A Comprehensive Economic Stimulus for our Failing Economy

This paper presents a comprehensive plan to fix the ailing American economy, through a five-step approach. First, the Federal Reserve must continue to broaden the scope of monetary policy, by purchasing and selling long-term securities. Manipulating expectations through FOMC statements is another tool at the Federal Reserve’s disposal. Secondly, the government must enact fiscal stimulus to stabilize the economy in the short and medium runs, through investment in infrastructure projects, green technology, fusion technology, and science education. Additionally, the new fiscal policy must tackle the mortgage meltdown, which is weighing down the entire economy. Third, the regulatory system must be changed to reduce the likelihood of another financial collapse, starting with the nationalization of the ratings agencies. Ratings should be updated faster, with a numeric grading system rather than the pre-existing letter grades. Fourth, our globalized economy insures that a coordinated globalized response is necessary to recover. Global cooperation to reduce inflation and avoid protectionist policies is vital. Finally, the American bailout policy must be made clear, only giving bailouts to companies that are sound but financially strapped and those that are too big to fail

Assessment of the Red Cell Proteome of Young Patients with Unexplained Hemolytic Anemia by Two-Dimensional Differential In-Gel Electrophoresis (DIGE)

Erythrocyte cytosolic protein expression profiles of children with unexplained hemolytic anemia were compared with profiles of close relatives and controls by two-dimensional differential in-gel electrophoresis (2D-DIGE). The severity of anemia in the patients varied from compensated (i.e., no medical intervention required) to chronic transfusion dependence. Common characteristics of all patients included chronic elevation of reticulocyte count and a negative workup for anemia focusing on hemoglobinopathies, morphologic abnormalities that would suggest a membrane defect, immune-mediated red cell destruction, and evaluation of the most common red cell enzyme defects, glucose-6-phosphate dehydrogenase and pyruvate kinase deficiency. Based upon this initial workup and presentation during infancy or early childhood, four patients classified as hereditary nonspherocytic hemolytic anemia (HNSHA) of unknown etiology were selected for proteomic analysis. DIGE analysis of red cell cytosolic proteins clearly discriminated each anemic patient from both familial and unrelated controls, revealing both patient-specific and shared patterns of differential protein expression. Changes in expression pattern shared among the four patients were identified in several protein classes including chaperons, cytoskeletal and proteasome proteins. Elevated expression in patient samples of some proteins correlated with high reticulocyte count, likely identifying a subset of proteins that are normally lost during erythroid maturation, including proteins involved in mitochondrial metabolism and protein synthesis. Proteins identified with patient-specific decreased expression included components of the glutathione synthetic pathway, antioxidant pathways, and proteins involved in signal transduction and nucleotide metabolism. Among the more than 200 proteins identified in this study are 21 proteins not previously described as part of the erythrocyte proteome. These results demonstrate the feasibility of applying a global proteomic approach to aid characterization of red cells from patients with hereditary anemia of unknown cause, including the identification of differentially expressed proteins as potential candidates with a role in disease pathogenesis

A Key Commitment Step in Erythropoiesis Is Synchronized with the Cell Cycle Clock through Mutual Inhibition between PU.1 and S-Phase Progression

During red blood cell development, differentiation and cell cycle progression are intimately and uniquely linked through interdependent mechanisms involving the erythroid transcriptional suppressor PU.1 and the cyclin-dependent kinase inhibitor p57KIP2

Implications of IFNβ and EphB2 mediated Ephrin-B Reverse Signaling on Inflammation, Antiviral Response and Neurotoxicity in HIV

