Molecular Dynamics Simulation of Dipalmitoylphosphatidylserine Bilayer with Na+ Counterions

AbstractWe performed a molecular dynamics simulation of dipalmitoylphosphatidylserine (DPPS) bilayer with Na+ counterions. We found that hydrogen bonding between the NH3+ group and the phosphate group leads to a reduction in the area per headgroup when compared to the area in dipalmitoylphosphatidylcholine bilayer. The Na+ ions bind to the oxygen in the carboxyl group of serine, thus giving rise to a dipolar bilayer similar to dipalmitoylphosphatidylethanolamine bilayer. The results of the simulation show that counterions play a crucial role in determining the structural and electrostatic properties of DPPS bilayer

Pylons ablaze: Examining the role of 5G COVID-19 conspiracy beliefs and support for violence

Amid increased acts of violence against telecommunication engineers and property, this pre‐registered study (N = 601 Britons) investigated the association between beliefs in 5G COVID‐19 conspiracy theories and the justification and willingness to use violence. Findings revealed that belief in 5G COVID‐19 conspiracy theories was positively correlated with state anger, which in turn, was associated with a greater justification of real‐life and hypothetical violence in response to an alleged link between 5G mobile technology and COVID‐19, alongside a greater intent to engage in similar behaviours in the future. Moreover, these associations were strongest for those highest in paranoia. Furthermore, we show that these patterns are not specific to 5G conspiratorial beliefs: General conspiracy mentality was positively associated with justification and willingness for general violence, an effect mediated by heightened state anger, especially for those most paranoid in the case of justification of violence. Such research provides novel evidence on why and when conspiracy beliefs may justify the use of violence

Vicarious Experience Affects Patients' Treatment Preferences for Depression

Depression is common in primary care but often under-treated. Personal experiences with depression can affect adherence to therapy, but the effect of vicarious experience is unstudied. We sought to evaluate the association between a patient's vicarious experiences with depression (those of friends or family) and treatment preferences for depressive symptoms.We sampled 1054 English and/or Spanish speaking adult subjects from July through December 2008, randomly selected from the 2008 California Behavioral Risk Factor Survey System, regarding depressive symptoms and treatment preferences. We then constructed a unidimensional scale using item analysis that reflects attitudes about antidepressant pharmacotherapy. This became the dependent variable in linear regression analyses to examine the association between vicarious experiences and treatment preferences for depressive symptoms.Our sample was 68% female, 91% white, and 13% Hispanic. Age ranged from 18-94 years. Mean PHQ-9 score was 4.3; 14.5% of respondents had a PHQ-9 score >9.0, consistent with active depressive symptoms. Analyses controlling for current depression symptoms and socio-demographic factors found that in patients both with (coefficient 1.08, p = 0.03) and without (coefficient 0.77, p = 0.03) a personal history of depression, having a vicarious experience (family and friend, respectively) with depression is associated with a more favorable attitude towards antidepressant medications.Patients with vicarious experiences of depression express more acceptance of pharmacotherapy. Conversely, patients lacking vicarious experiences of depression have more negative attitudes towards antidepressants. When discussing treatment with patients, clinicians should inquire about vicarious experiences of depression. This information may identify patients at greater risk for non-adherence and lead to more tailored patient-specific education about treatment

Human serine racemase structure/activity relationship studies provide mechanistic insight and point to position 84 as a hot spot for \u3ci\u3eβ\u3c/i\u3e-elimination function

There is currently great interest in human serine racemase, the enzyme responsible for producing the NMDA co-agonist D-serine. Reported correlation of D-serine levels with disorders including Alzheimer’s disease, ALS, and ischemic brain damage (elevated D-serine) and schizophrenia (reduced D-serine) has further piqued this interest. Reported here is a structure/activity relationship study of position Ser84, the putative re-face base. In the most extreme case of functional reprogramming, the S84D mutant displays a dramatic reversal of β-elimination substrate specificity in favor of L-serine over the normally preferred L-serine-O-sulfate (~1200-fold change in kcat/Km ratios) and L (L-THA; ~5000-fold change in kcat/Km ratios) alternative substrates. On the other hand, the S84T (which performs L-Ser racemization activity), S84A (good kcat but high Km for L-THA elimination), and S84N mutants (nearly WT efficiency for L-Ser elimination) displayed intermediate activity, all showing a preference for the anionic substrates, but generally attenuated compared with the native enzyme. Inhibition studies with L-erythro-β-hydroxyaspartate follow this trend, with both WT serine racemase and the S84N mutant being competitively inhibited, with Ki = 31 ± 1.5 μM and 1.5 ± 0.1mM, respectively, and the S84D being inert to inhibition. Computational modeling pointed to a key role for residue Arg-135 in binding and properly positioning the L-THA and L-serine-O-sulfate substrates and the L-erythro-β-hydroxyaspartate inhibitor. Examination of available sequence data suggests that Arg-135 may have originated for L-THA-like-β-elimination function in earlier evolutionary variants, and examination of available structural data suggests that a Ser84-H2O-Lys114 hydrogen-bonding network in human serine racemase lowers the pKa of the Ser84 re-face base

