Distribution and Redistribution of HIV-1 Nucleocapsid Protein in Immature, Mature, and Integrase-Inhibited Virions: a Role for Integrase in Maturation

During virion maturation, HIV-1 capsid protein assembles into a conical core containing the viral ribonucleoprotein (vRNP) complex, thought to be composed mainly of the viral RNA and nucleocapsid protein (NC). After infection, the viral RNA is reverse transcribed into double-stranded DNA, which is then incorporated into host chromosomes by integrase (IN) catalysis. Certain IN mutations (class II) and antiviral drugs (allosteric IN inhibitors [ALLINIs]) adversely affect maturation, resulting in virions that contain “eccentric condensates,” electron-dense aggregates located outside seemingly empty capsids. Here we demonstrate that in addition to this mislocalization of electron density, a class II IN mutation and ALLINIs each increase the fraction of virions with malformed capsids (from ∼12% to ∼53%). Eccentric condensates have a high NC content, as demonstrated by “tomo-bubblegram” imaging, a novel labeling technique that exploits the susceptibility of NC to radiation damage. Tomo-bubblegrams also localized NC inside wild-type cores and lining the spherical Gag shell in immature virions. We conclude that eccentric condensates represent nonpackaged vRNPs and that either genetic or pharmacological inhibition of IN can impair vRNP incorporation into mature cores. Supplying IN in trans as part of a Vpr-IN fusion protein partially restored the formation of conical cores with internal electron density and the infectivity of a class II IN deletion mutant virus. Moreover, the ability of ALLINIs to induce eccentric condensate formation required both IN and viral RNA. Based on these observations, we propose a role for IN in initiating core morphogenesis and vRNP incorporation into the mature core during HIV-1 maturation

Necessary and sufficient conditions of solution uniqueness in ℓ1\ell_1 minimization

This paper shows that the solutions to various convex $\ell_1$ minimization problems are \emph{unique} if and only if a common set of conditions are satisfied. This result applies broadly to the basis pursuit model, basis pursuit denoising model, Lasso model, as well as other $\ell_1$ models that either minimize $f(Ax-b)$ or impose the constraint $f(Ax-b)\leq\sigma$, where $f$ is a strictly convex function. For these models, this paper proves that, given a solution $x^*$ and defining I=\supp(x^*) and s=\sign(x^*_I), $x^*$ is the unique solution if and only if $A_I$ has full column rank and there exists $y$ such that $A_I^Ty=s$ and $|a_i^Ty|_\infty<1$ for $i\not\in I$. This condition is previously known to be sufficient for the basis pursuit model to have a unique solution supported on $I$. Indeed, it is also necessary, and applies to a variety of other $\ell_1$ models. The paper also discusses ways to recognize unique solutions and verify the uniqueness conditions numerically.Comment: 6 pages; revised version; submitte

Cognitive and Neuronal Link With Inflammation: A Longitudinal Study in People With and Without HIV Infection

BACKGROUND: Across many settings, lack of virologic control remains common in people with HIV (PWH) due to late presentation and lack of retention in care. This contributes to neuronal damage and neurocognitive impairment, which remain prevalent. More evidence is needed to understand these outcomes in both PWH and people without HIV (PWOH). METHODS: We recruited PWH initiating antiretroviral therapy (ART) as well as PWOH at two sites in the United States. 108 adults were enrolled (56 PWOH and 52 PWH), most of whom had a second assessment at least 24 weeks later (193 total assessments). Tumor necrosis factor alpha (TNFá), monocyte chemotactic protein-1 (MCP-1), neopterin, soluble CD14, and neurofilament light chain protein (NFL) were measured in plasma and cerebrospinal fluid (CSF). Using multivariate models including Bayesian Model Averaging (BMA), we analyzed factors associated with global neuropsychological (NP) performance (NPT-9) and CSF NFL at baseline and over time. RESULTS: At baseline, higher CSF MCP-1 and plasma sCD14 were associated with worse NPT-9 in PWH, while CSF HIV RNA decrease was the only marker associated with improved NPT-9 over time. Among PWH, higher CSF neopterin was most closely associated with higher NFL. Among PWOH, higher CSF MCP-1 was most closely associated with higher NFL. Following ART initiation, decrease in CSF MCP-1 was most closely associated with NFL decrease. CONCLUSION: Monocyte-associated CSF biomarkers are highly associated with neuronal damage in both PWH and PWOH. More research is needed to evaluate if therapies targeting monocyte-associated inflammation may ameliorate HIV-associated neurobehavioral diseases

