Insulin-like growth factors and related proteins in plasma and cerebrospinal fluids of HIV-positive individuals.

BackgroundClinically significant dysregulation of the insulin-like growth factor (IGF) family proteins occurs in HIV-infected individuals, but the details including whether the deficiencies in IGFs contribute to CNS dysfunction are unknown.MethodsWe measured the levels of IGF1, IGF2, IGFBP1, IGFBP2, and IGF2 receptor (IGF2R) in matching plasma and cerebrospinal fluid (CSF) samples of 107 HIV+ individuals from CNS HIV Antiretroviral Therapy Effects Research (CHARTER) and analyzed their associations with demographic and disease characteristics, as well as levels of several soluble inflammatory mediators (TNFα, IL-6, IL-10, IL-17, IP-10, MCP-1, and progranulin). We also determined whether IGF1 or IGF2 deficiency is associated with HIV-associated neurocognitive disorder (HAND) and whether the levels of soluble IGF2R (an IGF scavenging receptor, which we also have found to be a cofactor for HIV infection in vitro) correlate with HIV viral load (VL).ResultsThere was a positive correlation between the levels of IGF-binding proteins (IGFBPs) and those of inflammatory mediators: between plasma IGFBP1 and IL-17 (β coefficient 0.28, P = 0.009), plasma IGFBP2 and IL-6 (β coefficient 0.209, P = 0.021), CSF IGFBP1 and TNFα (β coefficient 0.394, P < 0.001), and CSF IGFBP2 and TNF-α (β coefficient 0.14, P < 0.001). As IGFBPs limit IGF availability, these results suggest that inflammation is a significant factor that modulates IGF protein expression/availability in the setting of HIV infection. However, there was no significant association between HAND and the reduced levels of plasma IGF1, IGF2, or CSF IGF1, suggesting a limited power of our study. Interestingly, plasma IGF1 was significantly reduced in subjects on non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) compared to protease inhibitor-based therapy (174.1 ± 59.8 vs. 202.8 ± 47.3 ng/ml, P = 0.008), suggesting a scenario in which ART regimen-related toxicity can contribute to HAND. Plasma IGF2R levels were positively correlated with plasma VL (β coefficient 0.37, P = 0.021) and inversely correlated with current CD4+ T cell counts (β coefficient -0.04, P = 0.021), supporting our previous findings in vitro.ConclusionsTogether, these results strongly implicate (1) an inverse relationship between inflammation and IGF growth factor availability and the contribution of IGF deficiencies to HAND and (2) the role of IGF2R in HIV infection and as a surrogate biomarker for HIV VL

The role of initial geometry in experimental models of wound closing

Wound healing assays are commonly used to study how populations of cells, initialised on a two-dimensional surface, act to close an artificial wound space. While real wounds have different shapes, standard wound healing assays often deal with just one simple wound shape, and it is unclear whether varying the wound shape might impact how we interpret results from these experiments. In this work, we describe a new kind of wound healing assay, called a sticker assay, that allows us to examine the role of wound shape in a series of wound healing assays performed with fibroblast cells. In particular, we show how to use the sticker assay to examine wound healing with square, circular and triangular shaped wounds. We take a standard approach and report measurements of the size of the wound as a function of time. This shows that the rate of wound closure depends on the initial wound shape. This result is interesting because the only aspect of the assay that we change is the initial wound shape, and the reason for the different rate of wound closure is unclear. To provide more insight into the experimental observations we describe our results quantitatively by calibrating a mathematical model, describing the relevant transport phenomena, to match our experimental data. Overall, our results suggest that the rates of cell motility and cell proliferation from different initial wound shapes are approximately the same, implying that the differences we observe in the wound closure rate are consistent with a fairly typical mathematical model of wound healing. Our results imply that parameter estimates obtained from an experiment performed with one particular wound shape could be used to describe an experiment performed with a different shape. This fundamental result is important because this assumption is often invoked, but never tested

In vivo 4-dimensional tracking of hematopoietic stem and progenitor cells in adult mouse calvarial bone marrow

Through a delicate balance between quiescence and proliferation, self renewal and production of differentiated progeny, hematopoietic stem cells (HSCs) maintain the turnover of all mature blood cell lineages. The coordination of the complex signals leading to specific HSC fates relies upon the interaction between HSCs and the intricate bone marrow microenvironment, which is still poorly understood[1-2]. We describe how by combining a newly developed specimen holder for stable animal positioning with multi-step confocal and two-photon in vivo imaging techniques, it is possible to obtain high-resolution 3D stacks containing HSPCs and their surrounding niches and to monitor them over time through multi-point time-lapse imaging. High definition imaging allows detecting ex vivo labeled hematopoietic stem and progenitor cells (HSPCs) residing within the bone marrow. Moreover, multi-point time-lapse 3D imaging, obtained with faster acquisition settings, provides accurate information about HSPC movement and the reciprocal interactions between HSPCs and stroma cells. Tracking of HSPCs in relation to GFP positive osteoblastic cells is shown as an exemplary application of this method. This technique can be utilized to track any appropriately labeled hematopoietic or stromal cell of interest within the mouse calvarium bone marrow space

Evolution of Design and Construction of Lornex L-L Tailings Dam

The evolution of the Lornex tailings disposal facility, in particular the Lower L-L Dam, throughout the design and construction phases is presented with the emphasis on how economic considerations have dictated this process. Major episodes described here include: the early conversion to an energy efficient t wo-dam storage scheme, the reduction of the size of the L-L Starter Dam, the buttressing of the Starter Dam in an area involving soft foundations, and the development of hydraulic means to use cycloned tailings sand for annual raising of the L-L Dam. Extensive instrumentation was installed to monitor the performance of the L-L dam in critical construction periods. This helped the designers to adapt the design of the dam to its actual performance in order to ensure its safety

Task-irrelevant auditory metre shapes visuomotor sequential learning

The ability to learn and reproduce sequences is fundamental to every-day life, and deficits in sequential learning are associated with developmental disorders such as specific language impairment. Individual differences in sequential learning are usually investigated using the serial reaction time task (SRTT), wherein a participant responds to a series of regularly timed, seemingly random visual cues that in fact follow a repeating deterministic structure. Although manipulating inter-cue interval timing has been shown to adversely affect sequential learning, the role of metre (the patterning of salience across time) remains unexplored within the regularly timed, visual SRTT. The current experiment consists of an SRTT adapted to include task-irrelevant auditory rhythms conferring a sense of metre. We predicted that (1) participants’ (n = 41) reaction times would reflect the auditory metric structure; (2) that disrupting the correspondence between the learned visual sequence and auditory metre would impede performance; and (3) that individual differences in sensitivity to rhythm would predict the magnitude of these effects. Altering the relationship via a phase shift between the trained visual sequence and auditory metre slowed reaction times. Sensitivity to rhythm was predictive of reaction times over all. In an exploratory analysis, we, moreover, found that approximately half of participants made systematically different responses to visual cues on the basis of the cues’ position within the auditory metre. We demonstrate the influence of auditory temporal structures on visuomotor sequential learning in a widely used task where metre and timing are rarely considered. The current results indicate sensitivity to metre as a possible latent factor underpinning individual differences in SRTT performance

Wood Diaphragm Deflections. Part I: Generalizing Standard Equations Using MechanicsBased Derivations for Panel Construction

Horizontal wood diaphragm systems, whether decked with conventional or mass timber panels, transfer wind and seismic loads to vertical elements of the lateral force-resisting system (LFRS), in flexible, rigid, or semi-rigid fashion. Characterizing and calculating the resulting diaphragm deflections determines the distribution of forces to critically loaded components and a significant portion of lateral building translations and rotations. Deflection equations for sheathed wood structural panel (WSP) diaphragms are well established in U.S. design standards in a 4-term expression that models flexural, shear, and fastener-slip deformations and its full derivation using principles of mechanics is provided herein. Derivations of similar equations for cross-laminated timber (CLT) diaphragms have yet to unfold, despite growing industry consensus that CLT panels make efficient slabs and decks. In this first of two companion papers, the corrected full derivation of the current 4-term WSP diaphragm deflection expression is provided and assessed, and two ways to quantify the cumulative contribution of fastener slip are presented in order to expand its usage to a wider variety of WSP and CLT configurations in current use. Building upon this generalized mechanics-based derivation, the authors are able to propose and assess in the companion paper a unified diaphragm deflection model to compute both WSP and CLT diaphragm deflections as implemented under current practice and guide further development

Study of new systems concepts for a Titan atmospheric probe

Results of a systems concepts study for a Titan Probe were examined. The key tradeoffs performed are described in detail. Mass breakdown of each Probe subsystem or major element were given. The mission analysis performed to determine compliance with the high altitude sampling and descent time requirements are described. The baseline Descent Module design was derived. The element of the Probe System left on the Carrier after separation were described

Rare Disasters and Risk Sharing with Heterogeneous Beliefs

Risks of rare economic disasters can have a large impact on asset prices. At the same time, difficulties in inference regarding both the likelihood and severity of disasters, as well as agency problems, can lead to significant disagreements among investors about disaster risk. We show that such disagreements generate strong risk-sharing motives, such that just a small number of optimists in the economy will significantly reduce the disaster risk premium. Our model highlights the “latent” nature of disaster risk. The disaster risk premium will likely be low and smooth during normal times but increases dramatically when the risk-sharing capacity of the optimists is reduced, e.g., following a disaster. The model also helps reconcile the difference in the amount of disaster risk implied by financial markets and international macroeconomic data, and provides caution to the approach of extracting disaster probabilities from asset prices, which will disproportionately reflect the beliefs of a small group of optimists. Finally, our model predicts an inverse U-shaped relation between the equity premium and the size of the disaster insurance market