Sono-photoacoustic imaging of gold nanoemulsions: Part I. Exposure thresholds

AbstractIntegrating high contrast bubbles from ultrasound imaging with plasmonic absorbers from photoacoustic imaging is investigated. Nanoemulsion beads coated with gold nanopsheres (NEB-GNS) are excited with simultaneous light (transient heat at the GNS's) and ultrasound (rarefactional pressure) resulting in a phase transition achievable under different scenarios, enhancing laser-induced acoustic signals and enabling specific detection of nanoprobes at lower concentration. An automated platform allowed dual parameter scans of both pressure and laser fluence while recording broadband acoustic signals. Two types of NEB-GNS and individual GNS were investigated and showed the great potential of this technique to enhance photoacoustic/acoustic signals. The NEB-GNS size distribution influences vaporization thresholds which can be reached at both permissible ultrasound and light exposures at deep penetration and at low concentrations of targets. This technique, called sono-photoacoustics, has great potential for targeted molecular imaging and therapy using compact nanoprobes with potentially high-penetrability into tissue

Iterative focused screening with biological fingerprints identifies selective Asc-1 inhibitors distinct from traditional high throughput screening

N-methyl-d-aspartate receptors (NMDARs) mediate glutamatergic signaling that is critical to cognitive processes in the central nervous system, and NMDAR hypofunction is thought to contribute to cognitive impairment observed in both schizophrenia and Alzheimer’s disease. One approach to enhance the function of NMDAR is to increase the concentration of an NMDAR coagonist, such as glycine or d-serine, in the synaptic cleft. Inhibition of alanine–serine–cysteine transporter-1 (Asc-1), the primary transporter of d-serine, is attractive because the transporter is localized to neurons in brain regions critical to cognitive function, including the hippocampus and cortical layers III and IV, and is colocalized with d-serine and NMDARs. To identify novel Asc-1 inhibitors, two different screening approaches were performed with whole-cell amino acid uptake in heterologous cells stably expressing human Asc-1: (1) a high-throughput screen (HTS) of 3 M compounds measuring 35S l-cysteine uptake into cells attached to scintillation proximity assay beads in a 1536 well format and (2) an iterative focused screen (IFS) of a 45 000 compound diversity set using a 3H d-serine uptake assay with a liquid scintillation plate reader in a 384 well format. Critically important for both screening approaches was the implementation of counter screens to remove nonspecific inhibitors of radioactive amino acid uptake. Furthermore, a 15 000 compound expansion step incorporating both on- and off-target data into chemical and biological fingerprint-based models for selection of additional hits enabled the identification of novel Asc-1-selective chemical matter from the IFS that was not identified in the full-collection HTS

Trends in the Association of Parental History of Obesity over 60 Years

Objective: The association of familial as compared to genetic factors in the current obesogenic environment, compared to earlier, leaner time periods, is uncertain. Design and Methods Participants from the Framingham Heart Study were classified according to parental obesity status in the Original, Offspring, and Third Generation cohorts; mean BMI levels were estimated and we compared the association of parental history across generations. Finally, a genetic risk score comprised of 32 well-replicated single nucleotide polymorphisms for BMI was examined in association with BMI levels in 1948, 1971, and 2002. Results: BMI was 1.49 kg/m2 higher per each affected parent among the Offspring, and increased to 2.09 kg/m2 higher among the Third Generation participants (p-value for the cohort comparison=0.007). Parental history of obesity was associated with increased weight gain (p<0.0001) and incident obesity (p=0.009). Despite a stronger association of parental obesity with offspring BMI in more contemporary time periods, we observed no change in the effect size of a BMI genetic risk score from 1948 to 2002 (p=0.11 for test of trend across the time periods). Conclusions: The association of parental obesity has become stronger in more contemporary time period, whereas the association of a BMI genetic risk score has not changed

