Introduced and Native Congeners Use Different Resource Allocation Strategies to Maintain Performance During Infection

Hosts can manage parasitic infections using an array of tactics, which are likely to vary contingent on coevolutionary history between the host and the parasite. Here we asked whether coping ability of congeners that differ in host-parasite coevolutionary history differed in response to experimental infections with a coccidian parasite. House sparrows (Passer domesticus) and gray-headed sparrows (Passer griseus) are sympatric and ecologically similar, but house sparrows are recent colonizers of Kenya, the site of our comparison, whereas gray-headed sparrows are native. We evaluated three variables as barometers of infection coping ability: vertical flight, pectoral muscle size, and fat score. We also measured routing of a dose of 13C-labeled leucine, an essential amino acid, among tissues to compare resource allocation strategies in response to infection. We found that burden effects on performance were minimal in both species, but house sparrows maintained considerably higher burdens than gray-headed sparrows regardless of exposure. House sparrows also had more exogeneous leucine tracer in all tissues after 24 h, demonstrating a difference in the way the two species allocate or distribute resources. We argue that house sparrows may be maintaining larger resource reserves to mitigate costs associated with exposure and infection. Additionally, in response to increased parasite exposure, gray-headed sparrows had less leucine tracer in their spleens and more in their gonads, whereas house sparrows did not change allocation, perhaps indicating a trade-off that is not experienced by the introduced species

No effect of diet-induced mild hyperhomocysteinemia on vascular methylating capacity, atherosclerosis progression, and specific histone methylation

Hyperhomocysteinemia (HHcy) is a risk factor for atherosclerosis through mechanisms which are still incompletely defined. One possible mechanism involves the hypomethylation of the nuclear histone proteins to favor the progression of atherosclerosis. In previous cell studies, hypomethylating stress decreased a specific epigenetic tag (the trimethylation of lysine 27 on histone H3, H3K27me3) to promote endothelial dysfunction and activation, i.e., an atherogenic phenotype. Here, we conducted a pilot study to investigate the impact of mild HHcy on vascular methylating index, atherosclerosis progression and H3K27me3 aortic content in apolipoprotein E-deficient (ApoE−/−) mice. In two different sets of experiments, male mice were fed high-fat, low in methyl donors (HFLM), or control (HF) diets for 16 (Study A) or 12 (Study B) weeks. At multiple time points, plasma was collected for (1) quantification of total homocysteine (tHcy) by high-performance liquid chromatography; or (2) the methylation index of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH ratio) by liquid chromatography tandem-mass spectrometry; or (3) a panel of inflammatory cytokines previously implicated in atherosclerosis by a multiplex assay. At the end point, aortas were collected and used to assess (1) the methylating index (SAM:SAH ratio); (2) the volume of aortic atherosclerotic plaque assessed by high field magnetic resonance imaging; and (3) the vascular content of H3K27me3 by immunohistochemistry. The results showed that, in both studies, HFLM-fed mice, but not those mice fed control diets, accumulated mildly elevated tHcy plasmatic concentrations. However, the pattern of changes in the inflammatory cytokines did not support a major difference in systemic inflammation between these groups. Accordingly, in both studies, no significant differences were detected for the aortic methylating index, plaque burden, and H3K27me3 vascular content between HF and HFLM-fed mice. Surprisingly however, a decreased plasma SAM: SAH was also observed, suggesting that the plasma compartment does not always reflect the vascular concentrations of these two metabolites, at least in this model. Mild HHcy in vivo was not be sufficient to induce vascular hypomethylating stress or the progression of atherosclerosis, suggesting that only higher accumulations of plasma tHcy will exhibit vascular toxicity and promote specific epigenetic dysregulation

Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results

Vα24-invariant natural killer T cells (NKTs) have anti-tumor properties that can be enhanced by chimeric antigen receptors (CARs). Here we report updated interim results from the first-in-human phase 1 evaluation of autologous NKTs co-expressing a GD2-specific CAR with interleukin 15 (IL15) (GD2-CAR.15) in 12 children with neuroblastoma (NB). The primary objectives were safety and determination of maximum tolerated dose (MTD). The anti-tumor activity of GD2-CAR.15 NKTs was assessed as a secondary objective. Immune response evaluation was an additional objective. No dose-limiting toxicities occurred; one patient experienced grade 2 cytokine release syndrome that was resolved by tocilizumab. The MTD was not reached. The objective response rate was 25% (3/12), including two partial responses and one complete response. The frequency of CD62L+NKTs in products correlated with CAR-NKT expansion in patients and was higher in responders (n = 5; objective response or stable disease with reduction in tumor burden) than non-responders (n = 7). BTG1 (BTG anti-proliferation factor 1) expression was upregulated in peripheral GD2-CAR.15 NKTs and is a key driver of hyporesponsiveness in exhausted NKT and T cells. GD2-CAR.15 NKTs with BTG1 knockdown eliminated metastatic NB in a mouse model. We conclude that GD2-CAR.15 NKTs are safe and can mediate objective responses in patients with NB. Additionally, their anti-tumor activity may be enhanced by targeting BTG1. ClinicalTrials.gov registration: NCT03294954

