Radon-based Image Reconstruction for MPI using a continuously rotating FFL

Magnetic particle imaging is a relatively new tracer-based medical imaging technique exploiting the non-linear magnetization response of magnetic nanoparticles to changing magnetic fields. If the data are generated by using a field-free line, the sampling geometry resembles the one in computerized tomography. Indeed, for an ideal field-free line rotating only in between measurements it was shown that the signal equation can be written as a convolution with the Radon transform of the particle concentration. In this work, we regard a continuously rotating field-free line and extend the forward operator accordingly. We obtain a similar result for the relation to the Radon data but with two additive terms resulting from the additional time-dependencies in the forward model. We jointly reconstruct particle concentration and corresponding Radon data by means of total variation regularization yielding promising results for synthetic data.Comment: YRM & CSE Workshop on Modeling, Simulation & Optimization of Fluid Dynamic Applications 202

Too much of a good thing: How modulating LTB4 actions restore host defense in homeostasis or disease

The ability to regulate inflammatory pathways and host defense mechanisms is critical for maintaining homeostasis and responding to infections and tissue injury. While unbalanced inflammation is detrimental to the host; inadequate inflammation might not provide effective signals required to eliminate pathogens. On the other hand, aberrant inflammation could result in organ damage and impair host defense. The lipid mediator leukotriene B4 (LTB4) is a potent neutrophil chemoattractant and recently, its role as a dominant molecule that amplifies many arms of phagocyte antimicrobial effector function has been unveiled. However, excessive LTB4 production contributes to disease severity in chronic inflammatory diseases such as diabetes and arthritis, which could potentially be involved in poor host defense in these groups of patients. In this review we discuss the cellular and molecular programs elicited during LTB4 production and actions on innate immunity host defense mechanisms as well as potential therapeutic strategies to improve host defense

Leukotriene B4 levels determine staphylococcus aureus skin infection outcome

Indiana University-Purdue University Indianapolis (IUPUI)Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of severe skin infections and due to antibiotic resistance there is an intrinsic need to develop new immunotherapeutic strategies. Skin immune responses to infections require the cross-talk between phagocytes and structural cells that involves the secretion of cytokines, chemokines, and lipids. Leukotriene B4 (LTB4) is a pleiotropic lipid mediator known as a chemoattractant, but is also necessary to promote antimicrobial activity through B leukotriene receptor 1 (BLT1) signaling. However, chronic LTB4 production is associated with inflammatory diseases, including diabetes. People with diabetes are more susceptible to infections. The determinants by which LTB4/BLT1 promotes protective or detrimental immune responses in homeostasis and diabetes are unknown. We hypothesize that LTB4 levels determine infection outcome; while LTB4 is necessary for infection control, excessive LTB4 levels promote overwhelming inflammation that impairs host defense. Our data show that skin macrophages were necessary for LTB4 production and that LTB4 was vital for neutrophil direction, abscess formation, IL 1β production, and MRSA clearance through reactive oxygen species production. Importantly, topical LTB4 ointment treatment enhances neutrophil direction, abscess formation, and bacterial clearance. Conversely, in the setting of diabetes, skin macrophages drove excessive LTB4 production that promoted overwhelming inflammation, uncontrolled neutrophil recruitment, poor abscess formation, and lack of bacterial control. Diabetic mice treated with a topical ointment to inhibit BLT1 dampened inflammation and restored host defense by improving abscess formation, bacterial clearance, and overall inflammatory responses in the skin. These data demonstrate the balance of LTB4-induced inflammation is critical for regulating optimal immune responses during infections. This work highlights the importance of investigating the role of inflammatory mediators in the settings of health and disease. Targeting LTB4/BLT1 has therapeutic potential to regulate inflammation during MRSA skin infection by enhancing immune responses in settings of vulnerability or decrease inflammation in diabetes

MicroRNA 21 is a homeostatic regulator of macrophage polarization and prevents prostaglandin E2-mediated M2 generation

Macrophages dictate both initiation and resolution of inflammation. During acute inflammation classically activated macrophages (M1) predominate, and during the resolution phase alternative macrophages (M2) are dominant. The molecular mechanisms involved in macrophage polarization are understudied. MicroRNAs are differentially expressed in M1 and M2 macrophages that influence macrophage polarization. We identified a role of miR-21 in macrophage polarization, and found that cross-talk between miR-21 and the lipid mediator prostaglandin E2 (PGE2) is a determining factor in macrophage polarization. miR-21 inhibition impairs expression of M2 signature genes but not M1 genes. PGE2 and its downstream effectors PKA and Epac inhibit miR-21 expression and enhance expression of M2 genes, and this effect is more pronounced in miR-21-/- cells. Among potential targets involved in macrophage polarization, we found that STAT3 and SOCS1 were enhanced in miR-21-/- cells and further enhanced by PGE2. We found that STAT3 was a direct target of miR-21 in macrophages. Silencing the STAT3 gene abolished PGE2-mediated expression of M2 genes in miR-21-/- macrophages. These data shed light on the molecular brakes involved in homeostatic macrophage polarization and suggest new therapeutic strategies to prevent inflammatory responses

