Identification of the Function of the Vpx Protein of Primate Lentiviruses: A Dissertation

Primate lentiviruses encode four “accessory proteins” including Vif, Vpu, Nef, and Vpr/ Vpx. Vif and Vpu counteract the antiviral effects of cellular restrictions to early and late steps in the viral replication cycle. The functions of Vpx/ Vpr are not well understood. This study presents evidence that the Vpx proteins of HIV-2/ SIVSMpromote HIV-1 infection by antagonizing an antiviral restriction in myeloid cells. Fusion of macrophages in which Vpx was essential for virus infection, with COS cells in which Vpx was dispensable for virus infection, generated heterokaryons that supported infection by wild-type SIV but not Vpx-deleted SIV. The restriction potently antagonized infection of macrophages by HIV-1, and expression of Vpx in macrophages in transovercame the restriction to HIV-1 and SIV infection. Similarly, the cellular restriction is the obstacle to transduction of macrophages by MLV. Neutralization of the restriction by Vpx rendered macrophages permissive to MLV infection. Vpx was ubiquitylated and both ubiquitylation and the proteasome regulated the activity of Vpx. The ability of Vpx to counteract the restriction to HIV-1 and SIV infection was dependent upon the HIV-1 Vpr interacting protein, damaged DNA binding protein 1 (DDB1), and DDB1 partially substituted for Vpx when fused to Vpr. This study further demonstrates that this restriction prevents transduction of quiescent monocytes by HIV-1. Although terminally differentiated macrophages are partially permissive to HIV-1, quiescent monocytes, which are macrophage precursors, are highly refractory to lentiviral infection. Monocyte-HeLa heterokaryons were resistant to HIV-1 infection, while heterokaryons formed between monocytes and HeLa cells expressing Vpx were permissive to HIV-1 infection, suggesting the resistance of quiescent monocytes to HIV-1 transduction is governed by a restriction factor. Encapsidation of Vpx within HIV-1 virions conferred the ability to infect quiescent monocytes. Introduction of Vpx into monocytes by pre-infection also rendered quiescent monocytes permissive to HIV-1 infection. Infection of monocytes by HIV-1 either with or without Vpx did not have an effect on temporal expression of CD71. In addition, Vpx increased permissivity of CD71– and CD71+cells to HIV-1 infection with no apparent bias. These results confirm that Vpx directly renders undifferentiated monocytes permissive to HIV-1 transduction without inducing their differentiation. The introduction of Vpx did not significantly alter APOBEC3G complex distribution, suggesting a restriction other than APOBEC3G was responsible for the resistance of monocytes to HIV-1. Collectively our results indicate that macrophages and monocytes harbor a potent antiviral restriction that is counteracted by the Vpx protein. The relative ability of primate lentiviruses and gammaretroviruses to transduce non-dividing myeloid-cells is dependent upon their ability to neutralize this restriction

Tensor Kernel Recovery for Spatio-Temporal Hawkes Processes

We estimate the general influence functions for spatio-temporal Hawkes processes using a tensor recovery approach by formulating the location dependent influence function that captures the influence of historical events as a tensor kernel. We assume a low-rank structure for the tensor kernel and cast the estimation problem as a convex optimization problem using the Fourier transformed nuclear norm (TNN). We provide theoretical performance guarantees for our approach and present an algorithm to solve the optimization problem. Moreover, we demonstrate the efficiency of our estimation with numerical simulations.Comment: 24 page

High-dimensional Bias-corrected Inference, with Applications to fMRI Studies

In neuroimaging studies, measures of neural structure and function are used to try to predict clinical outcomes in adults. Identifying biomarkers that reflect underlying neuropathological processes can provide promising neural targets for future therapeutic interventions. This identification is typically done using linear or generalized linear models (GLM) with many covariates and relatively few subjects. Thus, regularization is used to select the salient covariates in the model. In this thesis, we compare the performance of the least absolute shrinkage and selection operator (LASSO) regression, adaptive LASSO regression, debiased LASSO regression, and regularized zero-inflated Poisson (ZIP) regression model in two simulation settings. The performance of LASSO regression with Poisson and Gaussian models are similar but for all these approaches the zero-inflated model outperforms the rest. We apply these approaches to the data from the Longitudinal Assessment of Manic Symptoms (LAMS) study. We then study the bias correction of GLM and the application on ZIP data. We apply a decorrelated score approach to address Poisson distributed data and introduce Cornish-Fisher correction to the decorrelated score test. In high-dimension settings, the Cornish-Fisher correction can improve the performance of decorrelated score test for ZIP data

Orbital angular momentum mode-demultiplexing scheme with partial angular receiving aperture

For long distance orbital angular momentum (OAM) based transmission, the conventional whole beam receiving scheme encounters the difficulty of large aperture due to the divergence of OAM beams. We propose a novel partial receiving scheme, using a restricted angular aperture to receive and demultiplex multi-OAM-mode beams. The scheme is theoretically analyzed to show that a regularly spaced OAM mode set remain orthogonal and therefore can be de-multiplexed. Experiments have been carried out to verify the feasibility. This partial receiving scheme can serve as an effective method with both space and cost savings for the OAM communications. It is applicable to both free space OAM optical communications and radio frequency (RF) OAM communications

