A review of HIV restriction factors and viral countering mechanisms

Human immune system is powerful and it has evolved over the past thousands of years to protect us from various foreign pathogens. In fact, very few pathogens can threaten a man with a competent immune system. The notorious Human Immunodeficiency Virus may be among those very few pathogens as it attacks human immune system; however, it does not mean men are left utterly weaponless in the face of HIV infection. The adaptive arm of the human immune system has historically received more attention, given that most vaccines to viral pathogens are based on this type of immune response. In the context of HIV infection, however, attempts to induce antibody responses or cell-mediated immunity with vaccine have yielded little success. As a result, research resource has shifted to look at the first-line protection that precedes the adaptive immunity. Restriction factors are among this innate arm of the immune system. Since 2002, many restriction factors have been described, many in the context of their antiretroviral activities. In this thesis essay, I attempted to cover some of the best-studied HIV restriction factors to date, including their potential antiviral mechanisms and how virus has developed ways to circumvent their inhibition effects. Many restriction factors are now on the verge of being translated into clinical products, so I tried to include some of the latest translational applications of restriction factors in this article. A common theme for most restriction factors is a constant “arm race” between the virus and the host, and therefore, in the end, I have included a short discussion on how, in a human perspective, men managed to stay on the battlefield with the ever-mutating HIV virus

Material Removal Optimization Strategy of 3D Block Cutting Based on Geometric Computation Method

During the material removal stage in stone rough processing, milling type has been widely explored, which, however, may cause time and material consumption, as well as substantial stress for the environment. To improve the material removal rate and waste reuse rate in the rough processing stage for three-dimensional stone products with a special shape, in this paper, circular saw disc cutting is explored to cut a convex polyhedron out of a blank box, which approaches a target product. Unlike milling optimization, this problem cannot be well solved by mathematical methods, which have to be solved by geometrical methods instead. An automatic block cutting strategy is proposed intuitively by considering a series of geometrical optimization approaches for the first time. To obtain a big removal block, constructing cutting planes based on convex vertices is uniquely proposed. Specifically, the removal vertices (the maximum thickness of material removal) are searched based on the octree algorithm, and the cutting plane is constructed based on this thickness to guarantee a relatively big removal block. Moreover, to minimize the cutting time, the geometrical characteristics of the intersecting convex polygon of the cutting plane with the convex polyhedron are analyzed, accompanied by the constraints of the guillotine cutting mode. The optimization algorithm determining the cutting path is presented with a feed direction accompanied by the shortest cutting stroke, which confirms the shortest cutting time. From the big removal block and shortest cutting time, the suboptimal solution of the average material removal rate (the ratio of material removal volume to cutting time) is generated. Finally, the simulation is carried out on a blank box to approach a bounding sphere both on MATLAB and the Vericut platform. In this case study, for the removal of 85% of material with 19 cuts, the proposed cutting strategy achieves five times higher the average material removal rate than that of one higher milling capacity case

A Short-baseline Dual-antenna BDS/MIMU Integrated Navigation System

This paper puts forward a short-baseline dual-antenna BDS/MIMU integrated navigation, constructs the carrier phase double difference model of BDS (BeiDou Navigation Satellite System), and presents a 2-position initial orientation method on BDS. The Extended Kalman-filter has been applied for the integrated navigation system. The differences between MIMU and BDS position, velocity and carrier phase information are used as measurements. The experiment results indicate that the position error is less than 1m, the pitch angle error and roll angle error are less than 0.1°, and the heading angle error is about 1°. It shows that the new integrated navigation system has good performance and can be applied in various fields including USV and UAV

18F-Labeled GRPR Agonists and Antagonists: A Comparative Study in Prostate Cancer Imaging