Effect of Methylimidazole-Induced Hypothyroidism in a Model of Low Retinal Neovascular Incidence

PURPOSE. To determine the effect of methylimidazole (MMI)-induced hypothyroidism in a newborn rat model of low retinal neovascular (NV) incidence. METHODS. Control and MMI-exposed newborn rats were raised either in room air or variable oxygen (40/15) until P14. All groups were then exposed to room air between postnatal day (P)14 and P20. Dams drank either tap water or water containing MMI. Eyes of animals in all groups were enucleated, and retinas were removed and stained with adenosine diphosphatase and analyzed for peripheral avascularity, vascular density, and NV incidence and severity. RESULTS. In the control group, MMI treatment did not promote the development of retinal NV although a linear relationship (r ϭ 0.99, P Ͻ 0.01) was found between increased MMI dose and lower peripheral retinal vascular densities. In all the 40/15 groups, peripheral retinal vascular densities were lower (P Ͻ 0.05) than normal and were not a function of MMI dose. Increased MMI dose produced increased retinal incidence of NV (r ϭ 0.99, P Ͻ 0.05). CONCLUSIONS. These data are consistent with the notions that thyroid function contributes to normal retinal vascular density and that hypothyroidism can play a permissive role in the development of retinal NV. (Invest Ophthalmol Vis Sci. 2004; 45:919 -921) DOI:10.1167/iovs.03-0914 V ery-low-birth-weight infants are at substantially higher risk for blinding complications, such as the development of retinal neovascularization (NV) associated with retinopathy of prematurity (ROP). To minimize the impact of retinal NV on vision, photocoagulation is currently used, but it is a destructive approach that is not always effective. A better understanding is needed of the pathogenic factors involved in the formation of retinal NV in ROP so that new methods of prevention and treatment can be developed. To date, studies have demonstrated an important link between insulin-like growth factor (IGF)-1 and normal and abnormal retinal vascular development. 1-3 IGF-1 is, among other functions, a downstream modulator of thyroid activity. Infants born very prematurely (Ͻ27 weeks) are more likely to have low thyroxine (T 4 ) levels, indicating an abnormal hypothalamus-pituitary-thyroid axis function. In this study, we used a clinically relevant model of ROP involving newborn rats exposed to a variable oxygen environment from postnatal day (P)0 to P14 and then to room air between P15 and P20. 6 -8 In animals exposed to an oxygen environment that alternates between 40% and 15% every other day (the 40/15 model), only a small percentage (Ͻ10%) of the rat pups exhibit 1 clock hour of NV in the peripheral retina. -14 METHODS The animals were treated in accordance with the NIH Guide for the Care and Use of Laboratory Animals and the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. MMI Between P0 and P20, rat pups were raised in room air and received MMI (0.05%, 0.1%, 0.13%, or 0.15% wt/vol; Sigma-Aldrich, St. Louis, MO), added to the drinking water of the dam. Control dams and their pups drank untreated water. In the control and 0.13% and 0.15% MMI-treated 40/15 groups, measurements of T 4 , thyroid stimulating hormone (TSH), and IGF-1 were performed (Anilytics Inc., Gaithersburg, MD) on pooled blood samples. Pooled blood samples were used because of the limited amount of blood available from individual newborn rats (Ͻ30 g). However, retinal histopathology was not investigated, because 0.13% and 0.15% MMI doses usually resulted in substantial (Ͼ90%) pup attrition (data not shown). Animal Model 7 Briefly, Sprague-Dawley dams and litters (12-15 pups per litter) were housed in modified pediatric incubators where the oxygen levels were varied between 40% and 15% (40/15) every 24 hours for the first 14 days after birth. Rats were then allowed to recover in room air (21%) during the next 6 days until P20. The drinking water in one of two cages per incubator was supplemented with MMI between P0 and P20. Holes in the sides of the pediatric incubators were purposely not sealed so that the incubators would be somewhat leaky and minimize the unwanted buildup of carbon dioxide. Although we did not directly assess whether airflow at the holes reversed during the variable oxygen exposure, it is unlikely that this happened, because the computercontrolled (Oxycycler; Biospherix, Ltd., Redfield, NY) variable oxygen procedure constantly maintain positive pressure inside the incubator by injecting the appropriate mixture of 100% oxygen or nitrogen to maintain either a 40% or 15% oxygen environment. In addition, each incubator housed one untreated and one MMI-treated 40/15 cage and so these groups experienced similar variable oxygen exposures. From th

Validation of the SCID-hu Thy/Liv mouse model with four classes of licensed antiretrovirals.

BackgroundThe SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals.Methodology/principal findingsEndpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e.g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions.ConclusionGiven the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans