Single-Cell Profiling of Ebola Virus Disease In Vivo Reveals Viral and Host Dynamics.

Ebola virus (EBOV) causes epidemics with high mortality yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. Here, we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cells during EBOV infection in rhesus monkeys. We obtained 100,000 transcriptomes and 15,000,000 protein profiles, finding that immature, proliferative monocyte-lineage cells with reduced antigen-presentation capacity replace conventional monocyte subsets, while lymphocytes upregulate apoptosis genes and decline in abundance. By quantifying intracellular viral RNA, we identify molecular determinants of tropism among circulating immune cells and examine temporal dynamics in viral and host gene expression. Within infected cells, EBOV downregulates STAT1 mRNA and interferon signaling, and it upregulates putative pro-viral genes (e.g., DYNLL1 and HSPA5), nominating pathways the virus manipulates for its replication. This study sheds light on EBOV tropism, replication dynamics, and elicited immune response and provides a framework for characterizing host-virus interactions under maximum containment.

Mot1, Ino80C, and NC2 Function Coordinately to Regulate Pervasive Transcription in Yeast and Mammals.

Pervasive transcription initiates from cryptic promoters and is observed in eukaryotes ranging from yeast to mammals. The Set2-Rpd3 regulatory system prevents cryptic promoter function within expressed genes. However, conserved systems that control pervasive transcription within intergenic regions have not been well established. Here we show that Mot1, Ino80 chromatin remodeling complex (Ino80C), and NC2 co-localize on chromatin and coordinately suppress pervasive transcription in S. cerevisiae and murine embryonic stem cells (mESCs). In yeast, all three proteins bind subtelomeric heterochromatin through a Sir3-stimulated mechanism and to euchromatin via a TBP-stimulated mechanism. In mESCs, the proteins bind to active and poised TBP-bound promoters along with promoters of polycomb-silenced genes apparently lacking TBP. Depletion of Mot1, Ino80C, or NC2 by anchor away in yeast or RNAi in mESCs leads to near-identical transcriptome phenotypes, with new subtelomeric transcription in yeast, and greatly increased pervasive transcription in both yeast and mESCs.

Single-cell RNA sequencing of liver fine-needle aspirates captures immune diversity in the blood and liver in chronic hepatitis B patients.

BACKGROUND AND AIMS: HBV infection is restricted to the liver, where it drives exhaustion of virus-specific T and B cells and pathogenesis through dysregulation of intrahepatic immunity. Our understanding of liver-specific events related to viral control and liver damage has relied almost solely on animal models, and we lack useable peripheral biomarkers to quantify intrahepatic immune activation beyond cytokine measurement. Our objective was to overcome the practical obstacles of liver sampling using fine-needle aspiration and develop an optimized workflow to comprehensively compare the blood and liver compartments within patients with chronic hepatitis B using single-cell RNA sequencing. APPROACH AND RESULTS: We developed a workflow that enabled multi-site international studies and centralized single-cell RNA sequencing. Blood and liver fine-needle aspirations were collected, and cellular and molecular captures were compared between the Seq-Well S 3 picowell-based and the 10× Chromium reverse-emulsion droplet-based single-cell RNA sequencing technologies. Both technologies captured the cellular diversity of the liver, but Seq-Well S 3 effectively captured neutrophils, which were absent in the 10× dataset. CD8 T cells and neutrophils displayed distinct transcriptional profiles between blood and liver. In addition, liver fine-needle aspirations captured a heterogeneous liver macrophage population. Comparison between untreated patients with chronic hepatitis B and patients treated with nucleoside analogs showed that myeloid cells were highly sensitive to environmental changes while lymphocytes displayed minimal differences. CONCLUSIONS: The ability to electively sample and intensively profile the immune landscape of the liver, and generate high-resolution data, will enable multi-site clinical studies to identify biomarkers for intrahepatic immune activity in HBV and beyond.