Radiolabeled bombesin analogs are promising probes for cancer imaging of gastrin-releasing peptide receptor (GRPR). In this study, we developed 18F-labeled GRPR agonists and antagonists for positron emission tomography (PET) imaging of prostate cancer. GRPR antagonists ATBBN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH2CH3) and MATBBN (Gly-Gly-Gly-Arg-Asp-Asn-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH2CH3), and agonists AGBBN (Gln-Trp-Ala-Val-Gly-His-Leu-MetNH2) and MAGBBN (Gly-Gly-Gly-Arg-Asp-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-MetNH2) were radiolabeled with 18F via 4-nitrophenyl 2-18F-fluoropropionate. The in vitro receptor binding, cell uptake, and efflux properties of the radiotracers were studied on PC-3 cells. An in vivo PET study was performed on mice bearing PC-3 tumors. Direct 18F-labeling of known GRPR antagonist ATBBN and agonist AGBBN did not result in good tumor targeting or appropriate pharmacokinetics. Modification was made by introducing a highly hydrophilic linker Gly-Gly-Gly-Arg-Asp-Asn. Higher receptor binding affinity, much higher cell uptake and slower washout were observed for the agonist 18F-FP-MAGBBN over the antagonist 18F-FP-MATBBN. Both tracers showed good tumor/background contrast, with the agonist 18F-FP-MAGBBN having significantly higher tumor uptake than the antagonist 18F-FP-MATBBN (P < 0.01). In conclusion, Gly-Gly-Gly-Arg-Asp-Asn linker significantly improved the pharmacokinetics of the otherwise hydrophobic BBN radiotracers. 18F-labeled BBN peptide agonists may be the probes of choice for prostate cancer imaging due to their relatively high tumor uptake and retention as compared with the antagonist counterparts

Two‐Dimensional Design Strategy to Construct Smart Fluorescent Probes for the Precise Tracking of Senescence

The tracking of cellular senescence usually depends on the detection of senescence‐associated β‐galactosidase (SA‐β‐gal). Previous probes for SA‐β‐gal with this purpose only cover a single dimension: the accumulation of this enzyme in lysosomes. However, this is insufficient to determine the destiny of senescence because endogenous β‐gal enriched in lysosomes is not only related to senescence, but also to some other physiological processes. To address this issue, we introduce our fluorescent probes including a second dimension: lysosomal pH, since de‐acidification is a unique feature of the lysosomes in senescent cells. With this novel design, our probes achieved excellent discrimination of SA‐β‐gal from cancer‐associated β‐gal, which enables them to track cellular senescence as well as tissue aging more precisely. Our crystal structures of a model enzyme E. coli β‐gal mutant (E537Q) complexed with each probe further revealed the structural basis for probe recognition.<br/

AAV9-mediated gene delivery to liver grafts during static cold storage in a rat liver transplant model

IntroductionRecombinant adeno-associated virus (rAAV) is a novel strategy used clinically for gene delivery, but has not been characterized in the context of organ transplantation. We sought to determine the efficacy of rAAV-mediated gene delivery during static cold storage (SCS) prior to liver transplantation.MethodsA triple-plasmid transfection protocol was used to produce rAAV subtype-9 vectors containing firefly luciferase genomes in HEK293 cells. Lewis rat liver grafts were flushed and stored in cold HTK solution. Three experimental groups received rAAV at different doses, administered via the portal vein as a bolus during SCS. A control group did not receive rAAV (N = 2). Recipients then underwent syngeneic liver transplantation. Bioluminescence imaging to quantify in vivo luciferase expression was performed on post-operative days 7, 14, 28, and 56.ResultsControl animals demonstrated no bioluminescent activity, while animals receiving rAAV-treated livers had increasing bioluminescence, peaking at four weeks but sustained to the eight-week endpoint. This result was confirmed by experimental endpoint tissue luciferase activity assay.DiscussionrAAV mediates gene transduction in liver grafts when administered during SCS and has potential for gene therapy applications in solid organ transplantation

A sheep pangenome reveals the spectrum of structural variations and their effects on tail phenotypes