The Cholecystectomy As A Day Case (CAAD) Score: A Validated Score of Preoperative Predictors of Successful Day-Case Cholecystectomy Using the CholeS Data Set

Background Day-case surgery is associated with significant patient and cost benefits. However, only 43% of cholecystectomy patients are discharged home the same day. One hypothesis is day-case cholecystectomy rates, defined as patients discharged the same day as their operation, may be improved by better assessment of patients using standard preoperative variables. Methods Data were extracted from a prospectively collected data set of cholecystectomy patients from 166 UK and Irish hospitals (CholeS). Cholecystectomies performed as elective procedures were divided into main (75%) and validation (25%) data sets. Preoperative predictors were identified, and a risk score of failed day case was devised using multivariate logistic regression. Receiver operating curve analysis was used to validate the score in the validation data set. Results Of the 7426 elective cholecystectomies performed, 49% of these were discharged home the same day. Same-day discharge following cholecystectomy was less likely with older patients (OR 0.18, 95% CI 0.15–0.23), higher ASA scores (OR 0.19, 95% CI 0.15–0.23), complicated cholelithiasis (OR 0.38, 95% CI 0.31 to 0.48), male gender (OR 0.66, 95% CI 0.58–0.74), previous acute gallstone-related admissions (OR 0.54, 95% CI 0.48–0.60) and preoperative endoscopic intervention (OR 0.40, 95% CI 0.34–0.47). The CAAD score was developed using these variables. When applied to the validation subgroup, a CAAD score of ≤5 was associated with 80.8% successful day-case cholecystectomy compared with 19.2% associated with a CAAD score >5 (p < 0.001). Conclusions The CAAD score which utilises data readily available from clinic letters and electronic sources can predict same-day discharges following cholecystectomy

Host-Parasite Interactions in an Invasive Songbird

Introduced species are the greatest threat to biodiversity after habitat loss. Understanding the processes that permit organisms to become successful invaders may provide opportunities to prevent or limit their dispersal and establishment and thereby alleviate some of their harmful effects. The goal of my dissertation research has been to investigate whether invasive species have distinctive interactions with parasites, and some of the mechanisms that may underlie that variation. I used one of the world\u27s most successful vertebrate invaders as a case study: the house sparrow (Passer domesticus; Introduction). Previous research in the house sparrow suggested that loss of parasite diversity may contribute to invasion success. However, my work demonstrates that infection with common avian malaria parasites is primarily a function of environmental heterogeneity and is not a predictor of time since introduction for house sparrows that are currently expanding their range in Kenya (Chapter 1). Interestingly, in spite of a large proportion of the population being infected with avian malaria, a state that should reduce competitive ability of house sparrow populations, this species is still able to establish themselves among native competitors. Though there are a number of potential mechanisms that could explain this pattern, one of the most convincing explanations is that house sparrows, and perhaps other introduced species, have adaptive differences in immunity. As such, the findings of Chapter 1 inspired two studies in which my collaborators and I showed that house sparrows from two non-native populations seem capable of maintaining normal health, performance and behavior during immune challenge, a response often referred to as parasite tolerance. Specifically, in Chapter 2, we found that when Floridian house sparrows, established since ~1870, were challenged with synthetic pathogens that mimicked infection with a fungi, an RNA virus or Gram-negative bacteria, only individuals challenged by the synthetic bacteria showed measurable sickness behaviors and secretion of an inflammatory protein. In Chapter 3, we compared parasite tolerance in Kenyan house sparrows (introduced in ~2000) and a native congener, the grey-headed sparrow (P. griseus) to a common intestinal parasite of songbirds. We found that both species were tolerant in that they were able to maintain fat reserves, protein reserves and vertical flight ability during infection. However, house sparrows maintained burdens that were, on average, more than 10x those of grey-headed sparrows. Moreover, when examining nutrient allocation in the two species, house sparrows appeared to assimilate nutrients more efficiently than grey-headed sparrows and did not change how nutrients were allocated among immune and reproductive organs during experimental infection. Grey-headed sparrows, however, did shift nutrient allocation among immune and reproductive organs during experimental infection. Together, the larger nutrient pool and maintenance of nutrient allocation patterns in challenged house sparrows suggests that no physiological trade-offs occurred and that house sparrows experienced a lower cost of parasite exposure. In the fourth Chapter, I explored why house sparrows had such high coccidia burdens in comparison to their congeners. We suspected burden was a function of the frequency of exposure to coccidia. Consequently, we explored heterogeneity in foraging preferences and other behaviors in Floridian house sparrows and their role in coccidia burden. As expected, we found that house sparrows did not avoid contaminated food. In fact, they ate contaminated and uncontaminated foods indiscriminately. What was surprising was a lack of correlation between burden and consumption of contaminated foods and all of the behaviors we monitored (i.e., aggression, activity, feeding rates and defecation frequency). Overall, these data suggest that house sparrows do not benefit from typical parasite-avoidance behaviors. In sum, this dissertation research implies that house sparrows respond to parasite infection differently than many other known vertebrates, most likely in an effort to maximize efficient use of resources and, in so doing, augment competitive ability and invasion success