Delayed evaluation of combat-related penetrating neck trauma

ObjectiveThe approach to penetrating trauma of the head and neck has undergone significant evolution and offers unique challenges during wartime. Military munitions produce complex injury patterns that challenge conventional diagnosis and management. Mass casualties may not allow for routine exploration of all stable cervical blast injuries. The objective of this study was to review the delayed evaluation of combat-related penetrating neck trauma in patients after evacuation to the United States.MethodFrom February 2003 through April 2005, a series of patients with military-associated penetrating cervical trauma were evacuated to a single institution, prospectively entered into a database, and retrospectively reviewed.ResultsSuspected vascular injury from penetrating neck trauma occurred in 63 patients. Injuries were to zone II in 33%, zone III in 33%, and zone I in 11%. The remaining injuries involved multiple zones, including the lower face or posterior neck. Explosive devices wounded 50 patients (79%), 13 (21%) had high-velocity gunshot wounds, and 19 (30%) had associated intracranial or cervical spine injury. Of the 39 patients (62%) who underwent emergent neck exploration in Iraq or Afghanistan, 21 had 24 injuries requiring ligation (18), vein interposition or primary repair (4), polytetrafluoroethylene (PTFE) graft interposition (1), or patch angioplasty (1). Injuries occurred to the carotid, vertebral, or innominate arteries, or the jugular vein. After evacuation to the United States, all patients underwent radiologic evaluation of the head and neck vasculature. Computed tomography angiography was performed in 45 patients (71%), including six zone II injuries without prior exploration. Forty (63%) underwent diagnostic arteriography that detected pseudoaneurysms (5) or occlusions (8) of the carotid and vertebral arteries. No occult venous injuries were noted. Delayed evaluation resulted in the detection of 12 additional occult injuries and one graft thrombosis in 11 patients. Management included observation (5), vein or PTFE graft repair (3), coil embolization (2), or ligation (1).ConclusionsPenetrating multiple fragment injury to the head and neck is common during wartime. Computed tomography angiography is useful in the delayed evaluation of stable patients, but retained fragments produce suboptimal imaging in the zone of injury. Arteriography remains the imaging study of choice to evaluate for cervical vascular trauma, and its use should be liberalized for combat injuries. Stable injuries may not require immediate neck exploration; however, the high prevalence of occult injuries discovered in this review underscores the need for a complete re-evaluation upon return to the United States

Is Mitigation Translocation an Effective Strategy for Conserving Common Chuckwallas?

Mitigation translocation remains a popular conservation tool despite ongoing debate regarding its utility for population conservation. To add to the understanding of the effectiveness of mitigation translocation, in 2017 and 2018 we monitored a population of protected common chuckwallas (Sauromalus ater) following translocation away from the area of construction of a new highway near the South Mountains, Phoenix, Arizona, USA. We removed chuckwallas from the construction right-of-way, paint-marked and pit-tagged them, and then released them in a nearby municipal preserve. We deployed very high frequency radio-telemetry transmitters on a sub-sample of 15 translocated adult chuckwallas. We monitored the radio-marked chuckwallas once a day at 1- to 3-day intervals for up to 46 days to document survival, body mass, and post-release movements. The average distance moved following translocation was 359 ± 53 m. Using minimum convex polygons, the average home range size of translocated lizards was 0.9 ± 0.3 ha, which was 18–45 times larger than expected for the species. Following translocations, we surveyed the translocation sites 1 month later and again 1 year later to determine the presence of translocated chuckwallas. Translocated individuals were rarely observed a second time: in 2017, only 11 of 160 translocated chuckwallas were seen again, and in 2018, only 11 of 192 translocated chuckwallas were detected. In the light of low recapture rate, consistent loss of body mass, and large movements of marked lizards, we conclude that survival of translocated chuckwallas was low over a single year. In the future, efficacy of mitigation translocation could be better evaluated by assessing the spatial ecology of both resident and translocated individuals simultaneously using radio-telemetry

Clusterin, a haploinsufficient tumor suppressor gene in neuroblastomas

This article is available open access through the publisher’s website. Copyright @ 2009 The Authors.Background - Clusterin expression in various types of human cancers may be higher or lower than in normal tissue, and clusterin may promote or inhibit apoptosis, cell motility, and inflammation. We investigated the role of clusterin in tumor development in mouse models of neuroblastoma. Methods - We assessed expression of microRNAs in the miR-17-92 cluster by real-time reverse transcription–polymerase chain reaction in MYCN-transfected SH-SY5Y and SH-EP cells and inhibited expression by transfection with microRNA antisense oligonucleotides. Tumor development was studied in mice (n = 66) that were heterozygous or homozygous for the MYCN transgene and/or for the clusterin gene; these mice were from a cross between MYCN-transgenic mice, which develop neuroblastoma, and clusterin-knockout mice. Tumor growth and metastasis were studied in immunodeficient mice that were injected with human neuroblastoma cells that had enhanced (by clusterin transfection, four mice per group) or reduced (by clusterin short hairpin RNA [shRNA] transfection, eight mice per group) clusterin expression. All statistical tests were two-sided. Results - Clusterin expression increased when expression of MYCN-induced miR-17-92 microRNA cluster in SH-SY5Y neuroblastoma cells was inhibited by transfection with antisense oligonucleotides compared with scrambled oligonucleotides. Statistically significantly more neuroblastoma-bearing MYCN-transgenic mice were found in groups with zero or one clusterin allele than in those with two clusterin alleles (eg, 12 tumor-bearing mice in the zero-allele group vs three in the two-allele group, n = 22 mice per group; relative risk for neuroblastoma development = 4.85, 95% confidence interval [CI] = 1.69 to 14.00; P = .005). Five weeks after injection, fewer clusterin-overexpressing LA-N-5 human neuroblastoma cells than control cells were found in mouse liver or bone marrow, but statistically significantly more clusterin shRNA-transfected HTLA230 cells (3.27%, with decreased clusterin expression) than control-transfected cells (1.53%) were found in the bone marrow (difference = 1.74%, 95% CI = 0.24% to 3.24%, P = .026). Conclusions - We report, to our knowledge, the first genetic evidence that clusterin is a tumor and metastasis suppressor gene.Sport Aiding Medical Research for Kids (SPARKS), Great Ormond Street Hospital/National Health Service, the National Cancer Institute and University of Parma

Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism

Mutations in the SHANK family of genes have been consistently identified in genetic and genomic screens of autism spectrum disorder (ASD). The functional overlap of SHANK with several other ASD-associated genes suggests synaptic dysfunction as a convergent mechanism of pathophysiology in ASD. Although many ASD-related mutations result in alterations to synaptic function, the nature of those dysfunctions and the consequential behavioral manifestations are highly variable when expressed in genetic mouse models. To investigate the phylogenetic conservation of phenotypes resultant of Shank2 loss-of-function in a translationally relevant animal model, we generated and characterized a novel transgenic rat with a targeted mutation of the Shank2 gene, enabling an evaluation of gene-associated phenotypes, the elucidation of complex behavioral phenotypes, and the characterization of potential translational biomarkers. The Shank2 loss-of-function mutation resulted in a notable phenotype of hyperactivity encompassing hypermotivation, increased locomotion, and repetitive behaviors. Mutant rats also expressed deficits in social behavior throughout development and in the acquisition of operant tasks. The hyperactive phenotype was associated with an upregulation of mGluR1 expression, increased dendritic branching, and enhanced long-term depression (LTD) in the striatum but opposing morphological and cellular alterations in the hippocampus (HP). Administration of the mGluR1 antagonist JNJ16259685 selectively normalized the expression of striatally mediated repetitive behaviors and physiology but had no effect on social deficits. Finally, Shank2 mutant animals also exhibited alterations in electroencephalography (EEG) spectral power and event-related potentials, which may serve as translatable EEG biomarkers of synaptopathic alterations. Our results show a novel hypermotivation phenotype that is unique to the rat model of Shank2 dysfunction, in addition to the traditional hyperactive and repetitive behaviors observed in mouse models. The hypermotivated and hyperactive phenotype is associated with striatal dysfunction, which should be explored further as a targetable mechanism for impairment in ASD

Amygdala 5-HTT gene network moderates the effects of postnatal adversity on attention problems : anatomo-functional correlation and epigenetic changes

Variations in serotoninergic signaling have been related to behavioral outcomes. Alterations in the genome, such as DNA methylation and histone modifications, are affected by serotonin neurotransmission. The amygdala is an important brain region involved in emotional responses and impulsivity, which receives serotoninergic input. In addition, studies suggest that the serotonin transporter gene network may interact with the environment and influence the risk for psychiatric disorders. We propose to investigate whether/how interactions between the exposure to early life adversity and serotonin transporter gene network in the amygdala associate with behavioral disorders. We constructed a co-expression-based polygenic risk score (ePRS) reflecting variations in the function of the serotonin transporter gene network in the amygdala and investigated its interaction with postnatal adversity on attention problems in two independent cohorts from Canada and Singapore. We also described how interactions between ePRS-5-HTT and postnatal adversity exposure predict brain gray matter density and variation in DNA methylation across the genome. We observed that the expression-based polygenic risk score, reflecting the function of the amygdala 5-HTT gene network, interacts with postnatal adversity, to predict attention and hyperactivity problems across both cohorts. Also, both postnatal adversity score and amygdala ePRS-5-HTT score, as well as their interaction, were observed to be associated with variation in DNA methylation across the genome. Variations in gray matter density in brain regions linked to attentional processes were also correlated to our ePRS score. These results confirm that the amygdala 5-HTT gene network is strongly associated with ADHD-related behaviors, brain cortical density, and epigenetic changes in the context of adversity in young children