Human immunodeficiency virus-1 (HIV-1) is a retrovirus that can infiltrate and infect the central nervous system (CNS) leading to HIV-associated neurocognitive disorders (HAND). HAND is a condition behaviorally characterized by cognitive and neurological impairments, and pathologically characterized by rampant inflammation and loss of synaptic integrity. Although therapeutics exist to increase the lifespan of people living with HIV, the overall prevalence of HAND and the presence of HIV induced neuronal damage remains unchanged. Understanding the mechanisms underlying the neuropathology in HIV will guide the development of more efficacious therapeutics.One hallmark response to HIV is the type I interferon antiviral response. HIV-1, and an HIVgp120 transgenic (HIVgp120tg) mouse model, both activate the innate immune system, including the production of type 1 interferons (IFNs) α and β, and induction of IFN-stimulated genes (ISG). In this dissertation, we characterize IFNβ’s role in HIVgp120tg induced neuroHIV using an IFNβKO mouse model. The neuropathology observed in HIVgp120tg is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, IFNβKO results in an amelioration of neuronal presynaptic terminal damage but no protection of neuronal dendrites in the hippocampal CA1 region of HIVgp120tg mice. Additionally, female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in the cortex and hippocampus. IFNβKO abrogates or diminishes the induction of type I interferon related genes including MX1, DDX58, IRF7, and IRF9 in HIVgp120tg brains. Additionally, the effects of IFNβKO on MAPK activities with a pronounced reduction of active ERK1/2 and active p38 in the HIVgp120tg brain. In summary, these findings show that IFNβ’s absence in the presence of HIVgp120, is partially protective when assessing hippocampal pre-synaptic terminals and microglial counts, but partially damaging based on cortical dendritic assessment. Moreover, IFNβ plays a vital role in mediating the gp120 induced type I interferon response, expression of pro-inflammatory markers, and MAPK signaling. Additionally, we highlight the activation of ephrin-B/EphB in the CNS of people living with HIV driven, at least in part, by gp120 viral envelope protein and type I interferon, IFNβ. Furthermore, EphB2 mediated ephrin-B reverse signaling onto microglia induces a prominent pro-inflammatory and antiviral signature with the capacity for this microglial specific pro-inflammatory secretome profile to induce non-contact dependent neurotoxicity. Finally, knockdown of microglial ephrin-B1, a binding partner for EphB2, shows a partial alleviation of the microglial pro-inflammatory signature and resulting neurotoxicity. Elevated EphB2 and its signaling onto microglia may present as a novel mechanism of neuroinflammation, and mediator of neurotoxicity, seen in the context of neuroHIV and potentially other neurodegenerative diseases

Targeting Signaling Pathways in Cancer Stem Cells for Cancer Treatment

The Wnt, Hedgehog, and Notch pathways are inherent signaling pathways in normal embryogenesis, development, and hemostasis. However, dysfunctions of these pathways are evident in multiple tumor types and malignancies. Specifically, aberrant activation of these pathways is implicated in modulation of cancer stem cells (CSCs), a small subset of cancer cells capable of self-renewal and differentiation into heterogeneous tumor cells. The CSCs are accountable for tumor initiation, growth, and recurrence. In this review, we focus on roles of Wnt, Hedgehog, and Notch pathways in CSCs’ stemness and functions and summarize therapeutic studies targeting these pathways to eliminate CSCs and improve overall cancer treatment outcomes

Innate Immune Sensing of Viruses and Its Consequences for the Central Nervous System

Viral infections remain a global public health concern and cause a severe societal and economic burden. At the organismal level, the innate immune system is essential for the detection of viruses and constitutes the first line of defense. Viral components are sensed by host pattern recognition receptors (PRRs). PRRs can be further classified based on their localization into Toll-like receptors (TLRs), C-type lectin receptors (CLR), retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), NOD-like receptors (NLRs) and cytosolic DNA sensors (CDS). TLR and RLR signaling results in production of type I interferons (IFNα and -β) and pro-inflammatory cytokines in a cell-specific manner, whereas NLR signaling leads to the production of interleukin-1 family proteins. On the other hand, CLRs are capable of sensing glycans present in viral pathogens, which can induce phagocytic, endocytic, antimicrobial, and pro- inflammatory responses. Peripheral immune sensing of viruses and the ensuing cytokine response can significantly affect the central nervous system (CNS). But viruses can also directly enter the CNS via a multitude of routes, such as the nasal epithelium, along nerve fibers connecting to the periphery and as cargo of infiltrating infected cells passing through the blood brain barrier, triggering innate immune sensing and cytokine responses directly in the CNS. Here, we review mechanisms of viral immune sensing and currently recognized consequences for the CNS of innate immune responses to viruses

Interferon-β deficiency alters brain response to chronic HIV-1 envelope protein exposure in a transgenic model of NeuroHIV

Human immunodeficiency virus-1 (HIV-1) infects the central nervous system (CNS) and causes HIV-associated neurocognitive disorders (HAND) in about half of the population living with the virus despite combination anti-retroviral therapy (cART). HIV-1 activates the innate immune system, including the production of type 1 interferons (IFNs) α and β. Transgenic mice expressing HIV-1 envelope glycoprotein gp120 (HIVgp120tg) in the CNS develop memory impairment and share key neuropathological features and differential CNS gene expression with HIV patients, including the induction of IFN-stimulated genes (ISG). Here we show that knocking out IFNβ (IFNβKO) in HIVgp120tg and non-tg control mice impairs recognition and spatial memory, but does not affect anxiety-like behavior, locomotion, or vision. The neuropathology of HIVgp120tg mice is only moderately affected by the KO of IFNβ but in a sex-dependent fashion. Notably, in cerebral cortex of IFNβKO animals presynaptic terminals are reduced in males while neuronal dendrites are reduced in females. The IFNβKO results in the hippocampal CA1 region of both male and female HIVgp120tg mice in an ameliorated loss of neuronal presynaptic terminals but no protection of neuronal dendrites. Only female IFNβ-deficient HIVgp120tg mice display diminished microglial activation in cortex and hippocampus and increased astrocytosis in hippocampus compared to their IFNβ-expressing counterparts. RNA expression for some immune genes and ISGs is also affected in a sex-dependent way. The IFNβKO abrogates or diminishes the induction of MX1, DDX58, IRF7 and IRF9 in HIVgp120tg brains of both sexes. Expression analysis of neurotransmission related genes reveals an influence of IFNβ on multiple components with more pronounced changes in IFNβKO females. In contrast, the effects of IFNβKO on MAPK activities are independent of sex with pronounced reduction of active ERK1/2 but also of active p38 in the HIVgp120tg brain. In summary, our findings show that the absence of IFNβ impairs memory dependent behavior and modulates neuropathology in HIVgp120tg brains, indicating that its absence may facilitate development of HAND. Moreover, our data suggests that endogenous IFNβ plays a vital role in maintaining neuronal homeostasis and memory function

ACCT is a fast and accessible automatic cell counting tool using machine learning for 2D image segmentation

Abstract Counting cells is a cornerstone of tracking disease progression in neuroscience. A common approach for this process is having trained researchers individually select and count cells within an image, which is not only difficult to standardize but also very time-consuming. While tools exist to automatically count cells in images, the accuracy and accessibility of such tools can be improved. Thus, we introduce a novel tool ACCT: Automatic Cell Counting with Trainable Weka Segmentation which allows for flexible automatic cell counting via object segmentation after user-driven training. ACCT is demonstrated with a comparative analysis of publicly available images of neurons and an in-house dataset of immunofluorescence-stained microglia cells. For comparison, both datasets were manually counted to demonstrate the applicability of ACCT as an accessible means to automatically quantify cells in a precise manner without the need for computing clusters or advanced data preparation

Immunotherapies: Exploiting the Immune System for Cancer Treatment

Cancer is a condition that has plagued humanity for thousands of years, with the first depictions dating back to ancient Egyptian times. However, not until recent decades have biological therapeutics been developed and refined enough to safely and effectively combat cancer. Three unique immunotherapies have gained traction in recent decades: adoptive T cell transfer, checkpoint inhibitors, and bivalent antibodies. Each has led to clinically approved therapies, as well as to therapies in preclinical and ongoing clinical trials. In this review, we outline the method by which these 3 immunotherapies function as well as any major immunotherapeutic drugs developed for treating a variety of cancers

Phosphodiesterase 4D, miR-203 and selected cytokines in the peripheral blood are associated with canine atopic dermatitis.

Canine Atopic Dermatitis (AD) is a common complex and multifactorial disease involving immune dysregulation, genetic predisposition, skin barrier defects, environmental factors and allergic sensitization. To date, diagnosis of canine AD relies on a combination of patient history, clinical examination, allergy testing and response to diet trials/therapies with no reliable biomarkers available to distinguish AD from other diseases with similar clinical presentations. A handful of studies to identify potential biomarkers in the peripheral blood of AD dogs and healthy controls have been performed with some showing inconsistent and contradictory results. In this study, we, for the first time, report statistically significant increases in expression of phosphodiesterase 4D (PDE4D) gene in peripheral blood mononuclear cells (PBMCs) and miR-203 in plasma from AD dogs compared to healthy controls. In addition, we report a statistically non-significant change of the CD4+/CD8+ ratio, a dramatic decrease of three gene markers (PIAS1, RORA and SH2B1) as well as a panel of differential expression of cytokines in AD dogs in comparison to the healthy controls. Our study provides important insight into the complexities of canine AD, and further studies to verify the specificity of these findings for canine AD at a larger-scale are warranted