Molecular mechanisms of human innate immune restriction factors APOBEC3G and APOBEC3H for inhibiting the retrovirus HIV-1 and retrotransposon LINE1

The APOBEC3 restriction factors belong to a family of cytidine deaminases that are able to suppress the replication of viruses with a single-stranded DNA intermediate by inducing mutagenesis and functional inactivation of the virus. Of the seven common human APOBEC3 enzymes, only APOBEC3-D, -F, -G and -H appear to be relevant to HIV-1 restriction in CD4+ T cells. The restriction of HIV-1 by APOBEC3 enzymes occurs most potently in the absence of HIV-1 Vif, which counteracts APOBEC3s by inducing polyubiquitination and subsequent degradation of APOBEC3 enzymes. Virion-encapsidated APOBEC3s can deaminate cytosines to uracils in viral (-)DNA. Upon replication of (-)DNA to (+)DNA, the HIV-1 reverse transcriptase incorporates adenines opposite to the uracils hereby inducing C/G to T/A transition mutations. Among all APOBEC3 enzymes that are relevant to HIV-1 restriction, APOBEC3G is the most studied APOBEC3 enzyme. APOBEC3G has been shown to processively catalyze deamination reactions on single-stranded (-)DNA using a mechanism called facilitated diffusion, which involves sliding and jumping movements in search of target cytosine-containing motifs. This single-stranded DNA scanning mechanism allows APOBEC3G to efficiently deaminate multiple cytosines within one enzyme-DNA encounter and it is important for the mutational inactivation of HIV-1 in vivo. Vif attempts to neutralize APOBEC3G’s function not only by inducing proteasomal degradation, but also by several degradation-independent mechanisms, such as inhibiting APOBEC3G virion encapsidation, mRNA translation, and for those APOBEC3G molecules that still become virion encapsidated, Vif has been shown to inhibit APOBEC3G’s deamination activity. My Ph.D. thesis work investigated the molecular mechanism of degradation-independent Vif-mediated inhibition of APOBEC3G and APOBEC3H deamination activity. This research led to the development of the hypothesis that Vif has developed a unique interaction with each APOBEC3 enzyme due to the different selection pressures they impose on HIV-1. Thus, we investigated how the interaction of Vif differs between APOBEC3G and APOBEC3H and characterized the activity of APOBEC3H as a restriction factor. This research allowed us to have a better understanding of the molecular determinants that govern an efficient APOBEC3-degradatation by HIV-1 Vif and provide insights for APOBEC3-based HIV-1 therapeutics. Two Vif variants obtained from HIV-1 laboratory isolates, VifHXB2 and VifIIIB, were used to determine the degradation-independent effects of Vif on APOBEC3G. Biochemical assays using a model HIV-1 replication assay and synthetic single-stranded or partially double-stranded DNA substrates demonstrated that APOBEC3G has an altered processive mechanism in the presence of Vif, and this caused APOBEC3G to be less effective at inducing mutagenesis in a model HIV-1 replication assay. APOBEC3H is unique in that it is the only single-domain common APOBEC3 enzyme that restricts HIV-1. APOBEC3H exists in humans as seven haplotypes (I-VII) with different cellular stabilities. Amongst three stable APOBEC3H haplotypes, haplotype II and V occur most frequently in the population. I characterized the single-stranded DNA scanning mechanisms that haplotype II and V use to search their single-stranded substrate for cytosine-containing deamination motif. APOBEC3H haplotype II was able to processively deaminate its substrate using Brownian motion-driven movements termed sliding, jumping and intersegmental transfer, whereas haplotype V showed compromised sliding and intersegmental transfer abilities but was able to jump along single-stranded DNA. Since an Asp or Glu at amino acid 178 differentiates these two haplotypes, these data suggest this amino acid on predicted helix 6 contributes to processivity. I found the optimal processivity on ssDNA also required dimerization of APOBEC3H through the β2 strands. The diminished processivity of APOBEC3H haplotype V did not result in a reduced efficiency to restrict HIV-1 replication in single-cycle infectivity assay. This suggests a redundancy in the contribution of jumping and intersegmental transfer to mutagenic efficiency. VifHXB2, but not VifIIIB, can cause degradation of APOBEC3H even though APOBEC3H interacts with both Vif variants. APOBEC3G is degraded after interaction with both of these Vif variants. To define the parameters for efficient Vif-induced degradation of an APOBEC3 enzyme, I used an in vitro quantitative method to determine the binding strength of APOBEC3G and APOBEC3H with Vif variant heterotetramers (Vif/CBFβ/EloB/EloC), the most stable form of Vif. Our biochemical analysis, along with cellular experiments to determine Vif-induced degradation efficiency and APOBEC3-Vif interactions in cells, support a model in which the degradation efficiency of Vifs correlates with both the APOBEC3-Vif binding strength and APOBEC3-Vif interface. I also investigated how APOBEC3 enzymes restrict the replication of retrotransposon LINE-1. Retrotransposons are DNA sequences that replicate using a “copy-and-paste” mechanism through an RNA intermediate. The degradation of deaminated L1 cDNA rendered it difficult to detect any APOBEC3-induced G-to-A mutations while the addition of uracil DNA glycosylase inhibitor allowed for the recovery of the APOBEC3-mediated deamination events. I found that two stable A3H haplotypes (haplotype II and haplotype V) use a deamination-independent mechanism to restrict L1 mobilization and compared the ability of APOBEC3H’s to inhibit LINE1 with that of APOBEC3A and APOBEC3G, two APOBEC3s whose LINE1 restriction ability have been previously characterized. Taken together, these studies of the molecular mechanisms that APOBEC3G and APOBEC3H use to inhibit HIV-1 and LINE1 have allowed us to better understand their biological properties as cytidine deaminases and the determinants in APOBEC3s that made them efficient host innate immune restriction factors