Host-Parasite Interactions in an Invasive Songbird

Introduced species are the greatest threat to biodiversity after habitat loss. Understanding the processes that permit organisms to become successful invaders may provide opportunities to prevent or limit their dispersal and establishment and thereby alleviate some of their harmful effects. The goal of my dissertation research has been to investigate whether invasive species have distinctive interactions with parasites, and some of the mechanisms that may underlie that variation. I used one of the world\u27s most successful vertebrate invaders as a case study: the house sparrow (Passer domesticus; Introduction). Previous research in the house sparrow suggested that loss of parasite diversity may contribute to invasion success. However, my work demonstrates that infection with common avian malaria parasites is primarily a function of environmental heterogeneity and is not a predictor of time since introduction for house sparrows that are currently expanding their range in Kenya (Chapter 1). Interestingly, in spite of a large proportion of the population being infected with avian malaria, a state that should reduce competitive ability of house sparrow populations, this species is still able to establish themselves among native competitors. Though there are a number of potential mechanisms that could explain this pattern, one of the most convincing explanations is that house sparrows, and perhaps other introduced species, have adaptive differences in immunity. As such, the findings of Chapter 1 inspired two studies in which my collaborators and I showed that house sparrows from two non-native populations seem capable of maintaining normal health, performance and behavior during immune challenge, a response often referred to as parasite tolerance. Specifically, in Chapter 2, we found that when Floridian house sparrows, established since ~1870, were challenged with synthetic pathogens that mimicked infection with a fungi, an RNA virus or Gram-negative bacteria, only individuals challenged by the synthetic bacteria showed measurable sickness behaviors and secretion of an inflammatory protein. In Chapter 3, we compared parasite tolerance in Kenyan house sparrows (introduced in ~2000) and a native congener, the grey-headed sparrow (P. griseus) to a common intestinal parasite of songbirds. We found that both species were tolerant in that they were able to maintain fat reserves, protein reserves and vertical flight ability during infection. However, house sparrows maintained burdens that were, on average, more than 10x those of grey-headed sparrows. Moreover, when examining nutrient allocation in the two species, house sparrows appeared to assimilate nutrients more efficiently than grey-headed sparrows and did not change how nutrients were allocated among immune and reproductive organs during experimental infection. Grey-headed sparrows, however, did shift nutrient allocation among immune and reproductive organs during experimental infection. Together, the larger nutrient pool and maintenance of nutrient allocation patterns in challenged house sparrows suggests that no physiological trade-offs occurred and that house sparrows experienced a lower cost of parasite exposure. In the fourth Chapter, I explored why house sparrows had such high coccidia burdens in comparison to their congeners. We suspected burden was a function of the frequency of exposure to coccidia. Consequently, we explored heterogeneity in foraging preferences and other behaviors in Floridian house sparrows and their role in coccidia burden. As expected, we found that house sparrows did not avoid contaminated food. In fact, they ate contaminated and uncontaminated foods indiscriminately. What was surprising was a lack of correlation between burden and consumption of contaminated foods and all of the behaviors we monitored (i.e., aggression, activity, feeding rates and defecation frequency). Overall, these data suggest that house sparrows do not benefit from typical parasite-avoidance behaviors. In sum, this dissertation research implies that house sparrows respond to parasite infection differently than many other known vertebrates, most likely in an effort to maximize efficient use of resources and, in so doing, augment competitive ability and invasion success

The nNOS-p38MAPK Pathway Is Mediated by NOS1AP during Neuronal Death.

