New Zealand, a geographically remote Pacific island with easily sealable borders, implemented a nationwide 'lockdown' of all non-essential services to curb the spread of COVID-19. Here, we generate ...649 SARS-CoV-2 genome sequences from infected patients in New Zealand with samples collected during the 'first wave', representing 56% of all confirmed cases in this time period. Despite its remoteness, the viruses imported into New Zealand represented nearly all of the genomic diversity sequenced from the global virus population. These data helped to quantify the effectiveness of public health interventions. For example, the effective reproductive number, R
of New Zealand's largest cluster decreased from 7 to 0.2 within the first week of lockdown. Similarly, only 19% of virus introductions into New Zealand resulted in ongoing transmission of more than one additional case. Overall, these results demonstrate the utility of genomic pathogen surveillance to inform public health and disease mitigation.
β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer's disease (AD) and are thought to play crucial roles in a neurodegenerative cascade ...leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients' diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid-PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient's progression and design future clinical trials.
Previous studies have suggested that Plasmodium parasites can manipulate mosquito feeding behaviours such as probing, persistence and engorgement rate in order to enhance transmission success. Here, ...we broaden analysis of this ‘manipulation phenotype’ to consider proximate foraging behaviours, including responsiveness to host odours and host location. Using Anopheles stephensi and Plasmodium yoelii as a model system, we demonstrate that mosquitoes with early stage infections (i.e. non-infectious oocysts) exhibit reduced attraction to a human host, whereas those with late-stage infections (i.e. infectious sporozoites) exhibit increased attraction. These stage-specific changes in behaviour were paralleled by changes in the responsiveness of mosquito odourant receptors, providing a possible neurophysiological mechanism for the responses. However, we also found that both the behavioural and neurophysiological changes could be generated by immune challenge with heat-killed Escherichia coli and were thus not tied explicitly to the presence of malaria parasites. Our results support the hypothesis that the feeding behaviour of female mosquitoes is altered by Plasmodium, but question the extent to which this is owing to active manipulation by malaria parasites of host behaviour.
Abstract
The master regulator in hypoxic cell survival and adaptation is the hypoxia-inducible factor-1 (HIF-1) pathway. Altered HIF-1 regulated gene expression drives a tumour towards a more ...malignant phenotype. HIF-1 is thus a therapeutic target, and small molecule inhibitors such as NSC-134754 are being investigated. Glucose transporter 1 (GLUT-1) is an important downstream target of the HIF-1 pathway, with fundamental roles in intracellular glucose flux and availability. Given the intrinsic role of GLUT-1 in glucose metabolism, the ability of NSC-134754 to evoke a unique metabolic response in vitro and in vivo was investigated.
Human PC3LN5 prostate tumour cells were treated with 7.5µM NSC-134754 and incubated in a humidified hypoxic workstation (1.0% O2) for 24h. Western blot analysis demonstrated a reduction in GLUT-1 expression in treated cells compared to controls. GLUT-1 immunocytofluorescence confirmed control cells exhibited extensive membranous and diffuse cytoplasmic expression compared to treated cells.
Culture media and cell extracts were collected and metabolites analysed using 1H magnetic resonance spectroscopy (MRS). A significant decrease in glucose consumption (p<0.01) and lactate production (p<0.05) in NSC-134754 treated cells compared to control was determined. No significant differences in intracellular lactate concentration were found. However, treatment significantly increased intracellular glucose by >3 fold compared to control cells (p<0.01). Glutamine/glutamate metabolism was also significantly increased in NSC-134754 treated cells (p<0.05).
Mice bearing established (∼1cm diameter) orthotopic PC3LN5 prostate tumours were treated with either 100mg/kg i.p. NSC-134754 (n=4) or vehicle alone (n=5) for 24h. Subsequent semi-quantitative immunohistochemical analyses revealed a significant 28 ± 2% decrease in GLUT-1 membrane expression in the treated tumours compared to controls (p<0.01).
These data suggest that NSC-134754 has a profound effect on glucose metabolism in vitro and in vivo. Treatment of PC3LN5 cells for 24h in hypoxia significantly reduced the expression and distribution of GLUT-1, decreased glucose uptake and reduced lactate production. A reduction in glucose transport and lactate production have been shown to be indicators of response to therapy. The increased uptake and metabolism of glutamine/glutamate may reflect compensatory mechanisms for reduced glycolysis in order to sustain cellular bioenergetics. Interestingly, we have also shown that NSC-134754 increased intracellular glucose accumulation. Many glycolytic enzymes are known gene targets of HIF, thus a reduction in their availability (and hence glycolysis) could lead to glucose trapping. To our knowledge, this is a novel finding of a small molecule inhibitor of the HIF pathway. Increased intracellular glucose with decreased glucose uptake has been reported with other therapeutics in vitro.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4074. doi:10.1158/1538-7445.AM2011-4074
Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale ...neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)–Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group.
We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium.
In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen’s d = −0.17, p = .00054), and smaller amygdalae (d = −0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063).
Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain’s response to trauma.
Corals and the reef ecosystems that they support are in global decline due to increasing anthropogenic pressures such as climate change
. However, effective reef conservation strategies are hampered ...by a limited mechanistic understanding of coral biology and the functional roles of the diverse microbial communities that underpin coral health
. Here, we present an integrated genomic characterization of the coral species Porites lutea and its microbial partners. High-quality genomes were recovered from P. lutea, as well as a metagenome-assembled Cladocopium C15 (the dinoflagellate symbiont) and 52 bacterial and archaeal populations. Comparative genomic analysis revealed that many of the bacterial and archaeal genomes encode motifs that may be involved in maintaining association with the coral host and in supplying fixed carbon, B-vitamins and amino acids to their eukaryotic partners. Furthermore, mechanisms for ammonia, urea, nitrate, dimethylsulfoniopropionate and taurine transformation were identified that interlink members of the holobiont and may be important for nutrient acquisition and retention in oligotrophic waters. Our findings demonstrate the critical and diverse roles that microorganisms play within the coral holobiont and underscore the need to consider all of the components of the holobiont if we are to effectively inform reef conservation strategies.
Suicide is a pressing matter for the military. Not only does it pose a health risk, but suicide also compromises operational readiness. Despite provision of suicide prevention clinical best ...practices, the Department of Defense suffers several challenges (e.g., clinician shortages) limiting the agency's ability to effectively respond to service member suicide. Implementation of evidence-based suicide-specific group therapy is a possible solution to service member well-being needs and system challenges. Service members can also gain coping skills useful beyond managing suicidal thoughts and behaviors.
This 2-arm non-inferiority randomized controlled trial compares a group therapy format of Brief Cognitive Behavioral Therapy (i.e., G-BCBT) with Dialectical Behavior Therapy (DBT) Skills Group. Both therapies are delivered in-person at a United States Naval Medical Center. Participants (N = 136) are active-duty service members with recent suicidal thoughts or suicidal behavior. Evaluation features electronically delivered questionnaires at baseline, after each treatment session, and at 3- and 6-month follow-up.
The primary outcome concerns G-BCBT impacts on suicidal ideation. Secondary outcomes of interest are suicide attempt, psychological distress (e.g., symptoms of depression, anxiety), and self-regulatory skills (e.g., emotion regulation). We also examine self-regulatory skills as treatment moderators. Clinical trial strengths and limitations are reviewed.
This study was registered at Clinicaltrials.gov (protocol NCT05401838).
Oil reservoirs are major sites of methane production and carbon turnover, processes with significant impacts on energy resources and global biogeochemical cycles. We applied a cultivation-independent ...genomic approach to define microbial community membership and predict roles for specific organisms in biogeochemical transformations in Alaska North Slope oil fields. Produced water samples were collected from six locations between 1,128 m (24 to 27°C) and 2,743 m (80 to 83°C) below the surface. Microbial community complexity decreased with increasing temperature, and the potential to degrade hydrocarbon compounds was most prevalent in the lower-temperature reservoirs. Sulfate availability, rather than sulfate reduction potential, seems to be the limiting factor for sulfide production in some of the reservoirs under investigation. Most microorganisms in the intermediate- and higher-temperature samples were related to previously studied methanogenic and nonmethanogenic archaea and thermophilic bacteria, but one candidate phylum bacterium, a member of the Acetothermia (OP1), was present in Kuparuk sample K3. The greatest numbers of candidate phyla were recovered from the mesothermic reservoir samples SB1 and SB2. We reconstructed a nearly complete genome for an organism from the candidate phylum Parcubacteria (OD1) that was abundant in sample SB1. Consistent with prior findings for members of this lineage, the OD1 genome is small, and metabolic predictions support an obligately anaerobic, fermentation-based lifestyle. At moderate abundance in samples SB1 and SB2 were members of bacteria from other candidate phyla, including Microgenomates (OP11), Atribacteria (OP9), candidate phyla TA06 and WS6, and Marinimicrobia (SAR406). The results presented here elucidate potential roles of organisms in oil reservoir biological processes.
