Rocaglates induce gain-of-function alterations to eIF4A and eIF4F

Rocaglates are a diverse family of biologically active molecules that have gained tremendous interest in recent years due to their promising activities in pre-clinical cancer studies. As a result, this family of compounds has been significantly expanded through the development of efficient synthetic schemes. However, it is unknown whether all of the members of the rocaglate family act through similar mechanisms of action. Here, we present a comprehensive study comparing the biological activities of >200 rocaglates to better understand how the presence of different chemical entities influences their biological activities. Through this, we find that most rocaglates preferentially repress the translation of mRNAs containing purine-rich 5' leaders, but certain rocaglates lack this bias in translation repression. We also uncover an aspect of rocaglate mechanism of action in which the pool of translationally active eIF4F is diminished due to the sequestration of the complex onto RNA.P50 GM067041 - NIGMS NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHSPublished versio

Council of Academic Public Health Institutions Australasia, Public health education for a sustainable future ‘Call to Action’, 2021

The leadership role of public health professionals in fields such as environmental health, health promotion, epidemiology and public health medicine has never been more critical. The multidimensional health effects of climate change and more recent disruption caused by the COVID-19 pandemic have exacerbated existing global health and education inequities and undermined progress towards the 2030 United Nations’ Sustainable Development Goals (SDGs). Public health educators are responsible for shaping the knowledge, skills and qualities of their graduates, and supporting professionals from all sectors to respond to the heightened complexity and urgency of the challenges society faces. We need to do this in a dynamic environment characterised by reduced government funding, fluctuating enrolment patterns, digital transformation, the need for learners to be prepared for multiple career pathways, and a societal imperative to address both inter- and intragenerational inequity. Closing health and wellbeing outcome gaps between Indigenous and non-Indigenous communities is a prevailing public health priority across Australasia

Long-Term Cryogenic Propellant Storage for the TOPS Mission

Cryogenic propellants such as liquid hydrogen (LH2) and liquid oxygen (LOX) can dramatically enhance NASAs ability to explore the solar system because of their superior specific impulse (Isp) capability. Although these cryogenic propellants can be challenging to manage and store, they allow significant mass advantages over traditional hypergolic propulsion systems and are therefore technically enabling for many planetary science missions. New cryogenic storage techniques such as subcooling and the use of advanced insulation and low thermal conductivity support structures will allow for the long term storage and use of cryogenic propellants for solar system exploration and hence allow NASA to deliver more payloads to targets of interest, launch on smaller and less expensive launch vehicles, or both. Employing cryogenic propellants will allow NASA to perform missions to planetary destinations that would not be possible with the use of traditional hypergolic propellants. These new cryogenic storage technologies were implemented in a design study for the Titan Orbiter Polar Surveyor (TOPS) mission, with LH2 and LOX as propellants, and the resulting spacecraft design was able to achieve a 43 launch mass reduction over a TOPS mission, that utilized a conventional hypergolic propulsion system with mono-methyl hydrazine (MMH) and nitrogen tetroxide (NTO) propellants. This paper describes the cryogenic propellant storage design for the TOPS mission and demonstrates how these cryogenic propellants are stored passively for a decade-long Titan mission

Long-Term Cryogenic Propellant Storage for the Titan Orbiter Polar Surveyor (TOPS) Mission

Cryogenic propellants such as liquid hydrogen (LH2) and liquid oxygen (LOX) can dramatically enhance NASAs ability to explore the solar system because of their superior specific impulse (Isp) capability. Although these cryogenic propellants can be challenging to manage and store, they allow significant mass advantages over traditional hypergolic propulsion systems and are therefore technically enabling for many planetary science missions. New cryogenic storage techniques such as subcooling and the use of advanced insulation and low thermal conductivity support structures will allow for the long term storage and use of cryogenic propellants for solar system exploration and hence allow NASA to deliver more payloads to targets of interest, launch on smaller and less expensive launch vehicles, or both. Employing cryogenic propellants will allow NASA to perform missions to planetary destinations that would not be possible with the use of traditional hypergolic propellants. These new cryogenic storage technologies were implemented in a design study for the Titan Orbiter Polar Surveyor (TOPS) mission, with LH2 and LOX as propellants, and the resulting spacecraft design was able to achieve a 43 launch mass reduction over a TOPS mission, that utilized a conventional hypergolic propulsion system with mono-methyl hydrazine (MMH) and nitrogen tetroxide (NTO) propellants. This paper describes the cryogenic propellant storage design for the TOPS mission and demonstrates how these cryogenic propellants are stored passively for a decade-long Titan mission

Cryogenic Propulsion for the Titan Orbiter Polar Surveyor

Liquid hydrogen (LH2) and liquid oxygen (LO2) cryogenic propellants can dramatically enhance NASA sability to explore the solar system due to their superior specific impulse (Isp) capability. Although these cryogenic propellants can be challenging to manage and store, they allow significant mass advantages over traditional hypergolic propulsion systems and are therefore enabling for many planetary science missions. New cryogenic storage techniques such as sub-cooling and the use of advanced insulation and low thermal conductivity support structures will allow for the long term storage and use of cryogenic propellants for solar system exploration and hence allow NASA to deliver more payloads to targets of interest, launch on smaller and less expensive launch vehicles, or both. These new cryogenic storage technologies were implemented in a design study for the Titan Orbiter Polar Surveyor (TOPS) mission, with LH2 and LO2 as propellants, and the resulting spacecraft design was able to achieve a 43 launch mass reduction over a TOPS mission, that utilized a traditional hypergolic propulsion system with monomethylhydrazine (MMH) and nitrogen tetroxide (NTO) propellants. This paper describes the cryogenic propellant storage design for the TOPS mission and demonstrates how these cryogenic propellants are stored passively for a decade-long Titan mission that requires the cryogenics propellants to be stored for 8.5 years

Modelling spatiotemporal trends in the frequency of genetic mutations conferring insecticide target-site resistance in African mosquito malaria vector species

Background Resistance in malaria vectors to pyrethroids, the most widely used class of insecticides for malaria vector control, threatens the continued efficacy of vector control tools. Target-site resistance is an important genetic resistance mechanism caused by mutations in the voltage-gated sodium channel (Vgsc) gene that encodes the pyrethroid target-site. Understanding the geographic distribution of target-site resistance, and temporal trends across different vector species, can inform strategic deployment of vector control tools. Results We develop a Bayesian statistical spatiotemporal model to interpret species-specific trends in the frequency of the most common resistance mutations, Vgsc-995S and Vgsc- 995F, in three major malaria vector species Anopheles gambiae, An. coluzzii, and An. arabiensis over the period 2005-2017. The models are informed by 2418 observations of the frequency of each mutation in field sampled mosquitoes collected from 27 countries spanning western and eastern regions of Africa. For nine selected countries, we develop annual predictive maps which reveal geographically-structured patterns of spread of each mutation at regional and continental scales. The results show associations, as well as stark differences, in spread dynamics of the two mutations across the three vector species. The coverage of ITNs was an influential predictor of Vgsc allele frequencies, with modelled relationships between ITN coverage and allele frequencies varying across species and geographic regions. We found that our mapped Vgsc allele frequencies are a significant partial predictor of phenotypic resistance to the pyrethroid deltamethrin in An. gambiae complex populations. Conclusions Our predictive maps show how spatiotemporal trends in insecticide target-site resistance mechanisms in African An. gambiae vary across individual vector species and geographic regions. Molecular surveillance of resistance mechanisms will help to predict resistance phenotypes and track their spread

An Early Biomarker Algorithm Predicts Lethal Graft-Vs-Host Disease and Survival after Allogeneic Hematopoietic Cell Transplantation

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Biomarkers Predict Graft-Vs-Host Disease Outcomes Better Than Clinical Response after One Week of Treatment

Abstract Graft-versus-host disease (GVHD), the primary cause of non-relapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation, does not always respond to treatment with high dose systemic corticosteroids. We have recently shown that a combination of three biomarkers (TNFR1, ST2, and REG3α) measured at onset of GVHD can predict day 28 response to treatment and 6-month NRM (Levine, Lancet Haem, 2015). Our goal in the current study was to determine if the same biomarker-based Ann Arbor GVHD algorithm can alsopredict treatment response andmortality whenapplied after one week of systemic corticosteroid treatment. The study population consisted of 378 patients (pts) with acute GVHD from 11 centers in the Mount Sinai Acute GVHD International Consortium. All pts were treated with systemic steroids and provided a plasma or serum sample obtained after one week of treatment (±3 days). The median starting dose of systemic steroids for Grade II-IV GVHD was 2.0 mg/kg/day and for Grade I was 1.0 mg/kg/day, after which treatment varied. Patients were divided into test (n=236) and validation (n=142) cohorts. We applied the Ann Arbor GVHD algorithm to concentrations of TNFR1, ST2, and REG3α measured after one week of treatment to generate a predicted probability of 6-month NRM, which we term the treatment score (TS). We employed unsupervised k-medoidclustering to partition TS values from the test cohort into two groups (high and low). This unbiased approach identified a high score group made up of 25% of pts (n=58) in the test cohort. We observed that the day 28 response rate (complete, CR + partial, PR) was significantly lower in pts with high scores compared to low scores in the test cohort (24% vs 65%, p<0.0001) (Fig 1A). Analysis of the validation cohort using the same TS definitions showed similar differences in response rates (22% vs 61%, p<0.0001) (Fig 1B). Further, nearly four times as many pts with high scores in both cohorts died within 6 months from non-relapse causes compared to pts with low scores (test: 57% vs 17%, p<0.0001; validation: 57% vs 14%, p<0.0001) (Fig 1C/D). As expected, the majority of non-relapse deaths in pts treated for GVHD were directly attributable to GVHD (test: 95%; validation: 89%). Relapse rates for high and low score pts were similar (data not shown), and thus pts with a high TS experienced significantly worse overall survival in both cohorts (test: 37% vs 72%, p<0.0001; validation: 38% vs 79%, p<0.0001) (Fig 1E/F). Approximately half of the pts in each cohort (test: 48%; validation: 44%) responded (CR+PR) to the first week of steroids and these ptshad significantly lower 6-month NRM than non-responders (NR) (test: 17% vs 36%, p=0.0002; validation: 13% vs 36%, p=0.0014). Yet the TS continued to stratify mortality risk independently of clinical response. In the test cohort, pts with a high score comprised 16% of all early responders and experienced more than twice the NRM of early responders with a low score (33% vs 13%, p=0.022) (Fig 2A). Conversely, test cohort pts who did not respond by day 7, but had a low score, fared much better than non-responders with a high score (NRM 21% vs 68%, p<0.0001) (Fig 2B). Two thirds of early non-responders comprised this more favorable group. These highly significant results reproduced in the independent validation cohort in similar proportions (CR+PR: 45% vs 6%, p=0.0003; NR: 61% vs 22%, p=0.0001) (Fig 2C/D). Finally, a subset analysis revealed that pts classified as NR after one week of steroids due to isolated, yet persistent, grade I skin GVHD (24/378, 6%) overwhelmingly had low treatment scores (22/24, 92%) and experienced rates of NRM (9%) comparable to responders with low scores, thus forming a distinct, albeit small, subset of pts with non-responsive GVHD that fares particularly well (Fig 3). In conclusion, a treatment score based on three GVHD biomarkers measured after one week of steroids stratifies pts into two groups with distinct risks for treatment failure and 6-month NRM. It is particularly noteworthy that the TS identifies two subsets of pts with steroid refractory (SR) GVHD who have highly different outcomes (Fig 2B/D). The much larger group, approximately two thirds of all SR pts, may not need the same degree of treatment escalation as is traditional for clinical non-response, and thus overtreatment might be avoided. Because the TSis measured at a common decision making time point, it may prove useful to guide risk-adapted therapy. Disclosures Mielke: Novartis: Consultancy; MSD: Consultancy, Other: Travel grants; Celgene: Other: Travel grants, Speakers Bureau; Gilead: Other: Travel grants; JAZZ Pharma: Speakers Bureau. Kroeger:Novartis: Honoraria, Research Funding. Chen:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Jagasia:Therakos: Consultancy. Kitko:Therakos: Honoraria, Speakers Bureau. Ferrara:Viracor: Patents & Royalties: GVHD biomarker patent. Levine:Viracor: Patents & Royalties: GVHD biomarker patent

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts