parasitic effect, and the field strength effect are significantly enhanced, the proportion of parasitic resistance increases, and the non-intrinsic noise also increases, which seriously affects the working efficiency of the device. However, existing research mainly focuses on the intrinsic noise of MOSFET, and there is little research on the non-intrinsic noise; furthermore, the models describing the relationship between non-intrinsic noise, device structure, and bias have not yet been addressed. Therefore, in this paper, 90, 65, 32, 10, and 5 nm MOSFETs are studied. The rate of the intrinsic ballistic parameter is introduced to set up the source–drain current model and the non-intrinsic noise model. The source–drain current model is consistent with the theoretical model, numerical simulation, and experimental results in the literature. Finally, the relationship between the non-intrinsic noise and the bias and the device parameters are analyzed, and the conclusion is helpful to improve the working efficiency, lifetime, and response speed of nanoscale MOSFET devices. [ABSTRACT FROM AUTHOR]

The coring data in high water‐cut oilfields indicates that the reservoir permeability will change continuously with water flooding, while the existing reservoir numerical simulation software cannot consider the time‐varying phenomenon of permeability. With the enhancement of reservoir heterogeneity, the near‐wellbore profile control fails to stabilize the oil production and control the water cut. The in‐depth profile control has been widely used in oilfields as a new technology, and the types of profile control agents are diverse, with a complex mechanism that cannot be effectively described by the existing conventional numerical simulation software. Considering these two phenomena comprehensively, a new three‐dimensional, three‐phase, six‐component mathematical model that can take into account the time‐varying phenomenon of reservoir permeability is proposed for a new kind of in‐depth profile control system, namely, the core–shell coagulation system, and an integrated numerical simulation software is developed. The mechanism of the in‐depth profile control system can be perfectly demonstrated in the simulator with time‐variation of permeability. The results of sensitivity analysis show that the effect is influenced by three factors: the mix slug injecting concentration, the coagulant aid slug volume, and the concentration of the suspension dispersing agent. [ABSTRACT FROM AUTHOR]

Avalanche photodiodes (APDs) produce noise during operation, which affects the device performance. However, the previous research on its noise is mainly theoretical analysis and is only reflected as optical noise. Therefore, according to the characteristics of APD material and the mechanism of noise generation, the main noise of the device is analyzed in this paper. First, the test method of noise in APDs is established, including testing of dark noise, optical noise, and multiplication noise in high frequency bands. The main noises in APDs are 1/f noise, thermal noise, shot noise, generation recombination noise, and multiplication shot noise, and shot noise is suppressed by Fermi–Dirac distribution and Coulomb action. Second, the reliability of APDs is evaluated by measuring and analyzing the noise parameters of the device through thermal aging experiments. It is concluded that the defects introduced by thermal aging can be reflected by the change in noise, which is consistent with the results in the literature. This method can comprehensively obtain the noise in APDs, which is helpful to improve the working efficiency, life, and reliability of the device. [ABSTRACT FROM AUTHOR]

Protein trafficking in the endosomal system involves the recognition of specific signals within the cytoplasmic domains (CDs) of transmembrane proteins by clathrin adaptors. One such signal is the phosphoserine acidic cluster (PSAC), the prototype of which is in the endoprotease furin. How PSACs are recognized by clathrin adaptors has been controversial. We reported previously that HIV-1 Vpu, which modulates cellular immunoreceptors, contains a PSAC that binds to the μ subunits of clathrin adaptor protein (AP) complexes. Here, we show that the CD of furin binds the μ subunits of AP-1 and AP-2 in a phosphorylation-dependent manner. Moreover, we identify a potential PSAC in a cytoplasmic loop of the cellular transmembrane Serinc3, an inhibitor of the infectivity of retroviruses. The two serines within the PSAC of Serinc3 are phosphorylated by casein kinase II and mediate interaction with the μ subunits in vitro The sites of these serines vary among mammals in a manner suggesting host-pathogen conflict, yet the Serinc3 PSAC seems dispensable for anti-HIV activity and for counteraction by HIV-1 Nef. The CDs of Vpu and furin and the PSAC-containing loop of Serinc3 each bind the μ subunit of AP-2 (μ2) with similar affinities, but they appear to utilize different basic regions on μ2. The Serinc3 loop requires a region previously reported to bind the acidic plasma membrane lipid phosphatidylinositol 4,5-bisphosphate. These data suggest that the PSACs within different proteins recognize different basic regions on the μ surface, providing the potential to inhibit the activity of viral proteins without necessarily affecting cellular protein trafficking.

HIV-1 Vpu modulates cellular transmembrane proteins to optimize viral replication and provide immune-evasion, triggering ubiquitin-mediated degradation of some targets but also modulating endosomal trafficking to deplete them from the plasma membrane. Interactions between Vpu and the heterotetrameric clathrin adaptor protein (AP) complexes AP-1 and AP-2 have been described, yet the molecular basis and functional roles of such interactions are incompletely defined. To investigate the trafficking signals encoded by Vpu, we fused the cytoplasmic domain (CD) of Vpu to the extracellular and transmembrane domains of the CD8 α-chain. CD8-VpuCD was rapidly endocytosed in a clathrin- and AP-2-dependent manner. Multiple determinants within the Vpu CD contributed to endocytic activity, including phosphoserines of the β-TrCP binding site and a leucine-based ExxxLV motif. Using recombinant proteins, we confirmed ExxxLV-dependent binding of the Vpu CD to the α/σ2 subunit hemicomplex of AP-2 and showed that this is enhanced by serine-phosphorylation. Remarkably, the Vpu CD also bound directly to the medium (μ) subunits of AP-2 and AP-1; this interaction was dependent on serine-phosphorylation of Vpu and on basic residues in the μ subunits. We propose that the flexibility with which Vpu binds AP complexes broadens the range of cellular targets that it can misdirect to the virus' advantage.

As field effect transistors are reduced to nanometer dimensions, experimental and theoretical research has shown a gradual change in noise generation mechanisms. There are few studies on noise theory for small nanoscale transistors, and Monte Carlo (MC) simulations mainly focus on 2D devices with larger nanoscale dimensions. In this study, we employed MC simulation techniques to establish a 3D device simulation process. By setting device parameters and writing simulation programs, we simulated the raw data of channel current noise for a silicon-based metal–oxide–semiconductor field-effect transistor (MOSFET) with a 10 nm channel length and calculated the drain output current based on these data, thereby achieving static testing of the simulated device. Additionally, this study obtained a 3D potential distribution map of the device channel surface area. Based on the original data from the simulation analysis, this study further calculated the power spectral density of the channel current noise and analyzed how the channel current noise varies with gate voltage, source–drain voltage, temperature, and substrate doping density. The results indicate that under low-temperature conditions, the channel current noise of the 10 nm MOSFET is primarily composed of suppressed shot noise, with the proportion of thermal noise in the total noise slightly increasing as temperature rises. Under normal operating conditions, the channel current noise characteristics of the 10 nm MOSFET device are jointly characterized by suppressed shot noise, thermal noise, and cross-correlated noise. Among these noise components, shot noise is the main source of noise, and its suppression degree decreases as the bias voltage is reduced. These findings are consistent with experimental observations and theoretical analyses found in the existing literature. [ABSTRACT FROM AUTHOR]

BST2/tetherin, an antiviral restriction factor, inhibits the release of enveloped viruses from the cell surface. Human immunodeficiency virus-1 (HIV-1) antagonizes BST2 through viral protein u (Vpu), which downregulates BST2 from the cell surface. We report the crystal structure of a protein complex containing Vpu and BST2 cytoplasmic domains and the core of the clathrin adaptor protein complex 1 (AP1). This, together with our biochemical and functional validations, reveals how Vpu hijacks the AP1-dependent membrane trafficking pathways to mistraffick BST2. Vpu mimics a canonical acidic dileucine-sorting motif to bind AP1 in the cytosol, while simultaneously interacting with BST2 in the membrane. These interactions enable Vpu to build on an intrinsic interaction between BST2 and AP1, presumably causing the observed retention of BST2 in juxtanuclear endosomes and stimulating its degradation in lysosomes. The ability of Vpu to hijack AP-dependent trafficking pathways suggests a potential common theme for Vpu-mediated downregulation of host proteins.DOI: http://dx.doi.org/10.7554/eLife.02362.001.

Rh-catalyzed hydroaminomethylation has been developed with acid sulfoxantphos and ZSM-5. Linear amines were obtained in good yields (71–95%) with high l/b ratios (up to 132.4) and excellent TON values (up to 23 760). The ZSM-5 and SO3H group of ligands improved the performances of hydroformylation and reductive amination. [ABSTRACT FROM AUTHOR]