Modeling the Impact of Substituting Meat and Dairy Products with Plant-Based Alternatives on Nutrient Adequacy and Diet Quality.

BACKGROUND: Novel plant-based meat and dairy alternatives are designed to mimic and replace animal-sourced products, yet their nutritional composition differs from traditional alternatives such as legumes and beans. The nutritional impacts of switching from animal-sourced to traditional or novel plant-based alternatives remains unclear. OBJECTIVES: This study aimed to model the impact of partial and complete substitution of animal-sourced meat and dairy products with traditional or novel plant-based alternatives on diet quality and nutrient adequacy in a nationally representative sample of Australian adults. METHODS: Dietary data (1 24-h recall) from the Australian Health Survey 2011-2013 (n = 9115; ≥19 y) were analyzed. Four models simulated partial or complete substitution of animal-sourced meat and dairy with traditional or novel plant-based alternatives. Diet quality was assessed using the Dietary Guideline Index (DGI), and nutrient adequacy was determined using age- and sex-specific nutrient reference values. Modeled diets were compared to a baseline diet using survey-weighted paired t tests. RESULTS: DGI scores improved by 0.3% to 6.0% for all models across all sex and age groups compared to baseline. Improvements in diet quality were greatest for the complete substitution to traditional alternatives (5.1% average increase in DGI). Overall, inclusion of plant-based alternatives (complete or partial) decreased saturated fat and increased dietary fiber. Long-chain n-3 polyunsaturated fatty acids decreased to below adequate intakes for all complete substitution models. Substitution with traditional alternatives decreased sodium and increased calcium, whereas substitution with novel alternatives increased sodium and decreased calcium. CONCLUSIONS: All models using traditional alternatives, and the partial substitution using novel alternatives, showed small but statistically significant improvements in diet quality. Nutrient adequacy varied between models, with nutrients including saturated fat, sodium, calcium, and long-chain fatty acids implicated. Findings highlight the importance of informed choices when switching to traditional or novel plant-based alternatives to prevent suboptimal dietary intake.

Achieving high diet quality at eating occasions: findings from a nationally representative study of Australian adults.

This study examined differences in food groups consumed at eating occasions by the level of adherence to dietary guidelines in Australian adults (≤19 years) and whether consumption differed with respect to age, sex and education levels. Secondary analysis of the 2011-2012 National Nutrition and Physical Activity Survey (n 9054) was performed, using one 24-h dietary recall with self-reported eating occasions. Dietary Guideline Index scores were used to assess adherence to the 2013 Australian Dietary Guidelines. Mean differences (95 % CI) in servings of the five food groups and discretionary foods at eating occasions were estimated for adults with higher and lower diet quality, stratified by sex, age group and education. Using survey-based t-tests, differences of at least half a serving with P values < 0·05 were considered meaningful. Compared with adults with lower diet quality, women and men aged 19-50 years with higher diet quality consumed more serves of vegetables at dinner (mean difference (95 % CI), women; 1·0; 95 % CI (0·7, 1·2); men: 0·9; 95 % CI (0·6, 1·3)) and fewer serves of discretionary foods at snacks (women: -0·7; 95 % CI (-0·9, -0·5); men: -1·0; 95 % CI (-1·4, -0·7). Other food groups, such as grains, dairy products and alternatives, meats and alternatives, were not significantly different between adults with lower and higher diet quality, across any eating occasions and age groups. Discretionary food intake at lunch, dinner and snacks was consistently greater among adults with lower diet quality, regardless of education level. Our findings identify dinner and snacks as opportunities to increase vegetable intake and reduce discretionary food intake, respectively.

Frontostriatothalamic effective connectivity and dopaminergic function in the psychosis continuum.

Dysfunction of fronto-striato-thalamic (FST) circuits is thought to contribute to dopaminergic dysfunction and symptom onset in psychosis, but it remains unclear whether this dysfunction is driven by aberrant bottom-up subcortical signalling or impaired top-down cortical regulation. We used spectral dynamic causal modelling of resting-state functional MRI to characterize the effective connectivity of dorsal and ventral FST circuits in a sample of 46 antipsychotic-naïve first-episode psychosis patients and 23 controls and an independent sample of 36 patients with established schizophrenia and 100 controls. We also investigated the association between FST effective connectivity and striatal 18F-DOPA uptake in an independent healthy cohort of 33 individuals who underwent concurrent functional MRI and PET. Using a posterior probability threshold of 0.95, we found that midbrain and thalamic connectivity were implicated as dysfunctional across both patient groups. Dysconnectivity in first-episode psychosis patients was mainly restricted to the subcortex, with positive symptom severity being associated with midbrain connectivity. Dysconnectivity between the cortex and subcortical systems was only apparent in established schizophrenia patients. In the healthy 18F-DOPA cohort, we found that striatal dopamine synthesis capacity was associated with the effective connectivity of nigrostriatal and striatothalamic pathways, implicating similar circuits to those associated with psychotic symptom severity in patients. Overall, our findings indicate that subcortical dysconnectivity is evident in the early stages of psychosis, that cortical dysfunction may emerge later in the illness, and that nigrostriatal and striatothalamic signalling are closely related to striatal dopamine synthesis capacity, which is a robust marker for psychosis.

Developmental arrest of Drosophila larvae elicits presynaptic depression and enables prolonged studies of neurodegeneration.

Synapses exhibit an astonishing degree of adaptive plasticity in healthy and disease states. We have investigated whether synapses also adjust to life stages imposed by novel developmental programs for which they were never molded by evolution. Under conditions in which Drosophila larvae are terminally arrested, we have characterized synaptic growth, structure and function at the neuromuscular junction (NMJ). Although wild-type larvae transition to pupae after 5 days, arrested third instar (ATI) larvae persist for 35 days, during which time NMJs exhibit extensive overgrowth in muscle size, presynaptic release sites and postsynaptic glutamate receptors. Remarkably, despite this exuberant growth, stable neurotransmission is maintained throughout the ATI lifespan through a potent homeostatic reduction in presynaptic neurotransmitter release. Arrest of the larval stage in stathmin mutants also reveals a degree of progressive instability and neurodegeneration that was not apparent during the typical larval period. Hence, an adaptive form of presynaptic depression stabilizes neurotransmission during an extended developmental period of unconstrained synaptic growth. More generally, the ATI manipulation provides a powerful system for studying neurodegeneration and plasticity across prolonged developmental timescales.

Developing and validating a multi-criteria decision analytic tool to assess the value of cancer clinical trials: evaluating cancer clinical trial value.

BACKGROUND: Demonstrating safety and efficacy of new medical treatments requires clinical trials but clinical trials are costly and may not provide value proportionate to their costs. As most health systems have limited resources, it is therefore important to identify the trials with the highest value. Tools exist to assess elements of a clinical trial such as statistical validity but are not wholistic in their valuation of a clinical trial. This study aims to develop a measure of clinical trials value and provide an online tool for clinical trial prioritisation. METHODS: A search of the academic and grey literature and stakeholder consultation was undertaken to identify a set of criteria to aid clinical trial valuation using multi-criteria decision analysis. Swing weighting and ranking exercises were used to calculate appropriate weights of each of the included criteria and to estimate the partial-value function for each underlying metric. The set of criteria and their respective weights were applied to the results of six different clinical trials to calculate their value. RESULTS: Seven criteria were identified: 'unmet need', 'size of target population', 'eligible participants can access the trial', 'patient outcomes', 'total trial cost', 'academic impact' and 'use of trial results'. The survey had 80 complete sets of responses (51% response rate). A trial designed to address an 'Unmet Need' was most commonly ranked as the most important with a weight of 24.4%, followed by trials demonstrating improved 'Patient Outcomes' with a weight of 21.2%. The value calculated for each trial allowed for their clear delineation and thus a final value ranking for each of the six trials. CONCLUSION: We confirmed that the use of the decision tool for valuing clinical trials is feasible and that the results are face valid based on the evaluation of six trials. A proof-of-concept applying this tool to a larger set of trials with an external validation is currently underway.

The Ino80 complex prevents invasion of euchromatin into silent chromatin.

Here we show that the Ino80 chromatin remodeling complex (Ino80C) directly prevents euchromatin from invading transcriptionally silent chromatin within intergenic regions and at the border of euchromatin and heterochromatin. Deletion of Ino80C subunits leads to increased H3K79 methylation and noncoding RNA polymerase II (Pol II) transcription centered at the Ino80C-binding sites. The effect of Ino80C is direct, as it blocks H3K79 methylation by Dot1 in vitro. Heterochromatin stimulates the binding of Ino80C in vitro and in vivo. Our data reveal that Ino80C serves as a general silencing complex that restricts transcription to gene units in euchromatin.

Mechanism for epigenetic variegation of gene expression at yeast telomeric heterochromatin.

Yeast contains heterochromatin at telomeres and the silent mating-type loci (HML/HMR). Genes positioned within the telomeric heterochromatin of Saccharomyces cerevisiae switch stochastically between epigenetically bistable ON and OFF expression states. Important aspects of the mechanism of variegated gene expression, including the chromatin structure of the natural ON state and the mechanism by which it is maintained, are unknown. To address this issue, we developed approaches to select cells in the ON and OFF states. We found by chromatin immunoprecipitation (ChIP) that natural ON telomeres are associated with Rap1 binding and, surprisingly, also contain known characteristics of OFF telomeres, including significant amounts of Sir3 and H4K16 deacetylated nucleosomes. Moreover, we found that H3K79 methylation (H3K79me), H3K4me, and H3K36me, which are depleted from OFF telomeres, are enriched at ON telomeres. We demonstrate in vitro that H3K79me, but not H3K4me or H3K36me, disrupts transcriptional silencing. Importantly, H3K79me does not significantly reduce Sir complex binding in vivo or in vitro. Finally, we show that maintenance of H3K79me at ON telomeres is dependent on transcription. Therefore, although Sir proteins are required for silencing, we propose that epigenetic variegation of telomeric gene expression is due to the bistable enrichment/depletion of H3K79me and not the fluctuation in the amount of Sir protein binding to nucleosomes.

Mediator coordinates PIC assembly with recruitment of CHD1.

Murine Chd1 (chromodomain helicase DNA-binding protein 1), a chromodomain-containing chromatin remodeling protein, is necessary for embryonic stem (ES) cell pluripotency. Chd1 binds to nucleosomes trimethylated at histone 3 Lys 4 (H3K4me3) near the beginning of active genes but not to bivalent domains also containing H3K27me3. To address the mechanism of this specificity, we reproduced H3K4me3- and CHD1-stimulated gene activation in HeLa extracts. Multidimensional protein identification technology (MuDPIT) and immunoblot analyses of purified preinitiation complexes (PICs) revealed the recruitment of CHD1 to naive chromatin but enhancement on H3K4me3 chromatin. Studies in depleted extracts showed that the Mediator coactivator complex, which controls PIC assembly, is also necessary for CHD1 recruitment. MuDPIT analyses of CHD1-associated proteins support the recruitment data and reveal numerous components of the PIC, including Mediator. In vivo, CHD1 and Mediator are recruited to an inducible gene, and genome-wide binding of the two proteins correlates well with active gene transcription in mouse ES cells. Finally, coimmunoprecipitation of CHD1 and Mediator from cell extracts can be ablated by shRNA knockdown of a specific Mediator subunit. Our data support a model in which the Mediator coordinates PIC assembly along with the recruitment of CHD1. The combined action of the PIC and H3K4me3 provides specificity in targeting CHD1 to active genes.

lolal Is an Evolutionarily New Epigenetic Regulator of dpp Transcription during Dorsal-Ventral Axis Formation.

Secreted ligands in the Dpp/BMP family drive dorsal-ventral (D/V) axis formation in all Bilaterian species. However, maternal factors regulating Dpp/BMP transcription in this process are largely unknown. We identified the BTB domain protein longitudinals lacking-like (lolal) as a modifier of decapentaplegic (dpp) mutations. We show that Lolal is evolutionarily related to the Trithorax group of chromatin regulators and that lolal interacts genetically with the epigenetic factor Trithorax-like during Dpp D/V signaling. Maternally driven Lolal(HA) is found in oocytes and translocates to zygotic nuclei prior to the point at which dpp transcription begins. lolal maternal and zygotic mutant embryos display significant reductions in dpp, pMad, and zerknullt expression, but they are never absent. The data suggest that lolal is required to maintain dpp transcription during D/V patterning. Phylogenetic data revealed that lolal is an evolutionarily new gene present only in insects and crustaceans. We conclude that Lolal is the first maternal protein identified with a role in dpp D/V transcriptional maintenance, that Lolal and the epigenetic protein Trithorax-like are essential for Dpp D/V signaling and that the architecture of the Dpp D/V pathway evolved in the arthropod lineage after the separation from vertebrates via the incorporation of new genes such as lolal.

The impact of extensive loss of telecommunications on general practice: A case study in rural Victoria.

OBJECTIVE: To describe the impact of major loss of telecommunications on general practice in a rural region of Australia. DESIGN: A multi-stage qualitative study. Purposively selected participants were invited to contribute to initial data collection using an online survey, followed by interviews with selected participants. Thematic analysis of the data was performed by both research team members. SETTING: South-western Victoria, Australia. PARTICIPANTS: Individuals from organisations involved in Telstra recovery efforts, disaster management, health care and general practice staff. MAIN OUTCOME MEASURES: The survey collected freeform responses from participants. Semi-structured interviews further explored a variety of experiences from purposively selected participants. RESULTS: Organisations and practices in the region were prepared for major disasters, but not for the unusual and 'limited' disaster of losing telecommunications, including lack of Internet access and loss of telephone services. Although alternative measures were found for telecommunications, there was still a significant impact on many health-care-related activities and general practice functionality during the outage period. In particular, there was an increase in duties for administrative staff to compensate for loss of telecommunications. Patient traffic for many services decreased due to uncertainty about availability and continuation of business. CONCLUSIONS: The Warrnambool outage could be used as a case study illustrating the dramatic impact of communication loss. Major impacts include changes in patient traffic, increased administrative duties and slowing of patient care. When developing or assessing disaster management plans, general practices should consider the impact of telecommunication loss on functionality and prepare appropriate alternative, accessible and reliable measures.

Histone density is maintained during transcription mediated by the chromatin remodeler RSC and histone chaperone NAP1 in vitro.

ATPases and histone chaperones facilitate RNA polymerase II (pol II) elongation on chromatin. In vivo, the coordinated action of these enzymes is necessary to permit pol II passage through a nucleosome while restoring histone density afterward. We have developed a biochemical system recapitulating this basic process. Transcription through a nucleosome in vitro requires the ATPase remodels structure of chromatin (RSC) and the histone chaperone nucleosome assembly protein 1 (NAP1). In the presence of NAP1, RSC generates a hexasome. Despite the propensity of RSC to evict histones, NAP1 reprograms the reaction such that the hexasome is retained on the template during multiple rounds of transcription. This work has implications toward understanding the mechanism of pol II elongation on chromatin.

Patient reminder systems and asthma medication adherence: a systematic review.

OBJECTIVE: One of the most common reasons for medication non-adherence for asthma patients is forgetfulness. Daily medication reminder system interventions in the form of text messages, automated phone calls and audiovisual reminder devices can potentially address this problem. The aim of this review was to assess the effectiveness of reminder systems on patient daily asthma medication adherence. METHODS: We conducted a systematic review of the literature to identify randomized controlled trials (RCTs) which assessed the effect of reminder systems on daily asthma medication adherence. We searched all English-language articles in Pub Med (MEDLINE), CINAHL, EMBASE, PsychINFO and the Cochrane Library through May 2013. We abstracted data on the year of study publication, location, inclusion and exclusion criteria, patient characteristics, reminder system characteristics, effect on patient adherence rate and other outcomes measured. Descriptive statistics were used to summarize the characteristics and results of the studies. RESULTS: Five RCTs and one pragmatic RCT were included in the analysis. Median follow-up time was 16 weeks. All of the six studies suggested that the reminder system intervention was associated with greater levels of participant asthma medication adherence compared to those participants in the control group. None of the studies documented a change in asthma-related quality of life or clinical asthma outcomes. CONCLUSION: All studies in our analysis suggest that reminder systems increase patient medication adherence, but none documented improved clinical outcomes. Further studies with longer intervention durations are needed to assess effects on clinical outcomes, as well as the sustainability of effects on patient adherence.

Utility of 30-day mortality as a quality metric for palliative radiation treatment: A population-based analysis from Queensland, Australia.

INTRODUCTION: Palliative radiotherapy (PRT) is frequently used to treat symptoms of advanced cancer, however benefits are questionable when life expectancy is limited. The 30-day mortality rate after PRT is a potential quality indicator, and results from a recent meta-analysis suggest a benchmark of 16% as an upper limit. In this population-based study from Queensland, Australia, we examined 30-day mortality rates following PRT and factors associated with decreased life expectancy. METHODS: Retrospective population data from Queensland Oncology Repository was used. Study population data included 22,501 patients diagnosed with an invasive cancer who died from any cause between 2008 and 2017 and had received PRT. Thirty-day mortality rates were determined from the date of last PRT fraction to date of death. Cox proportional hazards models were used to identify factors independently associated with risk of death within 30 days of PRT. RESULTS: Overall 30-day mortality after PRT was 22.2% with decreasing trend in more recent years (P = 0.001). Male (HR = 1.20, 95% CI = 1.13-1.27); receiving 5 or less radiotherapy fractions (HR = 2.97, 95% CI = 2.74-3.22 and HR = 2.17, 95% CI = 2.03-2.32, respectively) and receiving PRT in a private compared to public facility (HR = 1.61, 95% CI = 1.51-1.71) was associated with decreased survival. CONCLUSION: The 30-day mortality rate in Queensland following PRT is higher than expected and there is scope to reduce unnecessarily protracted treatment schedules. We encourage other Australian and New Zealand centres to examine and report their own 30-day mortality rate following PRT and would support collaboration for 30-day mortality to become a national and international quality metric for radiation oncology centres.

A scalable synthesis of adjuvanting antigen depots based on metal-organic frameworks.

Vaccines have saved countless lives by preventing and even irradicating infectious diseases. Commonly used subunit vaccines comprising one or multiple recombinant proteins isolated from a pathogen demonstrate a better safety profile than live or attenuated vaccines. However, the immunogenicity of these vaccines is weak, and therefore, subunit vaccines require a series of doses to achieve sufficient immunity against the pathogen. Here, we show that the biomimetic mineralization of the inert model antigen, ovalbumin (OVA), in zeolitic imidazolate framework-8 (ZIF-8) significantly improves the humoral immune response over three bolus doses of OVA (OVA 3×). Encapsulation of OVA in ZIF-8 (OVA@ZIF) demonstrated higher serum antibody titers against OVA than OVA 3×. OVA@ZIF vaccinated mice displayed higher populations of germinal center (GC) B cells and IgG1+ GC B cells as opposed to OVA 3×, indicative of class-switching recombination. We show that the mechanism of this phenomenon is at least partly owed to the metalloimmunological effects of the zinc metal as well as the sustained release of OVA from the ZIF-8 composite. The system acts as an antigen reservoir for antigen-presenting cells to traffic into the draining lymph node, enhancing the humoral response. Lastly, our model system OVA@ZIF is produced quickly at the gram scale in a laboratory setting, sufficient for up to 20 000 vaccine doses.

The gut microbiome regulates the clinical efficacy of sulfasalazine therapy for IBD-associated spondyloarthritis.

Sulfasalazine is a prodrug known to be effective for the treatment of inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA), but the mechanistic role for the gut microbiome in regulating its clinical efficacy is not well understood. Here, treatment of 22 IBD-pSpA subjects with sulfasalazine identifies clinical responders with a gut microbiome enriched in Faecalibacterium prausnitzii and the capacity for butyrate production. Sulfapyridine promotes butyrate production and transcription of the butyrate synthesis gene but in F. prausnitzii in vitro, which is suppressed by excess folate. Sulfasalazine therapy enhances fecal butyrate production and limits colitis in wild-type and gnotobiotic mice colonized with responder, but not non-responder, microbiomes. F. prausnitzii is sufficient to restore sulfasalazine protection from colitis in gnotobiotic mice colonized with non-responder microbiomes. These findings reveal a mechanistic link between the efficacy of sulfasalazine therapy and the gut microbiome with the potential to guide diagnostic and therapeutic approaches for IBD-pSpA.

CanVaxKB: a web-based cancer vaccine knowledgebase.

Cancer vaccines have been increasingly studied and developed to prevent or treat various types of cancers. To systematically survey and analyze different reported cancer vaccines, we developed CanVaxKB (https://violinet.org/canvaxkb), the first web-based cancer vaccine knowledgebase that compiles over 670 therapeutic or preventive cancer vaccines that have been experimentally verified to be effective at various stages. Vaccine construction and host response data are also included. These cancer vaccines are developed against various cancer types such as melanoma, hematological cancer, and prostate cancer. CanVaxKB has stored 263 genes or proteins that serve as cancer vaccine antigen genes, which we have collectively termed 'canvaxgens'. Top three mostly used canvaxgens are PMEL, MLANA and CTAG1B, often targeting multiple cancer types. A total of 193 canvaxgens are also reported in cancer-related ONGene, Network of Cancer Genes and/or Sanger Cancer Gene Consensus databases. Enriched functional annotations and clusters of canvaxgens were identified and analyzed. User-friendly web interfaces are searchable for querying and comparing cancer vaccines. CanVaxKB cancer vaccines are also semantically represented by the community-based Vaccine Ontology to support data exchange. Overall, CanVaxKB is a timely and vital cancer vaccine source that facilitates efficient collection and analysis, further helping researchers and physicians to better understand cancer mechanisms.

Excess glutamate release triggers subunit-specific homeostatic receptor scaling.

Ionotropic glutamate receptors (GluRs) are targets for modulation in Hebbian and homeostatic synaptic plasticity and are remodeled by development, experience, and disease. We have probed the impact of synaptic glutamate levels on the two postsynaptic GluR subtypes at the Drosophila neuromuscular junction, GluRA and GluRB. We first demonstrate that GluRA and GluRB compete to establish postsynaptic receptive fields, and that proper GluR abundance and composition can be orchestrated in the absence of any synaptic glutamate release. However, excess glutamate adaptively tunes postsynaptic GluR abundance, echoing GluR scaling observed in mammalian systems. Furthermore, when GluRA vs. GluRB competition is eliminated, GluRB becomes insensitive to glutamate modulation. In contrast, GluRA is now homeostatically regulated by excess glutamate to maintain stable miniature activity, where Ca2+ permeability through GluRA receptors is required. Thus, excess glutamate, GluR competition, and Ca2+ signaling collaborate to selectively target GluR subtypes for homeostatic regulation at postsynaptic compartments.