Imbalance between HDAC and HAT activities drives aberrant STAT1/MyD88 expression in macrophages from type 1 diabetic mice

AIMS: To investigate the hypothesis that alteration in histone acetylation/deacetylation triggers aberrant STAT1/MyD88 expression in macrophages from diabetics. Increased STAT1/MyD88 expression is correlated with sterile inflammation in type 1 diabetic (T1D) mice. METHODS: To induce diabetes, we injected low-doses of streptozotocin in C57BL/6 mice. Peritoneal or bone marrow-differentiated macrophages were cultured in 5mM (low) or 25mM (high glucose). ChIP analysis of macrophages from nondiabetic or diabetic mice was performed to determine acetylation of lysine 9 in histone H3 in MyD88 and STAT1 promoter regions. Macrophages from diabetic mice were treated with the histone acetyltransferase inhibitor anacardic acid (AA), followed by determination of mRNA expression by qPCR. RESULTS: Increased STAT1 and MyD88 expression in macrophages from diabetic but not naive mice cultured in low glucose persisted for up to 6days. Macrophages from diabetic mice exhibited increased activity of histone acetyltransferases (HAT) and decreased histone deacetylases (HDAC) activity. We detected increased H3K9Ac binding to Stat1/Myd88 promoters in macrophages from T1D mice and AA in vitro treatment reduced STAT1 and MyD88 mRNA expression. CONCLUSIONS/INTERPRETATION: These results indicate that histone acetylation drives elevated Stat1/Myd88 expression in macrophages from diabetic mice, and this mechanism may be involved in sterile inflammation and diabetes comorbidities

The Native 3D Organization of Bacterial Polysomes

SummaryRecent advances have led to insights into the structure of the bacterial ribosome, but little is known about the 3D organization of ribosomes in the context of translating polysomes. We employed cryoelectron tomography and a template-matching approach to map 70S ribosomes in vitrified bacterial translation extracts and in lysates of active E. coli spheroplasts. In these preparations, polysomal arrangements were observed in which neighboring ribosomes are densely packed and exhibit preferred orientations. Analysis of characteristic examples of polysomes reveals a staggered or pseudohelical organization of ribosomes along the mRNA trace, with the transcript being sequestered on the inside, the tRNA entrance sites being accessible, and the polypeptide exit sites facing the cytosol. Modeling of elongating nascent polypeptide chains suggests that this arrangement maximizes the distance between nascent chains on adjacent ribosomes, thereby reducing the probability of intermolecular interactions that would give rise to aggregation and limit productive folding

Change in Body Mass Index before and after Alzheimer's Disease Onset

OBJECTIVES: A high body mass index (BMI) in middle-age or a decrease in BMI at late-age has been considered a predictor for the development of Alzheimer's disease (AD). However, little is known about the BMI change close to or after AD onset. METHODS: BMI of participants from three cohorts, the Washington Heights and Inwood Columbia Aging Project (WHICAP; population-based) and the Predictors Study (clinic-based), and National Alzheimer's Coordinating Center (NACC; clinic-based) were analyzed longitudinally. We used generalized estimating equations to test whether there were significant changes of BMI over time, adjusting for age, sex, education, race, and research center. Stratification analyses were run to determine whether BMI changes depended on baseline BMI status. RESULTS: BMI declined over time up to AD clinical onset, with an annual decrease of 0.21 (p=0.02) in WHICAP and 0.18 (p=0.04) kg/m2 in NACC. After clinical onset of AD, there was no significant decrease of BMI. BMI even increased (b=0.11, p=0.004) among prevalent AD participants in NACC. During the prodromal period, BMI decreased over time in overweight (BMI>/=25 and /=30) NACC participants. After AD onset, BMI tended to increase in underweight/normal weight (BMI<25) patients and decrease in obese patients in all three cohorts, although the results were significant in NACC study only. CONCLUSIONS: Our study suggests that while BMI declines before the clinical AD onset, it levels off after clinical AD onset, and might even increase in prevalent AD. The pattern of BMI change may also depend on the initial BMI