Miracle-dz/UniFAR-FTUs huggingface dataset:
Gilteritinib Inhibits Glutamine Uptake and Utilization in FLT3-ITD–Positive AML

Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy associated with frequent relapse and poor overall survival. The tyrosine kinase inhibitor gilteritinib is approved for the treatment of relapse/refractory AML with FLT3 mutations, yet its mechanism of action is not completely understood. Here, we sought to identify additional therapeutic targets that can be exploited to enhance gilteritinib's antileukemic effect. Based on unbiased transcriptomic analyses, we identified the glutamine transporter SNAT1 (SLC38A1) as a novel target of gilteritinib that leads to impaired glutamine uptake and utilization within leukemic cells. Using metabolomics and metabolic flux analyses, we found that gilteritinib decreased glutamine metabolism through the TCA cycle and cellular levels of the oncometabolite 2-hydroxyglutarate. In addition, gilteritinib treatment was associated with decreased ATP production and glutathione synthesis and increased reactive oxygen species, resulting in cellular senescence. Finally, we found that the glutaminase inhibitor CB-839 enhanced antileukemic effect of gilteritinib in ex vivo studies using human primary FLT3-ITD–positive AML cells harboring mutations in the enzyme isocitrate dehydrogenase, which catalyzes the oxidative decarboxylation of isocitrate, producing α-ketoglutarate. Collectively, this work has identified a previously unrecognized, gilteritinib-sensitive metabolic pathway downstream of SLC38A1 that causes decreased glutaminolysis and disruption of redox homeostasis. These findings provide a rationale for the development and therapeutic exploration of targeted combinatorial treatment strategies for this subset of relapse/refractory AML.
Oyster Recruitment and Persistence on Planted Versus Native Substrate over 13 Year in the Delaware Bay Oyster Fishery Resource

ABSTRACT Shell planting to enhance oyster recruitment and habitat in Delaware Bay, NJ was reinitiated in 2005 with 3 y of federal funding. Since then, annual plantings of locally available surf clam and ocean quahog shell have been funded by the oyster fishery. The cured shell is deployed directly onto sites already containing commercially viable numbers of market-sized oysters in areas that are routinely fished sustainably. The locations targeted to receive shell plants vary and are selected to provide the greatest benefit throughout the fished reef tract. Annual sampling that included shell plants from 2005 through 2017 permitted evaluation of their performance. New oysters set and survive preferentially on newly planted shell during the first season and later at the same level as native shell for at least 10 y so that the benefit of once-added shell is retained for over a decade. Recruitment to shell plants enhances “good” sets and makes a critical difference during years of “poor” set. Plant substrate, now with oysters of its own, significantly outperforms native substrate in recruitment and survival of oysters in the second and third years post-planting, with enhancement declining exponentially over the first 4 y. An estimated half-life for this decline is just under 1 y. Beyond 3 y, the plant-based substrate continues to perform at least as well as native substrate. Size–frequency analysis shows that first-year oysters on planted substrate are larger than those on native substrate and that this difference carries through the fourth year of a plant. The volume contributed by live and dead oysters on planted substrate increases over the first 5 y until the contribution to the reef from planted substrate volume matches that of native substrate, thus carrying the enhancement forward through time. Annual survey data from the first 4 y of shell plants show that on seven of eight beds, live plus dead oyster density (number m–2) was up to 2.8× greater on planted sites than on non-planted sites. Change in density averaged positive over time on both planted and non-planted sites but was greater on planted sites. Shell plants on beds in the Delaware Bay fishery provide 3–4 y of enhanced oyster productivity and continue to double the local native substrate productivity as they age, maintaining an active and productive fishery.
Nutrient dynamics and production performance of Shaver White laying hens housed in either enriched or conventional cage systems over an entire production cycle

The current data provide estimates of the flow of nitrogen (N), calcium (Ca) and phosphorus (P) in Shaver White layers housed under conventional cage (CC) and enriched cage (EC) systems from 19 to 63 wks of age. The experiment was conducted at the University of Manitoba poultry unit. Both feed disappearance (P < 0.01) (92.5 vs. 95.0 ± 0.6 g/hen/d, DM basis) and manure output (P < 0.01) (79.8 vs. 91.3 ± 1.2 g/hen/d, fresh basis and 27.0 vs. 28.1 ± 0.2 g/hen/d, DM basis) were lower in hens housed in EC compared to CC. Manure DM was 34.1 and 31.0 ± 0.3% for EC and CC, respectively. Feed conversion ratio; body weight; and egg production, weight and mass were not significantly different between the two systems. Although there was no difference in the overall manure N (EC: 1.94 vs. CC: 1.96 ± 0.02 g/hen/d, respectively), N balance was greater (P < 0.05) for the CC compared to EC system (85.0 vs. 30.2 ± 13.6 mg/hen/d, respectively). Lower (P < 0.01) Ca and P excretions were observed in EC (Ca: 2.11 vs. 2.29 ± 0.04 and P: 0.619 vs. 0.643 ± 0.005 g/hen/d) compared to CC. Overall egg N output was similar between the systems. Although lower Ca deposition (P < 0.0001) (2.07 vs. 2.13 ± 0.01 g/hen/d) and output (P < 0.05) (38.3 vs. 38.8 ± 0.15 mg/g egg) were noted in eggs from EC compared to CC, shell quality measurements were not different between the two systems. In addition, Ca outputs in eggs expressed as a proportion of Ca intake in both systems were similar (56.5 vs. 56.6 ± 0.51). Although overall mean P retention (-7.22 vs. -7.45 ± 0.71% P intake) was not different between the two groups of hens, Ca retention was higher (P < 0.05) in EC than CC hens (-1.37 vs. -4.76 ± 0.89% Ca intake, respectively). In addition to providing environmental enrichment and maintaining
High frequency of an otherwise rare phenotype in a small and isolated tiger population

Significance Small and isolated populations have low genetic variation due to founding bottlenecks and genetic drift. Few empirical studies demonstrate visible phenotypic change associated with drift using genetic data in endangered species. We used genomic analyses of a captive tiger pedigree to identify the genetic basis for a rare trait, pseudomelanism, in tigers. Genome sequencing and extensive genotyping of noninvasive samples across tiger range revealed unique spatial presence of this allele in the Similipal Tiger Reserve, India. Population genetic analyses confirmed that Similipal is a small and isolated population. Simulations suggest that intense founding bottlenecks could result in the observed patterns, implicating drift. Our study highlights ongoing phenotypic evolution, potentially from human-induced fragmentation, in endangered large carnivore populations. Most endangered species exist today in small populations, many of which are isolated. Evolution in such populations is largely governed by genetic drift. Empirical evidence for drift affecting striking phenotypes based on substantial genetic data are rare. Approximately 37% of tigers (Panthera tigris) in the Similipal Tiger Reserve (in eastern India) are pseudomelanistic, characterized by wide, merged stripes. Camera trap data across the tiger range revealed the presence of pseudomelanistic tigers only in Similipal. We investigated the genetic basis for pseudomelanism and examined the role of drift in driving this phenotype's frequency. Whole-genome data and pedigree-based association analyses from captive tigers revealed that pseudomelanism cosegregates with a conserved and functionally important coding alteration in Transmembrane Aminopeptidase Q (Taqpep), a gene responsible for similar traits in other felid species. Noninvasive sampling of tigers revealed a high frequency of the Taqpep p.H454Y mutation in Similipal (12 individuals, allele frequency = 0.58) and absence from all other tiger populations (395 individuals). Population genetic analyses confirmed few (minimal number) tigers in Similipal, and its genetic isolation, with poor geneflow. Pairwise FST (0.33) at the mutation site was high but not an outlier. Similipal tigers had low diversity at 81 single nucleotide polymorphisms (mean heterozygosity = 0.28, SD = 0.27). Simulations were consistent with founding events and drift as possible drivers for the observed stark difference of allele frequency. Our results highlight the role of stochastic processes in the evolution of rare phenotypes. We highlight an unusual evolutionary trajectory in a small and isolated population of an endangered species.
New Insights Into Osteoclast Biology

