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

Rule-based Cross-matching of Very Large Catalogs

The NASA Extragalactic Database (NED) has deployed a new rule-based cross-matching algorithm called Match Expert (MatchEx), capable of cross-matching very large catalogs (VLCs) with >10 million objects. MatchEx goes beyond traditional position-based cross-matching algorithms by using other available data together with expert logic to determine which candidate match is the best. Furthermore, the local background density of sources is used to determine and minimize the false-positive match rate and to estimate match completeness. The logical outcome and statistical probability of each match decision is stored in the database and may be used to tune the algorithm and adjust match parameter thresholds. For our first production run, we cross-matched the GALEX All Sky Survey Catalog (GASC), containing nearly 40 million NUV-detected sources, against a directory of 180 million objects in NED. Candidate matches were identified for each GASC source within a 7''.5 radius. These candidates were filtered on position-based matching probability and on other criteria including object type and object name. We estimate a match completeness of 97.6% and a match accuracy of 99.75%. Over the next year, we will be cross-matching over 2 billion catalog sources to NED, including the Spitzer Source List, the 2MASS point-source catalog, AllWISE, and SDSS DR 10. We expect to add new capabilities to filter candidate matches based on photometry, redshifts, and refined object classifications. We will also extend MatchEx to handle more heterogenous datasets federated from smaller catalogs through NED's literature pipeline

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

Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques.

Herpes simplex virus 2 (HSV-2) is a common sexually transmitted infection with a highly variable clinical course. Many infections quickly become subclinical, with episodes of spontaneous virus reactivation. To study host-HSV-2 interactions, an animal model of subclinical HSV-2 infection is needed. In an effort to develop a relevant model, rhesus macaques (RM) were inoculated intravaginally with two or three HSV-2 strains (186, 333, and/or G) at a total dose of 1 × 107 PFU of HSV-2 per animal. Infectious HSV-2 and HSV-2 DNA were consistently shed in vaginal swabs for the first 7 to 14 days after each inoculation. Proteins associated with wound healing, innate immunity, and inflammation were significantly increased in cervical secretions immediately after HSV-2 inoculation. There was histologic evidence of acute herpesvirus pathology, including acantholysis in the squamous epithelium and ballooning degeneration of and intranuclear inclusion bodies in epithelial cells, with HSV antigen in mucosal epithelial cells and keratinocytes. Further, an intense inflammatory infiltrate was found in the cervix and vulva. Evidence of latent infection and reactivation was demonstrated by the detection of spontaneous HSV-2 shedding post-acute inoculation (102 to 103 DNA copies/swab) in 80% of RM. Further, HSV-2 DNA was detected in ganglia in most necropsied animals. HSV-2-specifc T-cell responses were detected in all animals, although antibodies to HSV-2 were detected in only 30% of the animals. Thus, HSV-2 infection of RM recapitulates many of the key features of subclinical HSV-2 infection in women but seems to be more limited, as virus shedding was undetectable more than 40 days after the last virus inoculation.IMPORTANCE Herpes simplex virus 2 (HSV-2) infects nearly 500 million persons globally, with an estimated 21 million incident cases each year, making it one of the most common sexually transmitted infections (STIs). HSV-2 is associated with increased human immunodeficiency virus type 1 (HIV-1) acquisition, and this risk does not decline with the use of antiherpes drugs. As initial acquisition of both HIV and HSV-2 infections is subclinical, study of the initial molecular interactions of the two agents requires an animal model. We found that HSV-2 can infect RM after vaginal inoculation, establish latency in the nervous system, and spontaneously reactivate; these features mimic some of the key features of HSV-2 infection in women. RM may provide an animal model to develop strategies to prevent HSV-2 acquisition and reactivation

Array atomic force microscopy for real-time multiparametric analysis.

Nanoscale multipoint structure-function analysis is essential for deciphering the complexity of multiscale biological and physical systems. Atomic force microscopy (AFM) allows nanoscale structure-function imaging in various operating environments and can be integrated seamlessly with disparate probe-based sensing and manipulation technologies. Conventional AFMs only permit sequential single-point analysis; widespread adoption of array AFMs for simultaneous multipoint study is challenging owing to the intrinsic limitations of existing technological approaches. Here, we describe a prototype dispersive optics-based array AFM capable of simultaneously monitoring multiple probe-sample interactions. A single supercontinuum laser beam is utilized to spatially and spectrally map multiple cantilevers, to isolate and record beam deflection from individual cantilevers using distinct wavelength selection. This design provides a remarkably simplified yet effective solution to overcome the optical cross-talk while maintaining subnanometer sensitivity and compatibility with probe-based sensors. We demonstrate the versatility and robustness of our system on parallel multiparametric imaging at multiscale levels ranging from surface morphology to hydrophobicity and electric potential mapping in both air and liquid, mechanical wave propagation in polymeric films, and the dynamics of living cells. This multiparametric, multiscale approach provides opportunities for studying the emergent properties of atomic-scale mechanical and physicochemical interactions in a wide range of physical and biological networks

The effect of non-ideal market conditions on option pricing

Option pricing is mainly based on ideal market conditions which are well represented by the Geometric Brownian Motion (GBM) as market model. We study the effect of non-ideal market conditions on the price of the option. We focus our attention on two crucial aspects appearing in real markets: The influence of heavy tails and the effect of colored noise. We will see that both effects have opposite consequences on option pricing.Comment: 26 pages and 8 colored figures. Invited Talk in "Horizons in complex systems", Messina, 5-8 December 2001. To appear in Physica-