Compensatory Mechanisms and T Cell Migration In Mouse Models of Dopaminergic Loss

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and second most common neurodegenerative disorder. PD is characterized by the selective loss of dopaminergic neurons and dopamine neurotransmitter within the substantia nigra and termini in the striatum. Progressive loss of dopaminergic neurons occurs over many years in PD, and by the time movement disorder symptoms manifest, up to 50-70% of dopaminergic neurons have been lost. Several aspects of PD pathology have been described in detail, but a better understanding of PD progression is needed to develop more efficient treatments. Motor symptoms associated with PD do not manifest until significant numbers of dopaminergic neurons are lost, suggesting compensatory mechanisms play a role in maintaining normal motor function. However, little is known about these mechanisms and the role they play in delaying PD symptom onset. Only palliative treatment is now available for PD. This consists of principally of dopamine replacement therapy and L-DOPA considered the gold treatment standard. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, chronic administration of dopamine replacement drugs, L-DOPA or BL-1023 in the absence of further degeneration, resulted in improved motor function and consistent increases in the number of TH+ neurons in the substantia nigra. The increase in TH+ neurons was not associated with dopaminergic neurogenic activity, but rather a phenotypic shift of GAD67+ GABAergic neurons to express TH. These data represent a novel effect of dopamine replacement therapy as triggering putative compensatory mechanisms, presumably to restore dopamine levels in a dopamine depleted environment. An interleukin-23 (IL-23) knock-out mouse strain proven to have significantly reduced dopaminergic neuron population was used to test motor control and behavior. No significant differences were observed between knock-out and wild-type in any of the forced or unforced motor tests. These data suggest either insufficient dopaminergic loss to afford functional alterations or that compensation to the dopaminergic signaling pathway allowed for normal functioning. Taken together, compensatory mechanisms represent a novel pathway for PD treatment that include symptomatic benefits as well as potential regenerative strategies. Targeting such pathways may provide more effective therapeutics by avoiding the secondary toxicities of current pharmaceuticals

The Effect of Oral Reading Rate Feedback on Reading Performance

An attempt was made to determine the effects or oral reading rate feedback on reading performance of third grade children in a self-contained classroom, using self-selected materials. Two measuring devices were used. The Botel Reading Inventory (Word Opposites Test-Reading) showed a mean gain of 1.75 grade levels. The oral reading rate mean increase was 57 words per minute. All students achieved at third grade level or higher

The Role of Using Formative Assessments in Problem-based Learning: A Health Sciences Education Perspective

Practitioners in the field of pharmacy are often confronted with ill-structured problems. Specifically, pharmacists are tasked with making patient-specific recommendations that are both safe and effective, which requires combining knowledge from the biomedical, behavioral, and pharmaceutical sciences. Given the dynamic nature of pharmacy as a profession, the field has begun to explore learning strategies that go beyond mere content coverage to strategies that better support higher-order learning outcomes. One of these approaches is problem-based learning (PBL). While studies have focused on how to support PBL to improve learning outcomes, the role of assessment is often overlooked. Further exploration is thus needed since assessment plays a pivotal role in teaching and learning. This Voices paper will explore this idea within a larger context; we will also share the experience of how a subject matter expert (SME) worked with a team of instructional designers (IDs) to revise an existing course to more explicitly employ PBL and thus adopt an inquiry-based mindset needed for complex clinical decision making. Given the inherent challenges of assessment in PBL, further discussion will be focused on how to (a) design ill-structured problems, (b) align assessments to the PBL curriculum, and (c) how to hold students accountable in cases where a traditional grade is not attached

Dual destructive and protective roles of adaptive immunity in neurodegenerative disorders.

Inappropriate T cell responses in the central nervous system (CNS) affect the pathogenesis of a broad range of neuroinflammatory and neurodegenerative disorders that include, but are not limited to, multiple sclerosis, amyotrophic lateral sclerosis, Alzheimer\u27s disease and Parkinson\u27s disease. On the one hand immune responses can exacerbate neurotoxic responses; while on the other hand, they can lead to neuroprotective outcomes. The temporal and spatial mechanisms by which these immune responses occur and are regulated in the setting of active disease have gained significant recent attention. Spatially, immune responses that affect neurodegeneration may occur within or outside the CNS. Migration of antigen-specific CD4+ T cells from the periphery to the CNS and consequent immune cell interactions with resident glial cells affect neuroinflammation and neuronal survival. The destructive or protective mechanisms of these interactions are linked to the relative numerical and functional dominance of effector or regulatory T cells. Temporally, immune responses at disease onset or during progression may exhibit a differential balance of immune responses in the periphery and within the CNS. Immune responses with predominate T cell subtypes may differentially manifest migratory, regulatory and effector functions when triggered by endogenous misfolded and aggregated proteins and cell-specific stimuli. The final result is altered glial and neuronal behaviors that influence the disease course. Thus, discovery of neurodestructive and neuroprotective immune mechanisms will permit potential new therapeutic pathways that affect neuronal survival and slow disease progression

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

Selective VIP Receptor Agonists Facilitate Immune Transformation for Dopaminergic Neuroprotection in MPTP-Intoxicated Mice.

