mic Efficiency and Pareto Optimality in a Stochastic OLG Model with Production and Social Security

We analyze the interaction between risk sharing and capital accumulation in a stochastic OLG model with production. We give a complete characterization of interim Pareto optimality. Our characterization also subsumes equilibria with a PAYG social security system. In a competitive equilibrium interim Pareto optimality is equivalent to intergenerational exchange efficiency, which in turn implies dynamic efficiency. Furthermore, dynamic efficiency does not rule out a Pareto-improving role for a social security system. Social security can provide insurance against macroeconomic risk, namely aggregate productivity risk in the second period of life (old age) through dynamic risk sharing. We briefly relate our results to models without uncertainty where the notions of exchange efficiency, dynamic efficiency and interim Pareto optimality are all equivalent in a competitive equilibrium.Stochastic OLG Model, Dynamic Efficiency, Interim Pareto Optimality, Social Security, Risk Sharing

An adverse selection model of optimal unemployment insurance

We derive the shape of optimal unemployment insurance (UI) contracts when agents can exert search effort but face different search costs and have private information about their type. We derive a recursive solution of our dynamic adverse selection problem with repeated moral hazard. Conditions under which the UI agency should always offer separating contracts are identified. We show that the good searcher receives an information rent and that the bad searcher receives the minimal entitlement. From a methodological point of view, we achieve a precise characterization of the sets of jointly feasible entitlements. This allows us to map our analytical results one-toone to a numerical algorithm. According to our results the contract for the good searcher has a decreasing benefit profile, as the one he would be offered in a pure moral hazard environment. In contrast, the contract of the bad searcher is distorted by an adverse selection effect, so that it tends to have an upward-sloping benefit profile. We provide a comparative static analysis of changes in various parameters of our model. --Unemployment Insurance,Adverse Selection,Moral Hazard

Welfare Analysis in a Schumpeterian Growth Model with Capital

In this note we compare the laissez-faire steady-state solution in the Howitt and Aghion (1998) model to the social optimum. The analysis offers several new insights in comparison to the welfare analysis in Aghion and Howitt (1992). We find various new distortions between private and optimal solution. First, a monopoly distortion effect generates too little capital accumulation in the private solution because households' gross return per unit of capital will be lower than in the social optimum due to monopoly power. Second, a cost-benefit gap effect leads to excessive research in the private solution because the planner is interested in the average technology whereas the private researcher is interested in the leading-edge technology. Third, we decompose the well-known intertemporal spillover effect into three subeffects and clarify why the planner does not consider other factors than the interest rate to discount gains from innovation.Endogenous Growth Model

Expression of membrane C1q in human monocyte-derived macrophages is developmentally regulated and enhanced by interferon-γ

AbstractThe present study investigated when during ‘in vitro’ maturation macrophages (MΦ) express membrane C1q (mC1q), and whether cell activation affects expression and function of mC1q. Although C1q mRNA was repeatedly detected in freshly isolated monocytes using reverse transcriptase-polymerase chain reaction, C1q protein was observed only in developing MΦ from day 1 to 4 on using immunodetection and flow cytometry. However, the quantity of mC1q and other MΦ membrane proteins differed strikingly in cells from different donors. We report here for the first time that CD14+ and CD14− mC1q-bearing MΦ can develop, and that interferon-γ increases mC1q display at the cell surface, and mC1q-mediated phagocytosis

Molecular mechanisms of neuroinvasion by monocytes-macrophages in HIV-1 infection

HIV associated neurocognitive disorders and their histopathological correlates largely depend on the continuous seeding of the central nervous system with immune activated leukocytes, mainly monocytes/macrophages from the periphery. The blood-brain-barrier plays a critical role in this never stopping neuroinvasion, although it appears unaltered until the late stage of HIV encephalitis. HIV flux that moves toward the brain thus relies on hijacking and exacerbating the physiological mechanisms that govern blood brain barrier crossing rather than barrier disruption. This review will summarize the recent data describing neuroinvasion by HIV with a focus on the molecular mechanisms involved

CXCL12-induced neurotoxicity critically depends on NMDA receptor-gated and L-type Ca2+ channels upstream of p38 MAPK.

