Cell Type-Specific Intralocus Interactions Reveal Oligodendrocyte Mechanisms in MS.

Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocytes within the central nervous system (CNS). Despite widespread use of immunomodulatory therapies, patients may still face progressive disability because of failure of myelin regeneration and loss of neurons, suggesting additional cellular pathologies. Here, we describe a general approach for identifying specific cell types in which a disease allele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpoint likely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedly identified myeloid- and CNS-specific risk loci, including two sites that dysregulate transcriptional pause release in oligodendrocytes. Functional studies demonstrated inhibition of transcriptional elongation is a dominant pathway blocking oligodendrocyte maturation. Furthermore, pause release factors are frequently dysregulated in MS brain tissue. These data implicate cell-intrinsic aberrations outside of the immune system and suggest new avenues for therapeutic development. VIDEO ABSTRACT.

An efficient method of evaluating multiple concurrent management actions on invasive populations.

Evaluating the efficacy of management actions to control invasive species is crucial for maintaining funding and to provide feedback for the continual improvement of management efforts. However, it is often difficult to assess the efficacy of control methods due to limited resources for monitoring. Managers may view effort on monitoring as effort taken away from performing management actions. We developed a method to estimate invasive species abundance, evaluate management effectiveness, and evaluate population growth over time from a combination of removal activities (e.g., trapping, ground shooting) using only data collected during removal efforts (method of removal, date, location, number of animals removed, and effort). This dynamic approach allows for abundance estimation at discrete time points and the estimation of population growth between removal periods. To test this approach, we simulated over 1 million conditions, including varying the length of the study, the size of the area examined, the number of removal events, the capture rates, and the area impacted by removal efforts. Our estimates were unbiased (within 10% of truth) 81% of the time and were correlated with truth 91% of the time. This method performs well overall and, in particular, at monitoring trends in abundances over time. We applied this method to removal data from Mingo National Wildlife Refuge in Missouri from December 2015 to September 2019, where the management objective is elimination. Populations of feral swine on Mingo NWR have fluctuated over time but showed marked declines in the last 3-6 months of the time series corresponding to increased removal pressure. Our approach allows for the estimation of population growth across time (from both births and immigration) and therefore, provides a target removal rate (above that of the population growth) to ensure the population will decline. In Mingo NWR, the target monthly removal rate is 18% to cause a population decline. Our method provides advancement over traditional removal modeling approaches because it can be applied to evaluate management programs that use a broad range of removal techniques concurrently and whose management effort and spatial coverage vary across time.

Gas6 protein induces invasion and reduces inflammatory cytokines in oral squamous cell carcinoma.

BACKGROUND: Gas6 protein is involved in the progression of cancers and has been demonstrated to have a role in inflammation. Oral squamous cell carcinoma is a common form of oral cancer, and it commonly expresses Gas6. Our objective was to determine the effects of Gas6 on oral squamous cell carcinoma invasion and identify signaling molecules and cytokines associated with Gas6-mediated invasion. METHODS: Ca9-22 cells were cultured in the presence or absence of Gas6. Real-time cell invasion was evaluated, and cultured cells were lysed for Western blot analysis. Cell medium was collected and assayed for cytokine elaboration. RESULTS: Treatment of cells with Gas6 resulted in: (i) increased invasion, (ii) increased expression of Gas6 and AXL receptor, (iii) reduced invasion when AXL was inhibited, (iv) decreased ERK activation, (v) increased AKT activation, and (vi) decreased secretion of G-CSF, IL-2, IL-6, and IL-8. CONCLUSIONS: Gas6 increases invasion of oral squamous cell carcinoma, and the invasion correlates with the increased AKT and the downregulation of pro-inflammatory cytokines. These results may prove useful in providing avenues that explain the role of Gas6 in the development and progression of oral squamous cell carcinoma.

Cigarette smoke extract induces oral squamous cell carcinoma cell invasion in a receptor for advanced glycation end-products-dependent manner.