The activities of microorganisms in oil reservoirs impact petroleum resource quality and the global carbon cycle. We show that bacteria belonging to candidate phyla are present in some oil reservoirs and provide the first insights into their potential roles in biogeochemical processes based on several nearly complete genomes.
Abstract
Neuroblastoma (NBL) is the most common extracranial solid tumor of childhood, accounting for between 7-10% of paediatric cancers. The proto-oncogene MYCN is amplified in 25% of NBL and is ...associated with high-risk disease, enhanced tumor angiogenesis and poor survival. A genetically-engineered mouse model for high risk, MYCN-amplified NBL has been generated by directing expression of MYCN to the peripheral neural crest of transgenic mice. As part of a multi-parametric MRI study, we have evaluated the native spin-lattice relaxation time T1, sensitive to the ratio of bound to free water in tissue, as a potential noninvasive biomarker of treatment response of TH-MYCN NBL to three different classes of anti-cancer agent.
TH-MYCN mice with abdominal tumors were identified by palpation and imaged prior to and following treatment. Native T1 (ms) was quantified at 7T using an inversion recovery (IR)-trueFISP sequence. In control cohorts, tumor progression over 48 hours and 4 days was associated with no significant change in T1. A single 25mg/kg dose of cylophosphamide, the current standard of care for childhood NBL, caused a significant 54% reduction of tumor volume at 48 hours. Treatment of TH-MYCN NBL with CPM leads to extensive cell death, which occurs primarily through apoptosis, and this response was associated with a highly significant 15% reduction in native T1.
Given the hypervascular nature of NBL, their response to anti-vascular therapies was also investigated. Treatment with the pan VEGF receptor inhibitor cediranib (6mg/kg daily over 2 days) resulted in significant 19% anti-tumor activity and 8% reduction in T1 at 48 hours. Furthermore, this response was associated with a significant reduction in uptake of the perfusion marker Hoechst 33342 compared to control, but no difference in necrosis. Treatment with a single 200mg/kg dose of the colchicine derivative ZD6126 resulted in significant and unprecedented 43% anti-tumor activity at 24 hours, and which was also associated with a significant 14% reduction in native T1. Histology revealed a significant reduction in Hoechst 33342 uptake and extensive tumor necrosis.
Collectively, these data show a systematic reduction of native T1 in the TH-MYCN model with successful chemotherapy. The CPM and ZD6126-induced reduction in T1 is consistent with a histologically confirmed reduction in cell density and increased extravascular space following cytotoxic therapy. The reduction of T1 following treatment with cediranib may be attributable to the resolution of edema caused by reduced vascular permeability.
Accurate quantification of T1 affords a generic noninvasive biomarker for chemotherapy-mediated cell death in the TH-MYCN model. The high sensitivity of T1 will accelerate the pre-clinical evaluation of novel therapeutics for childhood neuroblastoma in this model. Quantitation of native T1 could be easily incorporated into conventional imaging protocols used in clinical trials.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5290. doi:10.1158/1538-7445.AM2011-5290
Gene expression is known to be affected by interactions between local genetic variation and DNA accessibility, with the latter organized into three-dimensional chromatin structures. Analyses of these ...interactions have previously been limited, obscuring their regulatory context, and the extent to which they occur throughout the genome. Here, we undertake a genome-scale analysis of these interactions in a genetically diverse population to systematically identify global genetic-epigenetic interaction, and reveal constraints imposed by chromatin structure. We establish the extent and structure of genotype-by-epigenotype interaction using embryonic stem cells derived from Diversity Outbred mice. This mouse population segregates millions of variants from eight inbred founders, enabling precision genetic mapping with extensive genotypic and phenotypic diversity. With 176 samples profiled for genotype, gene expression, and open chromatin, we used regression modeling to infer genetic-epigenetic interactions on a genome-wide scale. Our results demonstrate that statistical interactions between genetic variants and chromatin accessibility are common throughout the genome. We found that these interactions occur within the local area of the affected gene, and that this locality corresponds to topologically associated domains (TADs). The likelihood of interaction was most strongly defined by the three-dimensional (3D) domain structure rather than linear DNA sequence. We show that stable 3D genome structure is an effective tool to guide searches for regulatory elements and, conversely, that regulatory elements in genetically diverse populations provide a means to infer 3D genome structure. We confirmed this finding with CTCF ChIP-seq that revealed strain-specific binding in the inbred founder mice. In stem cells, open chromatin participating in the most significant regression models demonstrated an enrichment for developmental genes and the TAD-forming CTCF-binding complex, providing an opportunity for statistical inference of shifting TAD boundaries operating during early development. These findings provide evidence that genetic and epigenetic factors operate within the context of 3D chromatin structure.
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