Researching with Twitter timeline data: A demonstration via “everyday” socio-political talk around welfare provision

Increasingly, social media platforms are understood by researchers to be valuable sites of politically-relevant discussions. However, analyses of social media data are typically undertaken by focusing on ‘snapshots’ of issues using query-keyword search strategies. This paper develops an alternative, less issue-based, mode of analysing Twitter data. It provides a framework for working qualitatively with longitudinally-oriented Twitter data (user-timelines), and uses an empirical case to consider the value and the challenges of doing so. Exploring how Twitter users place “everyday” talk around the socio-political issue of UK welfare provision, we draw on digital ethnography and narrative analysis techniques to analyse 25 user-timelines and identify three distinctions in users’ practices: users’ engagements with welfare as TV entertainment or as a socio-political concern; the degree of sustained engagement with said issues, and; the degree to which users’ tweeting practices around welfare were congruent with or in contrast to their other tweets. With this analytic orientation, we demonstrate how a longitudinal analysis of user-timelines provides rich resources that facilitate a more nuanced understanding of user engagement in everyday socio-political discussions online

Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration

In the age of stem cell engineering it is critical to understand how stem cell activity is regulated during regeneration. Hairs are mini-organs that undergo cyclic regeneration throughout adult life1, and are an important model for organ regeneration. Hair stem cells located in the follicle bulge2 are regulated by the surrounding microenvironment, or niche3. The activation of such stem cells is cyclic, involving periodic -catenin activity4, 5, 6, 7. In the adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extrafollicular environment. Here we show that unexpected periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 in the dermis regulates this process. This BMP cycle is out of phase with the WNT/-catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signalling, respectively. Overexpression of noggin, a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wild-type host showed that follicles in donor and host can affect their cycling behaviours mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. These results show that BMPs may be the long-sought 'chalone' inhibitors of hair growth postulated by classical experiments. Taken together, results presented in this study provide an example of hierarchical regulation of local organ stem cell homeostasis by the inter-organ macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiological integration between these two thermo-regulatory organs. Our findings have practical importance for studies using mouse skin as a model for carcinogenesis, intra-cutaneous drug delivery and stem cell engineering studies, because they highlight the acute need to differentiate supportive versus inhibitory regions in the host skin

Magnetic vortex oscillator driven by dc spin-polarized current

Transfer of angular momentum from a spin-polarized current to a ferromagnet provides an efficient means to control the dynamics of nanomagnets. A peculiar consequence of this spin-torque, the ability to induce persistent oscillations of a nanomagnet by applying a dc current, has previously been reported only for spatially uniform nanomagnets. Here we demonstrate that a quintessentially nonuniform magnetic structure, a magnetic vortex, isolated within a nanoscale spin valve structure, can be excited into persistent microwave-frequency oscillations by a spin-polarized dc current. Comparison to micromagnetic simulations leads to identification of the oscillations with a precession of the vortex core. The oscillations, which can be obtained in essentially zero magnetic field, exhibit linewidths that can be narrower than 300 kHz, making these highly compact spin-torque vortex oscillator devices potential candidates for microwave signal-processing applications, and a powerful new tool for fundamental studies of vortex dynamics in magnetic nanostructures.Comment: 14 pages, 4 figure