Oral squamous cell carcinoma (OSCC) affects approximately 30,000 people and is associated with tobacco use. Little is known about the mechanistic effects of second-hand smoke in the development of OSSC. The receptor for advanced glycation end-products (RAGE) is a surface receptor that is upregulated by second-hand smoke and inhibited by semi-synthetic glycosaminoglycan ethers (SAGEs). Our objective was to determine the role of RAGE during cigarette smoke extract-induced cellular responses and to use SAGEs as a modulating factor of Ca9-22 OSCC cell invasion. Ca9-22 cells were cultured in the presence or absence of cigarette smoke extract and SAGEs. Cell invasion was determined and cells were lysed for western blot analysis. Ras and nuclear factor of kappa light polypeptide gene enhancer in B-cells (NF-κB) activation were determined. Treatment of cells with cigarette smoke extract resulted in: (i) increased invasion of OSCC; (ii) increased RAGE expression; (iii) inhibition of cigarette smoke extract-induced OSCC cell invasion by SAGEs; (iv) increased Ras, increased AKT and NF-κB activation, and downregulation by SAGEs; and (v) increased expression of matrix metalloproteinases (MMPs) 2, 9, and 14, and downregulation by SAGEs. We conclude that cigarette smoke extract increases invasion of OSCC cells in a RAGE-dependent manner. Inhibition of RAGE decreases the levels of its signaling molecules, which results in blocking the cigarette smoke extract-induced invasion.

Inhibition of the receptor for advanced glycation end-products (RAGE) protects from secondhand smoke (SHS)-induced intrauterine growth restriction IUGR in mice.

Intrauterine growth restriction (IUGR) is a disease affecting 10% of all pregnancies. IUGR is associated with maternal, fetal, or placental abnormalities. Studies investigating the effects of secondhand smoke (SHS) exposure and IUGR are limited. The receptor for advanced glycation end-products (RAGE) is a pro-inflammatory transmembrane receptor increased by SHS in the placenta. We tested the hypothesis that inhibition of RAGE during SHS exposure protects from smoke-induced IUGR. C57BL/6 mice were exposed to SHS or SHS + semi-synthetic glycosaminoglycan ethers (SAGEs) known to inhibit RAGE signaling. Trophoblast cells were treated with cigarette smoke extract (CSE) with or without SAGEs in order to address the effects of RAGE inhibition during trophoblast invasion in vitro. SHS-treated mice demonstrated a significant reduction in fetal weight (7.35-fold, P ≤ 0.0001) and placental weight (1.13-fold, P ≤ 0.0001) compared with controls. Mice co-treated with SHS and SAGEs were protected from SHS-induced fetal weights decreases. SHS treatment of C57BL/6 mice activated placental extracellular signal-regulated kinase (ERK) (3.0-fold, P ≤ 0.05), JNK (2.4-fold, P ≤ 0.05) and p38 (2.1-fold, P ≤ 0.05) and the expression of inflammatory mediators including TNF-α (1.34-fold, P ≤ 0.05) and IL-1ß (1.03-fold, P ≤ 0.05). SHS-mediated activation of these molecules was reduced to basal levels when SAGE was co-administered. Invasion of trophoblast cells decreased 92% (P < 0.002) when treated with CSE and CSE-mediated invasion was completely reversed by SAGEs. We conclude that RAGE inhibition protects against fetal weight loss during SHS-induced IUGR. These studies provide insight into tobacco-mediated IUGR development and clarify avenues that may be helpful in the alleviation of placental complications.

Review: Myopathies in broilers: supply chain approach to provide solutions to challenges related to raising fast growing birds.

This review is a summary of a Poultry Science Association symposium addressing myopathies in broilers' breast meat, focusing on the interactions between genetics, nutrition, husbandry, and meat processing. The Pectoralis major myopathies (woody breast [WB]; white striping [WS]; spaghetti meat [SM]) and Pectoralis minor ("feathering") are described, followed by discussing their prevalence, potential causes, current and future ways to mitigate, as well as detection methods (in live birds and meat) as well as ways to utilize affected meat. Overall, breast myopathies remain an important focus across the poultry industry and whilst a lot of data and knowledge has been gathered, it is clear that there is still a lot to understand. As there are multiple factors impacting the occurrence of breast myopathies, their reduction relies on a holistic approach. Ongoing balanced breeding strategies by poultry breeders is targeting the longer-term genetic component but comprehending the significant influence from nongenetic factors (short-term solutions such as nutrition) remains a key area of opportunity. Consequently, understanding the physiology and biological needs of the muscle through the life of the bird is critical to reduce the myopathies (e.g., minimizing oxidative stress) and gain more insight into their etiology.