BackgroundThe chemokine receptor CXCR4 (CD184) and its natural ligand CXCL12 contribute to many physiological processes, including decisions about cell death and survival in the central nervous system. In addition, CXCR4 is a co-receptor for human immunodeficiency virus (HIV)-1 and mediates the neurotoxicity of the viral envelope protein gp120. However, we previously observed that CXCL12 also causes toxicity in cerebrocortical neurons but the cellular mechanism remained incompletely defined.MethodsPrimary neuronal-glial cerebrocortical cell cultures from rat were exposed to a neurotoxicity-inducing CXCL12 concentration for different times and the activity of the stress-associated mitogen-activated protein kinase p38 (p38 MAPK) was assessed using an in vitro kinase assay. Neurotoxicity of CXCL12 and cellular localization of p38 MAPK was analyzed by immunofluorescence microscopy. Pharmacological inhibition of NMDA-type glutamate receptor-gated ion channels (NMDAR) of L-type Ca2+ channels was employed during 12- and 24-h exposure to neurotoxic amounts of CXCL12 to study the effects on active p38 MAPK and neuronal survival by Western blotting and microscopy, respectively. Neurotoxicity of CXCL12 was also assessed during pharmacological inhibition of p38 MAPK.ResultsHere, we show that a neurotoxic amount of CXCL12 triggers a significant increase of endogenous p38 MAPK activity in cerebrocortical cells. Immunofluorescence and Western blotting experiments with mixed neuronal-glial and neuron-depleted glial cerebrocortical cells revealed that the majority of active/phosphorylated p38 MAPK was located in neurons. Blockade of NMDAR-gated ion channels or L-type Ca2+ channels both abrogated an increase of active p38 MAPK and toxicity of CXCL12 in cerebrocortical neurons. Inhibition of L-type Ca2+ channels with nimodipine kept the active kinase at levels not significantly different from baseline while blocking NMDAR with MK-801 strongly reduced phosphorylated p38 MAPK below baseline. Finally, we confirmed that directly blocking p38 MAPK also abrogated neurotoxicity of CXCL12.ConclusionsOur findings link CXCL12-induced neuronal death to the regulation of NMDAR-gated ion channels and L-type Ca2+ channels upstream of p38 MAPK activation

Physical analysis of temperature-dependent effects of amplitude-modulated electromagnetic hyperthermia

Purpose: Preclinical studies and clinical observations suggest that amplitude modulation (AM) below 100 kHz may enhance the intratumoral power absorption of radiofrequency hyperthermia at 13.56 MHz; however, it remains unclear whether AM induces temperature-dependent effects.Methods: We established tumor models assuming typical tumor architectures or cell suspensions to analyze the effects of additional power dissipation. The preconditions for demodulation at cell membranes in situ were outlined. The bioheat transfer equation was solved analytically for the selected models and the possibility of circumscribed temperature increases (point heating) with dependency on the specific absorption rate (SAR) peaks was estimated for centimeter down to nanometer scales.Results: Very-low-frequency (VLF) AM radiofrequency can increase the SAR in the extracellular space or necrosis of tumors as compared to radiofrequencies alone. Such modulation-derived SAR peaks can induce higher temperatures (hot spots) in tumors with necrotic areas of millimeter to centimeter size. However, for lesions 1000, 10,000 and 1014 W/kg for diameters of ∼5 mm, ∼1 mm and ∼10 nm (nanoheating), respectively, would be required to explain the cell kill observed in pre-clinical and clinical data, even with VLF modulation.Conclusion: Our analysis suggests that VLF AM of radiofrequency hyperthermia for a theoretical tumor model cannot induce relevant temperature-dependent effects, as the associated temperature increases caused by the resultant SAR peaks are too small. Further investigation of possible non-temperature-dependent effects is recommended

The Long Noncoding RNA HEAL Regulates HIV-1 Replication through Epigenetic Regulation of the HIV-1 Promoter.

A major challenge in finding a cure for HIV-1/AIDS is the difficulty in identifying and eradicating persistent reservoirs of replication-competent provirus. Long noncoding RNAs (lncRNAs, >200 nucleotides) are increasingly recognized to play important roles in pathophysiology. Here, we report the first genome-wide expression analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs). We identified an lncRNA, which we named HIV-1-enhanced lncRNA (HEAL), that is upregulated by HIV-1 infection of MDMs, microglia, and T lymphocytes. Peripheral blood mononuclear cells of HIV-1-infected individuals show elevated levels of HEAL Importantly, HEAL is a broad enhancer of multiple HIV-1 strains because depletion of HEAL inhibited X4, R5, and dual-tropic HIV replications and the inhibition was rescued by HEAL overexpression. HEAL forms a complex with the RNA-binding protein FUS, which facilitates HIV replication through at least two mechanisms: (i) HEAL-FUS complex binds the HIV promoter and enhances recruitment of the histone acetyltransferase p300, which positively regulates HIV transcription by increasing histone H3K27 acetylation and P-TEFb enrichment on the HIV promoter, and (ii) HEAL-FUS complex is enriched at the promoter of the cyclin-dependent kinase 2 gene, CDK2, to enhance CDK2 expression. Notably, HEAL knockdown and knockout mediated by RNA interference (RNAi) and CRISPR-Cas9, respectively, prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment in vitro Our results suggest that silencing of HEAL or perturbation of the HEAL-FUS ribonucleoprotein complex could provide a new epigenetic silencing strategy to eradicate viral reservoirs and effect a cure for HIV-1/AIDS.IMPORTANCE Despite our increased understanding of the functions of lncRNAs, their potential to develop HIV/AIDS cure strategies remains unexplored. A genome-wide analysis of lncRNAs in HIV-1-infected primary monocyte-derived macrophages (MDMs) was performed, and 1,145 differentially expressed lncRNAs were identified. An lncRNA named HIV-1-enhanced lncRNA (HEAL) is upregulated by HIV-1 infection and promotes HIV replication in T cells and macrophages. HEAL forms a complex with the RNA-binding protein FUS to enhance transcriptional coactivator p300 recruitment to the HIV promoter. Furthermore, HEAL knockdown and knockout prevent HIV-1 recrudescence in T cells and microglia upon cessation of azidothymidine treatment, suggesting HEAL as a potential therapeutic target to cure HIV-1/AIDS