Structural variations (SVs) are a major contributor to genetic diversity and phenotypic variations, but their prevalence and functions in domestic animals are largely unexplored. Here we generated high-quality genome assemblies for 15 individuals from genetically diverse sheep breeds using Pacific Biosciences (PacBio) high-fidelity sequencing, discovering 130.3 Mb nonreference sequences, from which 588 genes were annotated. A total of 149,158 biallelic insertions/deletions, 6531 divergent alleles, and 14,707 multiallelic variations with precise breakpoints were discovered. The SV spectrum is characterized by an excess of derived insertions compared to deletions (94,422 vs. 33,571), suggesting recent active LINE expansions in sheep. Nearly half of the SVs display low to moderate linkage disequilibrium with surrounding single-nucleotide polymorphisms (SNPs) and most SVs cannot be tagged by SNP probes from the widely used ovine 50K SNP chip. We identified 865 population-stratified SVs including 122 SVs possibly derived in the domestication process among 690 individuals from sheep breeds worldwide. A novel 168-bp insertion in the 5' untranslated region (5' UTR) of HOXB13 is found at high frequency in long-tailed sheep. Further genome-wide association study and gene expression analyses suggest that this mutation is causative for the long-tail trait. In summary, we have developed a panel of high-quality de novo assemblies and present a catalog of structural variations in sheep. Our data capture abundant candidate functional variations that were previously unexplored and provide a fundamental resource for understanding trait biology in sheep

Energy Management Strategy of Hybrid Ships Using Nonlinear Model Predictive Control via a Chaotic Grey Wolf Optimization Algorithm

Reducing energy consumption and carbon emissions from ships is a major concern. The development of hybrid technologies offers a new direction for the rational distribution of energy. Therefore, this paper establishes a torque model for internal combustion engines and motors based on first principles and fitting the data collected from the test platform; in turn, it develops a model for fuel consumption and carbon emissions. Furthermore, the effect of irregular waves using an extended Kalman filter is estimated as well as feedback to the controller as a disturbance variable. Then, a parallel hybrid ship energy management strategy based on a new real-time nonlinear model of predictive control is designed to achieve energy conservation and emission decrease. A hybrid algorithm of chaotic optimization combined with grey wolf optimization is utilized to solve the nonlinear optimization problem in the nonlinear model predictive control strategy and a local refined search is performed using sequential quadratic programming. Through the comparison of fuel consumption, carbon emissions, real-time performance, and the engine load path, the superiority of the nonlinear model predictive control energy management strategy based on the chaotic grey wolf optimization algorithm is verified

A Short-baseline Dual-antenna BDS/MIMU Integrated Navigation System

This paper puts forward a short-baseline dual-antenna BDS/MIMU integrated navigation, constructs the carrier phase double difference model of BDS (BeiDou Navigation Satellite System), and presents a 2-position initial orientation method on BDS. The Extended Kalman-filter has been applied for the integrated navigation system. The differences between MIMU and BDS position, velocity and carrier phase information are used as measurements. The experiment results indicate that the position error is less than 1m, the pitch angle error and roll angle error are less than 0.1°, and the heading angle error is about 1°. It shows that the new integrated navigation system has good performance and can be applied in various fields including USV and UAV

Liver Transplantation for Hepatocellular Carcinoma after Downstaging or Bridging Therapy with Immune Checkpoint Inhibitors

Liver transplantation offers excellent outcomes for patients with HCC. For those who initially present within the Milan criteria, bridging therapy is essential to control disease while awaiting liver transplant. For those who present beyond the Milan criteria, a liver transplant may still be considered following successful downstaging. Since the introduction of atezolizumab as part of the first-line treatment for HCC in 2020, there has been increasing interest in the use of ICIs as bridging or downstaging therapies prior to liver transplant. A total of six case reports/series have been published on this topic, with mixed outcomes. Overall, liver transplantation can be performed safely following prolonged ICI use, though ICIs may increase the risk of fulminant acute rejection early in the post-operative period. A minimal washout period between the last dose of ICI and liver transplantation has been identified as an important factor predicting transplant outcomes; however, further research is needed