LLatrieval: LLM-Verified Retrieval for Verifiable Generation

Verifiable generation aims to let the large language model (LLM) generate text with corresponding supporting documents, which enables the user to flexibly verify the answer and makes it more trustworthy. Its evaluation not only measures the correctness of the answer, but also the answer's verifiability, i.e., how well the answer is supported by the corresponding documents. In typical, verifiable generation adopts the retrieval-read pipeline, which is divided into two stages: 1) retrieve relevant documents of the question. 2) according to the documents, generate the corresponding answer. Since the retrieved documents can supplement knowledge for the LLM to generate the answer and serve as evidence, the retrieval stage is essential for the correctness and verifiability of the answer. However, the widely used retrievers become the bottleneck of the entire pipeline and limit the overall performance. They often have fewer parameters than the large language model and have not been proven to scale well to the size of LLMs. Since the LLM passively receives the retrieval result, if the retriever does not correctly find the supporting documents, the LLM can not generate the correct and verifiable answer, which overshadows the LLM's remarkable abilities. In this paper, we propose LLatrieval (Large Language Model Verified Retrieval), where the LLM updates the retrieval result until it verifies that the retrieved documents can support answering the question. Thus, the LLM can iteratively provide feedback to retrieval and facilitate the retrieval result to sufficiently support verifiable generation. Experimental results show that our method significantly outperforms extensive baselines and achieves new state-of-the-art results

COGNITIVE CORRELATES OF GAIT SPEED AMONG OLDER ADULTS FROM SIX COUNTRIES: FINDINGS FROM THE COSMIC COLLABORATION

Using data from population-based cohorts of older adults 65+ from six countries across three continents (N=6472), we aimed to (1) describe and (2) identify predictors of usual and rapid gait speed from studies participating in the Cohort Studies of Memory in an International Consortium (COSMIC) collaboration. We investigated whether clinical (BMI, hypertension, stroke, APOE status), psychological (cognition, mood, general health) and behavioral factors (smoking, drinking, physical activity) predicted gait speed similarly across cohorts; we used regression models controlling for demographics. Unadjusted usual gait speed ranged from 0.52-1.09 m/s and rapid gait speed ranged from 1.20-1.68 m/s. Lower BMI and better cognitive function consistently predicted faster usual and rapid gait speed in all cohorts. These patterns were not attenuated by demographics. Other psychological and behavioral factors were less consistently associated with gait. Taken together, gait speed is variable across ethnogeographic regions, but the influence of cognitive on gait is remarkably consistent

Discordant Biological and Chronological Age: Implications for Cognitive Decline and Frailty.

BACKGROUND: Older adults with discordant biological and chronological ages (BA and CA) may vary in cognitive and physical function from those with concordant BA and CA. METHODS: To make our approach clinically accessible, we created easy-to-interpret participant groups in the Health, Aging, and Body Composition Study (N = 2 458, 52% female participants, 65% White participants, age: 73.5 ± 2.8) based on medians of CA, and a previously validated BA index comprised of readily available clinical tests. Joint models estimated associations of BA-CA group with cognition (Modified Mini-Mental State Examination [3MS] and Digit Symbol Substitution Test [DSST]) and frailty over 10 years. RESULTS: The sample included the following: 32%, Young group (BA and CA < median); 21%, Prematurely Aging group (BA ≥ median, CA < median), 27%, Old group (BA and CA ≥ median), and 20%, Resilient group (BA < median, CA ≥ median). In education-adjusted models of cognition, among those with CA < median, the Prematurely Aging group performed worse than the Young at baseline (3MS and DSST p < .0001), but among those with CA ≥ median, the Resilient group did not outperform the Old group (3MS p = .31; DSST p = .25). For frailty, the Prematurely Aging group performed worse than the Young group at baseline (p = .0001), and the Resilient group outperformed the Old group (p = .003). For all outcomes, groups did not differ on change over time based on the same pairwise comparisons (p ≥ .40). CONCLUSIONS: Discordant BA and CA identify groups who have greater cognitive and physical functional decline or are more protected than their CA would suggest. This information can be used for risk stratification

Primate Lentiviral Vpx Commandeers DDB1 to Counteract a Macrophage Restriction

Primate lentiviruses encode four “accessory proteins” including Vif, Vpu, Nef, and Vpr/Vpx. Vif and Vpu counteract the antiviral effects of cellular restrictions to early and late steps in the viral replication cycle. We present evidence that the Vpx proteins of HIV-2/SIVSM promote virus infection by antagonizing an antiviral restriction in macrophages. Fusion of macrophages in which Vpx was essential for virus infection, with COS cells in which Vpx was dispensable for virus infection, generated heterokaryons that supported infection by wild-type SIV but not Vpx-deleted SIV. The restriction potently antagonized infection of macrophages by HIV-1, and expression of Vpx in macrophages in trans overcame the restriction to HIV-1 and SIV infection. Vpx was ubiquitylated and both ubiquitylation and the proteasome regulated the activity of Vpx. The ability of Vpx to counteract the restriction to HIV-1 and SIV infection was dependent upon the HIV-1 Vpr interacting protein, damaged DNA binding protein 1 (DDB1), and DDB1 partially substituted for Vpx when fused to Vpr. Our results indicate that macrophage harbor a potent antiviral restriction and that primate lentiviruses have evolved Vpx to counteract this restriction