Donald C. Fraser Papers, 1941-1945

An impressive collection of World War II letters from Fraser to his wife Irene in Fargo, dating from 1941 to 1945 while he was in training in Montana and California, and with the 188th Field Artillery in Europe

UV-B perceived by the UVR8 photoreceptor inhibits plant thermomorphogenesis

Small increases in ambient temperature can elicit striking effects on plant architecture, collectively termed thermomorphogenesis [1]. In Arabidopsis thaliana, these include marked stem elongation and leaf elevation, responses that have been predicted to enhance leaf cooling [ 2, 3, 4 and 5]. Thermomorphogenesis requires increased auxin biosynthesis, mediated by the bHLH transcription factor PHYTOCHROME-INTERACTING FACTOR 4 (PIF4) [ 6, 7 and 8], and enhanced stability of the auxin co-receptor TIR1, involving HEAT SHOCK PROTEIN 90 (HSP90) [9]. High-temperature-mediated hypocotyl elongation additionally involves localized changes in auxin metabolism, mediated by the indole-3-acetic acid (IAA)-amido synthetase Gretchen Hagen 3 (GH3).17 [10]. Here we show that ultraviolet-B light (UV-B) perceived by the photoreceptor UV RESISTANCE LOCUS 8 (UVR8) [11] strongly attenuates thermomorphogenesis via multiple mechanisms inhibiting PIF4 activity. Suppression of thermomorphogenesis involves UVR8 and CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1)-mediated repression of PIF4 transcript accumulation, reducing PIF4 abundance. UV-B also stabilizes the bHLH protein LONG HYPOCOTYL IN FAR RED (HFR1), which can bind to and inhibit PIF4 function. Collectively, our results demonstrate complex crosstalk between UV-B and high-temperature signaling. As plants grown in sunlight would most likely experience concomitant elevations in UV-B and ambient temperature, elucidating how these pathways are integrated is of key importance to the understanding of plant development in natural environments

Formation of octapod MnO nanoparticles with enhanced magnetic properties through kinetically-controlled thermal decomposition of polynuclear manganese complexes

Polynuclear manganese complexes are used as precursors for the synthesis of manganese oxide nanoparticles (MnO NPs). Altering the thermal decomposition conditions can shift the nanoparticle product from spherical, thermodynamically-driven NPs to unusual, kinetically-controlled octapod structures. The resulting increased surface area profoundly alters the NP's surface-dependent magnetism and may have applications in nanomedicine

IL-10 differentially controls the infiltration of inflammatory macrophages and antigen-presenting cells during inflammation

The inflammatory activation and recruitment of defined myeloid populations is essential for controlling the bridge between innate and adaptive immunity and shaping the immune response to microbial challenge. However, these cells exhibit significant functional heterogeneity and the inflammatory signals that differentially influence their effector characteristics are poorly characterized. In this study, we defined the phenotype of discrete subsets of effective antigen-presenting cells (APCs) in the peritoneal cavity during peritonitis. When the functional properties of these cells were compared to inflammatory monocyte-derived macrophages we noted differential responses to the immune-modulatory cytokine IL-10. In contrast to the suppressive actions of IL-10 on inflammatory macrophages, the recruitment of APCs was relatively refractory and we found no evidence for selective inhibition of APC differentiation. This differential response of myeloid cell subsets to IL-10 may thus have limited impact on development of potentially tissue-damaging adaptive immune responses, whilst restricting the magnitude of the inflammatory response. These findings may have clinical relevance in the context of peritoneal dialysis patients, where recurrent infections are associated with immune-mediated membrane dysfunction, treatment failure and increased morbidity

Influence of vitamin D supplementation by sunlight or oral D3 on exercise performance

Purpose: To determine the relationship between vitamin D status and exercise performance in a large, prospective cohort study of young men and women across seasons (Study-1). Then, in a randomized, placebo-controlled trial, to investigate the effects on exercise performance of achieving vitamin D sufficiency (serum 25(OH)D ≥ 50 nmol·L-1) by a unique comparison of safe, simulated-sunlight and oral vitamin D3 supplementation in wintertime (Study-2).  Methods: In Study-1, we determined 25(OH)D relationship with exercise performance in 967 military recruits. In Study-2, 137 men received either placebo, simulated-sunlight (1.3x standard erythemal dose in T-shirt and shorts, three-times-per-week for 4-weeks and then once-per-week for 8-weeks) or oral vitamin D3 (1,000 IU[BULLET OPERATOR]day-1 for 4-weeks and then 400 IU[BULLET OPERATOR]day-1 for 8-weeks). We measured serum 25(OH)D by LC-MS/MS and endurance, strength and power by 1.5-mile run, maximum-dynamic-lift and vertical jump, respectively.  Results: In Study-1, only 9% of men and 36% of women were vitamin D sufficient during wintertime. After controlling for body composition, smoking and season, 25(OH)D was positively associated with endurance performance (P ≤ 0.01, [INCREMENT]R2 = 0.03–0.06, small f2 effect sizes): 1.5-mile run time was ~half-a-second faster for every 1 nmol·L-1 increase in 25(OH)D. No significant effects on strength or power emerged (P > 0.05). In Study-2, safe simulated-sunlight and oral vitamin D3 supplementation were similarly effective in achieving vitamin D sufficiency in almost all (97%); however, this did not improve exercise performance (P > 0.05).  Conclusion: Vitamin D status was associated with endurance performance but not strength or power in a prospective cohort study. Achieving vitamin D sufficiency via safe, simulated summer sunlight or oral vitamin D3 supplementation did not improve exercise performance in a randomized-controlled trial

Determination of a microRNA signature of protective kidney ischemic preconditioning originating from proximal tubules

Ischemic preconditioning (IPC) is effective in limiting subsequent ischemic acute kidney injury in experimental models. MicroRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. We evaluated the time- and dose-dependence of benefit from IPC in a rat model of functional (bilateral) ischemia–reperfusion injury (IRI). We found optimal protection from subsequent injury following short, repetitive sequences of preconditioning insult. We subsequently used hybridization array and microRNA sequencing to characterize microRNA signatures of protective IPC and of IRI. These approaches identified a profile of microRNA changes consequent on IRI, that were limited by prior IPC. To localize these signals within the kidney, we used laser capture microdissection and RT-qPCR to measure microRNA abundance in nephron segments, pinpointing microRNA changes principally to glomeruli and proximal tubules. Our data describe a unique microRNA signature for IRI in the rat kidney. Pulsatile IPC reduces kidney damage following IRI and diminishes this microRNA signal. We have also identified candidate microRNAs that may act as biomarkers of injury and therapeutic targets in this context

Unconventional human T cells accumulate at the site of infection in response to microbial ligands and induce local tissue remodeling

The antimicrobial responsiveness and function of unconventional human T cells are poorly understood, with only limited access to relevant specimens from sites of infection. Peritonitis is a common and serious complication in individuals with end-stage kidney disease receiving peritoneal dialysis. By analyzing local and systemic immune responses in peritoneal dialysis patients presenting with acute bacterial peritonitis and monitoring individuals before and during defined infectious episodes, our data show that Vg9/ Vd2+ gd T cells and mucosal-associated invariant T cells accumulate at the site of infection with organisms producing (E)-4- hydroxy-3-methyl-but-2-enyl pyrophosphate and vitamin B2, respectively. Such unconventional human T cells are major producers of IFN-g and TNF-a in response to these ligands that are shared by many microbial pathogens and affect the cells lining the peritoneal cavity by triggering local inflammation and inducing tissue remodeling with consequences for peritoneal membrane integrity. Our data uncover a crucial role for Vg9/Vd2 T cells and mucosal-associated invariant T cells in bacterial infection and suggest that they represent a useful predictive marker for important clinical outcomes, which may inform future stratification and patient management. These findings are likely to be applicable to other acute infections where local activation of unconventional T cells contributes to the antimicrobial inflammatory response

Microwave-assisted synthesis of highly crystalline, multifunctional iron oxide nanocomposites for imaging applications

We report a reproducible single-step, microwave-assisted approach for the preparation of multifunctional magnetic nanocomposites comprising superparamagnetic iron oxide (Fe3O4) cores, a polyelectrolyte stabilizer and an organic dye with no requirement for post-processing. The stabilisers poly(sodium 4-styrenesulfonate) (PSSS) and sodium polyphosphate (SPP) have been thoroughly investigated and from analysis using electron microscopy, dynamic light scattering measurements, magnetic hysteresis and magnetic resonance (MR) imaging, we show that the higher degree of Fe3O4 nanoparticle crystallinity achieved with the PSSS stabiliser leads to enhanced magnetic behaviour and thus better contrast agent relaxivity compared to the less crystalline, poorly defined particles obtained when SPP is employed as a stabiliser. We also demonstrate the potential for obtaining a multifunctional magnetic-fluorescent nanocomposite using our microwave-assisted synthesis. In this manner, we demonstrate the intimate link between synthetic methodology (microwave heating with a polyelectrolyte stabilizer) and the resulting properties (particle size, shape, and magnetism) and how this underpins the functionality of the resulting nanocomposites as agents for biomedical imaging

The transcription factor Gata6 links tissue macrophage phenotype and proliferative renewal

Tissue-resident macrophages are heterogeneous as a consequence of anatomical niche–specific functions. Many populations self-renew independently of bone marrow in the adult, but the molecular mechanisms of this are poorly understood. We determined a transcriptional profile for the major self-renewing population of peritoneal macrophages in mice. These cells specifically expressed the transcription factor Gata6. Selective deficiency of Gata6 in myeloid cells caused substantial alterations in the transcriptome of peritoneal macrophages. Gata6 deficiency also resulted in dysregulated peritoneal macrophage proliferative renewal during homeostasis and in response to inflammation, which was associated with delays in the resolution of inflammation. Our investigations reveal that the tissue macrophage phenotype is under discrete tissue-selective transcriptional control and that this is fundamentally linked to the regulation of their proliferation renewal

Seroprevalence following the second wave of pandemic 2009 H1N1 influenza in Pittsburgh, PA, USA

Background: In April 2009, a new pandemic strain of influenza infected thousands of persons in Mexico and the United States and spread rapidly worldwide. During the ensuing summer months, cases ebbed in the Northern Hemisphere while the Southern Hemisphere experienced a typical influenza season dominated by the novel strain. In the fall, a second wave of pandemic H1N1 swept through the United States, peaking in most parts of the country by mid October and returning to baseline levels by early December. The objective was to determine the seroprevalence of antibodies against the pandemic 2009 H1N1 influenza strain by decade of birth among Pittsburgh-area residents. Methods and Findings: Anonymous blood samples were obtained from clinical laboratories and categorized by decade of birth from 1920-2009. Using hemagglutination-inhibition assays, approximately 100 samples per decade (n = 846) were tested from blood samples drawn on hospital and clinic patients in mid-November and early December 2009. Age specific seroprevalences against pandemic H1N1 (A/California/7/2009) were measured and compared to seroprevalences against H1N1 strains that had previously circulated in the population in 2007, 1957, and 1918. (A/Brisbane/59/2007, A/Denver/1/ 1957, and A/South Carolina/1/1918). Stored serum samples from healthy, young adults from 2008 were used as a control group (n = 100). Seroprevalences against pandemic 2009 H1N1 influenza varied by age group, with children age 10-19 years having the highest seroprevalence (45%), and persons age 70-79 years having the lowest (5%). The baseline seroprevalence among control samples from 18-24 year-olds was 6%. Overall seroprevalence against pandemic H1N1 across all age groups was approximately 21%. Conclusions: After the peak of the second wave of 2009 H1N1, HAI seroprevalence results suggest that 21% of persons in the Pittsburgh area had become infected and developed immunity. Extrapolating to the entire US population, we estimate that at least 63 million persons became infected in 2009. As was observed among clinical cases, this sero-epidemiological study revealed highest infection rates among school-age children. © 2010 Zimmer et al