Osteoclasts are multinucleated cells that are characterized by their unique ability to resorb large quantities of bone. Therefore, they are frequently the target of therapeutic interventions to ameliorate bone loss. In an adult organism, osteoclasts derive from hematopoietic stem cells and differentiate into osteoclasts within a multistep process under the influence of macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL). Historically, the osteoclast life cycle has been defined as linear, whereby lineage‐committed mononuclear precursors fuse to generate multinucleated highly specialized and localized bone phagocytic cells, which then undergo apoptosis within weeks. Recent advances through lineage tracing, single cell RNA sequencing, parabiosis, and intravital imaging approaches have challenged this dogma, revealing they have greater longevity and the capacity to circulate and undergo cell recycling. Indeed, these new insights highlight that under homeostatic conditions very few incidences of osteoclast apoptosis occur. More importantly, as we revisit the formation and fate of the osteoclast, novel methods to target osteoclast biology in bone pathology and regeneration are emerging. This review briefly summarizes the historical life cycle of osteoclasts and highlights recent discoveries made through advanced methodologies, which have led to a paradigm shift in osteoclast biology. These findings are discussed in light of both existing and emerging bone targeted therapeutics, bone pathologies, and communication between osteoclasts and cells resident in bone or at distant sites. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
Is Someone Listening?

Smart devices with the capability to record audio can create a trade-off for users between convenience and privacy. To understand how users experience this trade-off, we report on data from 35 interview, focus group, and design workshop participants. Participants' perspectives on smart-device audio privacy clustered into the pragmatist, guardian, and cynic perspectives that have previously been shown to characterize privacy concerns in other domains. These user groups differed along four axes in their audio-related behaviors (for example, guardians alone say they often move away from a microphone when discussing a sensitive topic). Participants surfaced three usage phases that require design consideration with respect to audio privacy: 1) adoption, 2) in-the-moment recording, and 3) downstream use of audio data. We report common design solutions that participants created for each phase (such as indicators showing when an app is recording audio and annotations making clear when an advertisement was selected based on past audio recording).
Defending lightweight virtual switches from cross-app poisoning attacks with vIFC

We present vIFC, a conceptual architecture for Information Flow Control (IFC) policy enforcement in lightweight programmable data planes (PDP) virtualization solutions. In contrast to existing solutions for preventing Cross-App Poisoning Attacks (CAP) like ProvSDN, our solution can monitor and prevent CAP attacks launched against lightweight virtual switches emulated by a general-purpose switch program or composed in a single switch program.
The RNA binding protein human antigen R is a gatekeeper of liver homeostasis

NAFLD is initiated by steatosis and can progress through fibrosis and cirrhosis to HCC. The RNA binding protein human antigen R (HuR) controls RNAs at the posttranscriptional level; hepatocyte HuR has been implicated in the regulation of diet‐induced hepatic steatosis. The present study aimed to understand the role of hepatocyte HuR in NAFLD development and progression to fibrosis and HCC.
Pertussis Vaccine Candidate Based on Outer Membrane Vesicles Derived From Biofilm Culture

Outer membrane vesicles (OMV) derived from Bordetella pertussis—the etiologic agent of the resurgent disease called pertussis—are safe and effective in preventing bacterial colonization in the lungs of immunized mice. Vaccine formulations containing those OMV are capable of inducing a mixed Th1/Th2/Th17 profile, but even more interestingly, they may induce a tissue-resident memory immune response. This immune response is recommended for the new generation of pertussis-vaccines that must be developed to overcome the weaknesses of current commercial acellular vaccines (second-generation of pertussis vaccine). The third-generation of pertussis vaccine should also deal with infections caused by bacteria that currently circulate in the population and are phenotypically and genotypically different [in particular those deficient in the expression of pertactin antigen, PRN(-)] from those that circulated in the past. Here we evaluated the protective capacity of OMV derived from bacteria grown in biofilm, since it was observed that, by difference with older culture collection vaccine strains, circulating clinical B. pertussis isolates possess higher capacity for this lifestyle. Therefore, we performed studies with a clinical isolate with good biofilm-forming capacity. Biofilm lifestyle was confirmed by both scanning electron microscopy and proteomics. While scanning electron microscopy revealed typical biofilm structures in these cultures, BipA, fimbria, and other adhesins described as typical of the biofilm lifestyle were overexpressed in the biofilm culture in comparison with planktonic culture. OMV derived from biofilm (OMVbiof) or planktonic lifestyle (OMVplank) were used to formulate vaccines to compare their immunogenicity and protective capacities against infection with PRN(+) or PRN(-) B. pertussis clinical isolates. Using the mouse protection model, we detected that OMVbiof-vaccine was more immunogenic than OMVplank-vaccine in terms of both specific antibody titers and quality, since OMVbiof-vaccine induced antibodies with higher avidity. Moreover, when OMV were administered at suboptimal quantity for protection, OMVbiof-vaccine exhibited a significantly adequate and higher protective capacity against PRN(+) or PRN(-) than OMVplank-vaccine. Our findings indicate that the vaccine based on B. pertussis biofilm-derived OMV induces high protection also against pertactin-deficient strains, with a robust immune response.
A Correlation Between Differentiation Phenotypes of Infused T Cells and Anti-Cancer Immunotherapy