Gravitational and Autoregressive Analysis Spatial Diffusion of COVID-19 in Hubei Province, China

The spatial diffusion of epidemic disease follows distance decay law in geography, but different diffusion processes may be modeled by different mathematical functions under different spatio-temporal conditions. This paper is devoted to modeling spatial diffusion patterns of COVID-19 stemming from Wuhan city to Hubei province. The methods include gravity and spatial auto-regression analyses. The local gravity model is derived from allometric scaling and global gravity model, and then the parameters of the local gravity model are estimated by observational data and linear regression. The main results are as below. The local gravity model based on power law decay can effectively describe the diffusion patterns and process of COVID-19 in Hubei Province, and the goodness of fit of the gravity model based on negative exponential decay to the observation data is not satisfactory. Further, the goodness of fit of the model to data entirely became better and better over time, the size elasticity coefficient increases first and then decreases, and the distance attenuation exponent decreases first and then increases. Moreover, the significance of spatial autoregressive coefficient in the model is low, and the confidence level is less than 80%. The conclusions can be reached as follows. (1) The spatial diffusion of COVID-19 of Hubei bears long range effect, and the size of a city and the distance of the city to Wuhan affect the total number of confirmed cases. (2) Wuhan direct transmission is the main process in the spatial diffusion of COVID-19 in Hubei at the early stage, and the horizontal transmission between regions is not significant. (3) The effect of spatial isolation measures taken by Chinese government against the transmission of COVID-19 is obvious. This study suggests that the role of gravity should be taken into account to prevent and control epidemic disease.Comment: 24 pages, 3 figures, 5 table

A suitable method for alpine wetland delineation: An example for the headwater area of the yellow river, Tibetan Plateau

Alpine wetlands are one of the most important ecosystems in the Three Rivers Source Area, China, which plays an important role in regulating the regional hydrological cycle and carbon cycle. Accordingly, Wetland area and its distribution are of great significance for wetland management and scientific research. In our study, a new wetland classification model which based on geomorphological types and combine object-oriented and decision tree classification model (ODTC), and used a new wetland classification system to accurately extract the wetland distributed in the Headwater Area of the Yellow River (HAYR) of the Qinghai-Tibet Plateau (QTP), China. The object-oriented method was first used to segment the image into several areas according to similarity in Pixels and Textures, and then the wetland was extracted through a decision tree constructed based on geomorphological types. The wetland extracted by the model was compared with that by other seven commonly methods, such as support vector machine (SVM) and random forest (RF), and it proved the accuracy was improved by 10%–20%. The overall classification accuracy rate was 98.9%. According to our results, the HAYR’s wetland area is 3142.3 km2, accounting for 16.1% of the study area. Marsh wetlands and flood wetlands accounted for 37.7% and 16.7% respectively. A three-dimensional map of the area showed that alpine wetlands in the research region are distributed around lakes, piedmont groundwater overflow belts, and inter-mountain catchment basin. This phenomenon demonstrates that hydrogeological circumstances influence alpine wetlands’ genesis and evolution. This work provides a new approach to investigating alpine wetlands

Design, Implementation and Modeling of Flooding Disaster-Oriented USV

Although there exist some unmanned surface platforms, and parts of them have been applied in flooding disaster relief, the autonomy of these platforms is still so weak that most of them can only work under the control of operators. The primary reason is the difficulty of obtaining a dynamical model that is sufficient rich for model-based control and sufficient simple for model parameters identification. This makes them difficult to be used to achieve some high-performance autonomous control, such as robust control with respect to disturbances and unknown dynamics and trajectory tracking control in complicated and dynamical surroundings. In this chapter, a flooding disaster-oriented unmanned surface vehicle (USV) designed and implemented by Shenyang Institute of Automation, Chinese Academy of Sciences (SIA, CAS) is introduced first, including the hardware and software structures. Then, we propose a quasi-linear parameter varying (qLPV) model to approach the dynamics of the USV system. We first apply this to solve a structured modeling problem and then introduce model error to solve an unstructured modeling problem. Subsequently, the qLPV model identification results are analyzed and the superiority compared to two linear models is demonstrated. At last, extensive application experiments, including rescuing rope throwing using an automatic pneumatic and water sampling in a 2.5 m radius circle, are described in detail to show the performance of course keeping control and GPS point tracking control based on the proposed model