Efficacy and Quality Attributes of Antimicrobial Agent Application via a Commercial Electrostatic Spray Cabinet To Inactivate Salmonella on Chicken Thigh Meat.

ABSTRACT: Salmonella is a foodborne pathogen associated with poultry meat. This study aimed to determine the efficiency and quality attributes of two antimicrobial agents to reduce Salmonella on raw chicken meat when applied individually and in combination using an electrostatic spray cabinet. Thus, 5 log CFU/g of nonpathogenic, rifampin-resistant Salmonella Typhimurium was inoculated on skinless, boneless, raw chicken thigh meat and passed through an electrostatic spray cabinet while being sprayed with 5% lauric arginate (LAE), and 100, 1,000, 1,500, and 1,750 ppm of peracetic acid (PAA). Spraying of 5% LAE for 45 s significantly reduced Salmonella by 5 log (P < 0.05). The 1,500 ppm of PAA reduced Salmonella significantly within 45 s (1.157 log). Spraying of 1,500 ppm of PAA followed by LAE within 15 s reduced Salmonella significantly more than vice versa (P < 0.05). The color, water holding capacity, and texture did not differ significantly but resulted in significantly strong aroma and flavor. Both LAE and PAA efficiently reduced Salmonella when applied in an electrostatic spray cabinet on raw chicken thigh meat. The results suggest that the sequential order of application of antimicrobial agents is important to improve the safety and quality of raw chicken thigh meat.

Eye hue and the oculocardiac reflex.

During operations for squint nodal rhythm and other more serious arrhythmias such as heart block and multifocal ventricular extrasystoles, as well as the oculocardiac reflex, are shown to occur more frequently in patients with brown or hazel eyes than in patients with blue or grey eyes.

Post-traumatic hyperlipofuscinosis in the human retinal pigment epithelium.

Light microscopy (including fluorescence microscopy) and electron microscopy were applied to a study of the photoreceptor-retinal pigment epithelium (RPE) complex in a human eye which had been severely traumatised nine months prior to enucleation. The main feature of interest was a massive accumulation of lipofuscin in the retinal pigment epithelium at the posterior pole, and quantitative fluorescence microscopy provided values three times those obtained in appropriate control tissue. The photoreceptor layer was normal at the posterior pole but became progressively atrophic towards the periphery. The concentration of lipopofuscin was proportional to the degree of preservation of the retinal photoreceptors. By electron microscopy the cells in the RPE were seen to be packed with a mixture of lipofuscin granules and melanolysosomal complexes, but occasional photoreceptor phagosomes were found. Bruch's membrane and the choriocapillaris were normal. We attribute this hitherto unreported abnormality of the RPE after trauma to a dysfunction consequent on an overload of the monolayer by photoreceptor debris at the time of trauma.

First reports of pseudorabies and winter ticks (Dermacentor albipictus) associated with an emerging feral swine (Sus scrofa) population in New Hampshire.

The expansion of feral swine (Sus scrofa) populations into new geographic regions is of concern not only due to increased range but also because they carry diseases and parasites that pose a threat to humans, livestock, and wildlife into new areas. Recently, emerging feral swine populations have been reported in the northeastern US and due to their adaptive nature will likely continue to spread. During 2009-2012, 49 feral swine were removed from three counties in New Hampshire. Of these, serum samples were submitted from 34 for disease surveillance testing. One of the feral swine was antibody-positive for pseudorabies virus (PRV) making it the first documented infection in feral swine in New Hampshire. Infestations of winter tick (Dermacentor albipictus) were also documented on two of the feral swine which had only been reported previously on feral swine in Texas. Feral swine may not only serve as an important host for an economically important commercial swine pathogen like PRV, but they could also increase host diversity for parasites such as the winter tick, a species that can regionally impact moose (Alces alces) survival. These findings warrant further investigation of expanding and established feral swine populations in New Hampshire as pathogen hosts and support continued effort to reduce numbers or regionally eradicate feral swine.