T-cell therapy, usually with ex-vivo expansion, is very promising to treat cancer. Differentiation status of infused T cells is a crucial parameter for their persistence and antitumor immunity. Key phenotypic molecules are effective and efficient to analyze differentiation status. Differentiation status is crucial for T cell exhaustion, in-vivo lifespan, antitumor immunity, and even antitumor pharmacological interventions. Strategies including cytokines, Akt, Wnt and Notch signaling, epigenetics, and metabolites have been developed to produce less differentiated T cells. Clinical trials have shown better clinical outcomes from infusion of T cells with less differentiated phenotypes. CD27+, CCR7+ and CD62L+ have been the most clinically relevant phenotypic molecules, while Tscm and Tcm the most clinically relevant subtypes. Currently, CD27+, CD62L+ and CCR7+ are recommended in the differentiation phenotype to evaluate strategies of enhancing stemness. Future studies may discover highly clinically relevant differentiation phenotypes for specific T-cell production methods or specific subtypes of cancer patients, with the advantages of precision medicine.
Letter to the Editor: Is HBV genotype strongly associated with HCC risk in patients with chronic hepatitis B?

We read the article by McMahon et al with great interest. The authors found that hepatitis B virus (HBV) genotype was strongly associated with hepatocellular carcinoma (HCC) incidence in the Hepatitis B Alaska cohort and suggested that HBV genotype should be considered in risk factor stratification of HCC. Although inspiring, several issues warrant further clarification.
Seamless Wayfinding by a Deafblind Adult on an Urban College Campus: A Case Study on Wayfinding Performance, Information Preferences, and Technology Requirements

This article reports on an empirical evaluation of the experience, performance, and perception of a deafblind adult participant in an experimental case study on pedestrian travel in an urban environment. The case study assessed the degree of seamlessness of the wayfinding experience pertaining to routes that traverse both indoor and outdoor spaces under different modalities of technology-aided pedestrian travel. Specifically, an adult deafblind pedestrian traveler completed three indoor/outdoor routes on an urban college campus using three supplemental wayfinding support tools: a mobile application, written directions, and a tactile map. A convergent parallel mixed-methods approach was used to synthesize insights from a pre-travel questionnaire, route travel video recordings, post-travel questionnaire, and post-travel interview. Our results indicate that wayfinding performance and confidence differed considerably between the three wayfinding support tools. The tactile map afforded the most successful wayfinding and highest confidence. Wayfinding performance and confidence were lowest for the mobile application modality. The simplicity of use of a wayfinding tool is paramount for reducing cognitive load during wayfinding. In addition, information that does not match individual, user-specific information preferences and needs inhibits wayfinding performance. Current practice pertaining to the representation of digital spatial data only marginally accounts for the complexity of pedestrian human wayfinding across the gamut of visual impairment, blindness, and deafblindness. Robust orientation and mobility training and skills remain key for negotiating unexpected or adverse wayfinding situations and scenarios, irrespective of the use of a wayfinding tool. A substantial engagement of the deafblind community in both research and development is critical for achieving universal and equitable usability of mobile wayfinding technology.
Prognostic Relevance of Pancreatic Adenocarcinoma Whole-Tumor Transcriptomic Subtypes and Components

Purpose: Our team previously defined six quantitative transcriptomic components, and a classification in five subtypes by association of these components. In this study, we compared the robustness of quantitative components and qualitative classifications from different transcriptomic profiling techniques, investigated their clinical relevance, and proposed a new prognostic model. Experimental Design: A total of 210 patients from a multicentric cohort and 149 patients from a monocentric cohort were included in this study. RNA microarray profiles were obtained from 165 patients of the multicentric cohort. RNA sequencing (RNA-seq) profiles were obtained from all the patients. Results: For the patients with both RNA microarray and RNA-seq profiles, the concordance in subtype assignment was partial with an 82.4% coherence rate. The correlation between the two technique projections of the six components ranged from 0.85 to 0.95, demonstrating an advantage of robustness. On the basis of the Akaike information criterion, the RNA components showed more prognostic value in univariate or multivariate models than the subtypes. Using the monocentric cohort for training, we developed a multivariate Cox regression model using all six components and clinicopathologic characteristics (node invasion and resection margins) on disease-free survival (DFS). This prognostic model was highly associated with DFS (P < 0.001). The evaluation of the model in the multicentric cohort showed significant association with DFS and overall survival (P < 0.001). Conclusions: We described the advantage of the prognostic value and robustness of the whole-tumor transcriptomic components than subtypes. We created and validated a new DFS-based multivariate Cox regression prognostic model, including six pancreatic adenocarcinoma transcriptomic component levels and pathologic characteristics.
Technical Note: Clinical modeling and validation of breast tissue expander metallic ports in a commercial treatment planning system for proton therapy.

PURPOSE To validate breast tissue expander metallic port (MP) models in a commercial treatment planning system (TPS) in proton pencil beam scanning (PBS) treatments for breast cancer patients with breast tissue expanders. METHODS AND MATERIALS Three types of MPs taken out of a Mentor CPX4, a Natrelle 133, and a PMT Integra breast tissue expanders and a 650cc saline filled Mentor CPX4 expander were placed on top of acrylic slabs, and scanned using a Siemens Somatom Definition AS Open RT CT scanner. Structure templates for each of the MPs were designed within Eclipse TPS. The CT numbers for the metallic parts were overridden to reflect measured or calculated relative proton stopping powers (RPSPs). Mock targets were contoured in acrylic to represent post-mastectomy chest-wall radiation therapy (PMRT) targets. Plans with different beam incident angles were optimized using the Eclipse TPS to deliver uniform prescription dose to the target using Hitachi Probeat-V PBS beams. Eclipse calculated doses and an in-house Monte Carlo (MC) code calculated doses were compared to the measured Gafchromic EBT3 film doses in acrylic. RESULTS TPS/MC and film dose comparison results showed that: 1) 3%/2mm/10% threshold Gamma pass rates were better than 90.8% in the acrylic target region for all plans; 2) comparing TPS and film doses for the individual beam plans in the MP dose shadow areas, the area with dose difference above 5% ((ΔA)5%) ranged from 1.1cm2 to 5.0cm2 , and the maximum dose difference ((ΔD)0.01cm2 ) ranged from 12.5% to 25.0%; 3) comparing MC and film doses for the individual beam plans in the MP dose shadow areas, the (ΔA)5% varied from 1.1cm2 to 2.9cm2 and (ΔD)0.01cm2 varied from 8.5% to 24.2%; 4) for a plan composed of three individual beams treating through the Mentor CPX4 expander, the TPS (ΔA)5% was less than 0.13cm2 , and the (ΔD)0.01cm2 was less than 6% in the MP dose shadow areas. CONCLUSIONS It is feasible to treat patients with tissue expanders using multiple PBS beams using a structure template with CT number overridden to represent the measured/calculated RPSP for MPs for PBS treatment planning. MC dose was more accurate than analytical dose in the areas with high dose gradient caused by the density heterogeneity of the breast tissue expander MPs. This article is protected by copyright. All rights reserved.