Neuronal nitric oxide synthase (nNOS) and p38MAPK are strongly implicated in excitotoxicity, a mechanism common to many neurodegenerative conditions, but the intermediary mechanism is unclear. NOS1AP is encoded by a gene recently associated with sudden cardiac death, diabetes-associated complications, and schizophrenia (Arking et al., 2006; Becker et al., 2008; Brzustowicz, 2008; Lehtinen et al., 2008). Here we find it interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulus induces recruitment of NOS1AP to nNOS in rat cortical neuron culture. Excitotoxic activation of p38MAPK and subsequent neuronal death are reduced by competing with the nNOS:NOS1AP interaction and by knockdown with NOS1AP-targeting siRNAs. We designed a cell-permeable peptide that competes for the unique PDZ domain of nNOS that interacts with NOS1AP. This peptide inhibits NMDA-induced recruitment of NOS1AP to nNOS and in vivo in rat, doubles surviving tissue in a severe model of neonatal hypoxia-ischemia, a major cause of neonatal death and pediatric disability. The highly unusual sequence specificity of the nNOS:NOS1AP interaction and involvement in excitotoxic signaling may provide future opportunities for generation of neuroprotectants with high specificity

The discovery of two distant, massive clusters of galaxies in the ROSAT All-Sky Survey

We discuss the radio, optical, and X-ray properties of two newly discovered, very X-ray luminous, distant clusters of galaxies. Both systems were noted as cluster candidates in a cross-correlation of data from the WENSS radio survey and the ROSAT All-Sky Survey. Follow-up observations performed by us and the Massive Cluster Survey (MACS) team confirmed both sources as distant galaxy clusters. The first cluster, MACS J0717.5+3745 at a redshift of z= 0.5548, contains a very extended, steep-spectrum radio source offset from the cluster core, making it the most distant radio relic known. The second cluster, MACS J1621.3+3810 at z= 0.465, is a strong cooling flow with a relatively weak central radio source. We present results from ROSAT High-Resolution Imager (HRI) observations of both clusters as well as from optical imaging and VLA radio interferometry observations. Our discoveries demonstrate that distant clusters can be efficiently identified in a relatively shallow X-ray survey, that radio/X-ray selection is efficient, and that both cooling flow and non-cooling flow clusters are selected

A spectacular giant arc in the massive cluster lens MACSJ1206.2-0847

We discuss the X-ray and optical properties of the massive galaxy cluster MACSJ1206.2-0847 (z=0.4385), discovered in the Massive Cluster Survey (MACS). Our Chandra observation of the system yields a total X-ray luminosity of 2.4 x 10^45 erg/s (0.1-2.4 keV) and a global gas temperature of (11.6 +/- 0.7) keV, very high values typical of MACS clusters. In both optical and X-ray images MACSJ1206 appears close to relaxed in projection, with a pronounced X-ray peak at the location of the brightest cluster galaxy (BCG); we interpret this feature as the remnant of a cold core. A spectacular giant gravitational arc, 15" in length, bright (V~21) and unusually red (R-K=4.3), is seen 20" west of the BCG; we measure a redshift of z=1.036 for the lensed galaxy. From our HST image of the cluster we identify the giant arc and its counter image as a seven-fold imaged system. An excess of X-ray emission in the direction of the arc coincides with a mild galaxy overdensity and could be the remnant of a minor merger with a group of galaxies. We derive estimates of the total cluster mass as well as of the mass of the cluster core using X-ray, dynamical, and gravitational-lensing techniques. For the mass enclosed by the giant arc (r<119 kpc) our strong-lensing analysis based on HST imaging yields a very high value of 1.1 x 10^14 M_sun, inconsistent with the much lower X-ray estimate of 0.5 x 10^14 M_sun. Similarly, the virial estimate of 4 x 10^15 M_sun for the total cluster mass, derived from multi-object spectroscopy of 38 cluster members, is significantly higher than the corresponding X-ray estimate of 1.7 x 10^15 M_sun. We take the discrepant mass estimates to be indicative of substructure along the line of sight during an ongoing merger event, an interpretation that is supported by the system's very high velocity dispersion of 1580 km/s.Comment: 13 pages, 14 figures, accepted for publication in MNRA