Intermediate-term outcome after PSMA-PET guided high-dose radiotherapy of recurrent high-risk prostate cancer patients

Background By the use of PSMA positron emission tomography (PET) detection of prostate cancer lesions with a high sensitivity and specificity combined with a favorable lesion to background contrast is feasible. Therefore, PSMA-PET is increasingly used for planning of radiotherapy treatment; however, any data on intermediate-term outcome is missing so far. Methods Patients with high-risk or very high risk prostate cancer, referred for salvage radiotherapy (SRT, n = 22) between 2013 and 2015, underwent PSMA-PET prior to therapy. Irradiation was planned on PET data with boost to macroscopic tumors/metastases. Treatment related toxicity was measured using Common Terminology Criteria for Adverse Events (CTCAE, v4.0). Result Findings in PSMA-PET led to treatment modifications in 77% of SRT patients compared to available CT information. One patient did not receive irradiation due to disseminated disease, the other patients received increased boost doses to macroscopic disease and/or inclusion of additional target volumes. Toxicity was low as only 2 patients reported toxicities > grade 1. With a Median follow-up time of 29 in patients that were not lost to follow-up, prolonged PSA responses below baseline were observed in the majority of patients (14 of 20). In hormone-naïve SRT patients (n = 11), radiotherapy led to prolonged PSA decrease in 8/11 patients, however with 3 of these 8 patients receiving repeated PSMA based irradiation of novel lesions during follow-up. Conclusion PSMA-PET guided planning of radiotherapy led to change of treatment in the majority of patients. Treatment related toxicity was well tolerated and promising results regarding intermediate-term PSA decrease were observed. Trial registration No trial registration was performed due to retrospective evaluation

Risk adapted dose-intensified postoperative radiation therapy in prostate cancer patients using a simultaneous integrated boost technique applied with helical Tomotherapy

Background Postoperative adjuvant radiation therapy (ART) in T3 and R1 prostate cancer as well as salvage radiation therapy (SRT) in case of postoperative biochemical failure (BF) are established treatments. Dose- intensified postoperative radiation therapy (RT) schemes have shown superior biochemical control accompanied by increased toxicity rates. In our study we evaluate a novel risk adapted dose-intensified postoperative RT scheme. Methods A consecutive series of prostate cancer patients receiving postoperative RT after radical prostatectomy using helical Tomotherapy between 04/2012 and 04/2015 was analyzed retrospectively. RT was administered using a simultaneous integrated boost (SIB) to the area at risk (37 fractions of 1.9 Gy, total dose: 70.3 Gy) being defined based on histopathological findings (T3/R1 region) and in few cases according to additional diagnostic imaging. The whole prostate bed was treated with a dose of 66.6 Gy (37 fractions of 1.8 Gy). Primary endpoints were acute and late genitourinary (GU) and gastrointestinal (GI) toxicities. Secondary endpoints included patient reported outcome as assessed by the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence questionnaire (ICIQ) and prostate cancer specific Quality of Life questionnaire QLQ-PR25, as well as rates of BF. Results A total of 69 patients were analyzed. Sixteen patients underwent ART and 53 patients SRT, respectively. The median follow-up was 20 months (range, 8–41 months). Seven (10.1%) and four (5.8%) patients experienced acute grade 2 GU and GI toxicity. Two patients (2.9%) had late grade 2 GU toxicity, whereas no late grade 2 GI nor any grade 3 acute or late GU or GI events were observed. When compared to the baseline IPSS scores (p = 1.0) and ICIQ scores (p = 0.87) were not significantly different at the end of follow-up. Patient reported Quality of life (QoL) showed also no significant difference. A total of seven patients (10.1%) experienced a biochemical recurrence with the 2-year biochemical progression-free survival (bPFS) being 91%. Conclusions Postoperative RT for prostate cancer patients with a risk adapted dose-intensified SIB using helical tomotherapy is feasible and associated with favorable acute and late GU and GI toxicity rates, no significant change of IPSS-, ICIQ scores and patient reported QoL and results in promising bPFS rates