Highly sensitive magnetic properties and large linear magnetoresistance in antiferromagnetic CrxSe(0.875\lex\le1)single crystals

CrxSe (x\le1) is a class of quasi-layered binary compounds with potential applications in spintronics due to its intriguing antiferromagnetic properties. In this work, CrxSe single crystals with high Cr content (x=0.87, 0.91 and 0.95) were grown, and their magnetic and transport properties were investigated in detail. It is found that with small increase of Cr content, the N\'eel temperature (TN) of the samples can dramatically increase from 147 K to 257 K, accompanied with obvious changes in the magnetic anisotropy and hysteresis. The phenomena of field-induced spin-flop transitions were unveiled in these alloys, indicating their comparatively low anisotropy. The magnetoresistance (MR) of the three compounds showed positive dependence at low temperatures and particularly, non-saturated linear positive MR was observed in Cr0.91Se and Cr0.95Se, with a large value of 16.2% achieved in Cr0.91Se (10K, 9T). The calculated Fermi surface and MR showed that the quasi-linear MR is a product of carrier compensation. Our work revealed highly sensitive magnetic and transport properties in the Cr-Se compounds, which can lay foundation when constructing further antiferromagnetic spintronic devices based on them

Atatürk, Türk Dili ve Yazı İnkılâbı

Özet: Dünyada çok nadir lider bir ömürde hem savaş alanında hem kültür alanında o kadar çok zafer kazanmıştır. Atatürk her yönüyle o nadir liderlerden biridir. O kendi düşünce sistemiyle, öngörüşüyle ve çevreye zamanında motivasyon vererek faaliyete geçirmesiyle Türkiye’ye ve Türk halkına yeni ufuklar açmıştır. Atatürk, bir fikir adamı olarak, milli kültürün temel direklerinden birinin dil olduğunu biliyordu. Bu sebeple konuşma dili ile yazı dilini ve halkın dili ile aydınların dilini yakınlaştırmak için dil inkılâbını teşvik etti. Dil inkılâbının ilk safhası olarak 1 Kasım 1928’de yazı inkılâbı gerçekleşti ve Latin harfleri kanunla kabul edildi. Böylece, yazı inkılâbı, Türk dilinin ve Türk kültürünün tarihinde bir dönüm noktası oldu ve kısa zamanda Türkçe kendi yumuşaklığı ve ahenkliği ile yeniden bütün güzelliğini meydana çıkardı. Anahtar kelimeler: Atatürk, Türk dili, Türk dilinin Latin alfabesi, Türkçede vokaller, Türkçede konsonantlar

An efficient approach to separate CO2 using supersonic flows for carbon capture and storage

The mitigation of CO2 emissions is an effective measure to solve the climate change issue. In the present study, we propose an alternative approach for CO2 capture by employing supersonic flows. For this purpose, we first develop a computational fluid dynamics (CFD) model to predict the CO2 condensing flow in a supersonic nozzle. Adding two transport equations to describe the liquid fraction and droplet number, the detailed numerical model can describe the heat and mass transfer characteristics during the CO2 phase change process under the supersonic expansion conditions. A comparative study is performed to evaluate the effect of CO2 condensation using the condensation model and dry gas assumption. The results show that the developed CFD model predicts accurately the distribution of the static temperature contrary to the dry gas assumption. Furthermore, the condensing flow model predicts a CO2 liquid fraction up to 18.6% of the total mass, which leads to the release of the latent heat to the vapour phase. The investigation performed in this study suggests that the CO2 condensation in supersonic flows provides an efficient and eco-friendly way to mitigate the CO2 emissions to the environment

Growth of high-quality CrI3 single crystals and engineering of its magnetic properties via V and Mn doping

CrI3, as a soft van der Waals layered magnetic material, has been widely concerned and explored for its magnetic complexity and tunability. In this work, high quality and large size thin CrI3, V and Mn doped single crystals were prepared by chemical vapor transfer method. A remarkable irreversible Barkhausen effect was observed in CrI3 and CrMn0.06I3, which can be attributed to the low dislocation density that facilitates movement of the domain walls. In addition, the introduction of the doping element Mn allows higher saturation magnetization intensity. Cr0.5V0.5I3 exhibits substantially increased coercivity force and larger magnetocrystalline anisotropy compared to CrI3, while kept similar Curie temperature and good environmental stability. The first principles calculations suggest direct and narrowed band gaps in Cr0.5V0.5I3 and VI3 comparing to CrI3. The smaller band gaps and good hard magnetic property make Cr0.5V0.5I3 an alternative choice to future research of spintronic devices

Diane Walch Reick v. Donald Thomas Reick : Brief of Respondent

Appeal from the order of the Second Judicial District Court for Weber County: The Honorable John F. Wahlquist, Judge