UNLABELLED: Vasoactive intestinal peptide (VIP) mediates a broad range of biological responses by activating two related receptors, VIP receptor 1 and 2 (VIPR1 and VIPR2). Although the use of native VIP facilitates neuroprotection, clinical application of the hormone is limited due to VIP\u27s rapid metabolism and inability to distinguish between VIPR1 and VIPR2 receptors. In addition, activation of both receptors by therapeutics may increase adverse secondary toxicities. Therefore, we developed metabolically stable and receptor-selective agonists for VIPR1 and VIPR2 to improve pharmacokinetic and pharmacodynamic therapeutic end points. Selective agonists were investigated for their abilities to protect mice against MPTP-induced neurodegeneration used to model Parkinson\u27s disease (PD). Survival of tyrosine hydroxylase neurons in the substantia nigra was determined by stereological tests after MPTP intoxication in mice pretreated with either VIPR1 or VIPR2 agonist or after adoptive transfer of splenic cell populations from agonist-treated mice administered to MPTP-intoxicated animals. Treatment with VIPR2 agonist or splenocytes from agonist-treated mice resulted in increased neuronal sparing. Immunohistochemical tests showed that agonist-treated mice displayed reductions in microglial responses, with the most pronounced effects in VIPR2 agonist-treated, MPTP-intoxicated mice. In parallel studies, we observed reductions in proinflammatory cytokine release that included IL-17A, IL-6, and IFN-γ and increases in GM-CSF transcripts in CD4(+) T cells recovered from VIPR2 agonist-treated animals. Moreover, a phenotypic shift of effector to regulatory T cells was observed. These results support the use of VIPR2-selective agonists as neuroprotective agents for PD treatment. SIGNIFICANCE STATEMENT: Vasoactive intestinal peptide receptor 2 can elicit immune transformation in a model of Parkinson\u27s disease (PD). Such immunomodulatory capabilities can lead to neuroprotection by attenuating microglial activation and by slowing degradation of neuronal cell bodies and termini in MPTP-intoxicated mice. The protective mechanism arises from altering a Th1/Th2 immune cytokine response into an anti-inflammatory and neuronal sparing profile. These results are directly applicable for the development of novel PD therapies

Loss of Dnmt3b function upregulates the tumor modifier Ment and accelerates mouse lymphomagenesis

DNA methyltransferase 3B (Dnmt3b) belongs to a family of enzymes responsible for methylation of cytosine residues in mammals. DNA methylation contributes to the epigenetic control of gene transcription and is deregulated in virtually all human tumors. To better understand the generation of cancer-specific methylation patterns, we genetically inactivated Dnmt3b in a mouse model of MYC-induced lymphomagenesis. Ablation of Dnmt3b function using a conditional knockout in T cells accelerated lymphomagenesis by increasing cellular proliferation, which suggests that Dnmt3b functions as a tumor suppressor. Global methylation profiling revealed numerous gene promoters as potential targets of Dnmt3b activity, the majority of which were demethylated in Dnmt3b–/– lymphomas, but not in Dnmt3b–/– pretumor thymocytes, implicating Dnmt3b in maintenance of cytosine methylation in cancer. Functional analysis identified the gene Gm128 (which we termed herein methylated in normal thymocytes [Ment]) as a target of Dnmt3b activity. We found that Ment was gradually demethylated and overexpressed during tumor progression in Dnmt3b–/– lymphomas. Similarly, MENT was overexpressed in 67% of human lymphomas, and its transcription inversely correlated with methylation and levels of DNMT3B. Importantly, knockdown of Ment inhibited growth of mouse and human cells, whereas overexpression of Ment provided Dnmt3b+/+ cells with a proliferative advantage. Our findings identify Ment as an enhancer of lymphomagenesis that contributes to the tumor suppressor function of Dnmt3b and suggest it could be a potential target for anticancer therapies

Saccharomyces cerevisiae Fermentation Products That Mitigate Foodborne Salmonella in Cattle and Poultry

Prior studies revealed that yeast fermentation products, specifically XPC™ and related products (Diamond V, Cedar Rapids, IA), serve as viable food safety tools across multiple food animal species including cattle and poultry. Providing this supplement in feed leads to reduced prevalence, load, virulence, and antibiotic resistance of foodborne pathogens such as Salmonella and Escherichia coli O157:H7. These findings are worthy of further study, especially when coupled with the enhanced growth and performance observed with these products. Mechanistically, XPC appears to modulate these effects through the immune system and gut microbiome. Herein we further investigated this product and demonstrate that XPC mediates an enhancement of immunocyte killing of Salmonella in calves fed the product. Additionally, these studies reveal that XPC reduces the lymph node infiltration, invasiveness, and antibiotic resistance of Salmonella in dairy calves fed the product-consistent with findings observed in poultry and adult beef cattle. Furthermore, the reduction in invasiveness does not lead to a rebound hyperinvasive phenotype in Salmonella obtained from XPC-fed animals. In summary, these studies suggest that XPC reduces the invasion of Salmonella and may alter various phenotypic characteristics of the pathogen

Silverstein and WFB Prevalence of and Disparities in Barriers to Care Experienced by Youth with Type 1 Diabetes

To describe the prevalence of access and process barriers to health care and to examine their relationship to sociodemographic and disease factors in a large and diverse cohort of US youth with type 1 diabetes