Biology subjects

Hanson, D.

Publications and source records attributed to Hanson, D..

12 recordsLinked to original sources

bioRxiv2025

In silico drug sensitivity predicts subgroup-specific therapeutics in medulloblastoma patients

BackgroundMedulloblastoma is the most common malignant pediatric brain tumor. Survival rates vary widely between subgroups, with an average overall survival of 70%. Recurrent medulloblastoma is highly aggressive, treatment-resistant, and usually fatal. In addition, current treatments are highly toxic to the developing brain and surviving patients suffer from lifelong side effects. Therefore, novel therapeutic options are urgently needed. MethodsTo inform risk-based, personalized therapy, we developed a novel platform called DrugSeq, which allows predictions of drug sensitivities in patients across medulloblastoma subgroups. We used a perturbagen-response dataset to calculate transcriptional response signatures for each drug and compared this to patient medulloblastoma tumor gene expression. We then stratified patients by molecular subgroup and used an ANOVA analysis to identify drugs that selectively targeted each subgroup. ResultsWe found distinct differences in transcriptional profiles and predicted drug sensitivity for each medulloblastoma subgroup. We identified several kinase inhibitors, epigenetic inhibitors, and several drugs that have been investigated in drug repositioning studies for cancer. ConclusionsWe posit that DrugSeq may identify novel therapies and facilitate patient stratification in clinical trials, leading to more successful targeted medulloblastoma therapies that improve tumor response while minimizing late toxicities. This computational tool can also be used for other cancers to stratify patients based on any clinical or molecular feature. Key points DrugSeq calculates drug sensitivity for medulloblastoma tumors stratified by subgroup. DrugSeq platform may inform patient stratification strategies in clinical trials. Importance of the StudyMedulloblastoma is the most common malignant pediatric brain tumor. Current standard-of-care typically includes surgical resection, multi-agent chemotherapy, and radiation. However, survival rates vary widely between subgroups, ranging from 45 to 90%, depending on age and molecular features. In addition, surviving children frequently suffer from debilitating late side effects of therapy including neurocognitive impairment, epilepsy, stroke, subsequent cancer, endocrinopathies, and early mortality. Therefore, novel therapeutic options are urgently needed. However, a one-size-fits-all approach for therapy is unlikely to be effective given the well-characterized intertumor heterogeneity of medulloblastoma.

cancer biology↗

bioRxiv2025

Evidence for active regulation of transpiration in non-stomatal plants

O_LIBryophyta (mosses) are a basal group of plants that lack stomata in their haploid form, as well as developed vascular tissue and a hydrophobic cuticle. Consequently, these plants are classified as poikilohydric, meaning poor control over water loss and are often assumed to reach equilibrium with ambient humidity. This classification does not fully align with the diverse strategies observed in mosses. C_LIO_LIWe studied gas exchange in 14 species from Albuquerque and Boston, USA, under controlled dehydration conditions. C_LIO_LIOur results revealed significant variation in transpiration rates, cell wall equilibrium humidity, and desiccation times across species. These differences could not be explained by tissue water storage relative to the transpiring surface area, suggesting that water loss is not entirely passive. Additionally, species with better water control also presented traits of an avoidance strategy, including elastic tissues, high capacitance, and less negative osmotic potential, suggesting an adaptive constraint. C_LIO_LIThese findings point to a basal, non-stomatal mechanism of water loss control through cell membranes and/or cell walls. Potentially, this mechanism is homologous to the non-stomatal control recently identified in angiosperms, which induces unsaturated conditions in the substomatal cavities. Bryophyta presents a valuable non-stomatal model for further investigating this mechanism and its evolutionary significance. C_LI

plant biology↗

bioRxiv2025

A bivalent self-amplifying RNA vaccine against yellow fever and Zika viruses

IntroductionYellow fever (YFV) and Zika (ZIKV) viruses cause significant morbidity and mortality, despite the existence of an approved YFV vaccine and the development of multiple ZIKV vaccine candidates to date. New technologies may improve access to vaccines against these pathogens. We previously described a nanostructured lipid carrier (NLC)-delivered self-amplifying RNA (saRNA) vaccine platform with excellent thermostability and immunogenicity, appropriate for prevention of tropical infectious diseases. MethodsYFV and ZIKV prM-E antigen-expressing saRNA constructs were created using a TC-83 strain Venezuelan equine encephalitis virus-based replicon and complexed with NLC by simple mixing. Monovalent and bivalent vaccine formulations were injected intramuscularly into C57BL/6 mice and Syrian golden hamsters, and the magnitude, durability, and protective efficacy of the resulting immune responses were then characterized. Results and discussionMonovalent vaccines established durable neutralizing antibody responses to their respective flaviviral targets, with little evidence of cross-neutralization. Both vaccines additionally elicited robust antigen-reactive CD4+ and CD8+ T cell populations. Notably, humoral responses to YFV saRNA-NLC vaccination were comparable to those in YF-17D-vaccinated animals. Bivalent formulations established humoral and cellular responses against both viral targets, commensurate to those established by monovalent vaccines, without evidence of saRNA interference or immune competition. Finally, both monovalent and bivalent vaccines completely protected mice and hamsters against lethal ZIKV and YFV challenge. We present a bivalent saRNA-NLC vaccine against YFV and ZIKV capable of inducing robust and efficacious neutralizing antibody and cellular immune responses against both viruses. These data support the development of other multivalent saRNA-based vaccines against infectious diseases.

immunology↗

bioRxiv2023

Sale of critically endangered sharks in the United States

Shark meat is widely available in the United States in grocery stores and seafood markets. The meat is often mislabeled or generically labeled as "shark". The ambiguity of these generic labels makes it challenging to assess the conservation implications of this practice and for consumers to avoid species with high mercury concentrations. For this study we purchased and DNA barcoded 30 shark products purchased in the United States to determine their species identity and conservation status. These samples consisted of 19 filets sold in grocery stores, seafood markets, and Asian specialty markets (mostly in North Carolina) and 11 ordered online as "jerky". 70% of samples were "soft mislabeled" (i.e., labeled generically as shark but not as a specific species). Of the nine samples labeled to species, eight were mislabeled (e.g., spinner shark labeled as mako shark). Only one sample was correctly labeled. All 30 samples were identified as shark and came from 11 different species, including three species listed by the IUCN as Critically Endangered: great hammerhead, scalloped hammerhead, and tope. The first two species have been found to contain very high levels of mercury, illustrating the implications of seafood mislabeling for human health. The widespread availability of shark meat in U.S. grocery stores is surprising given the dramatic decline of shark populations globally. Moreover, the fact that nearly all shark meat is either mislabeled or not labeled to species amplifies the problem. Accurate, verified product labels for shark meat would benefit consumers and shark conservation efforts, and should be a priority for the seafood industry.

genetics↗

bioRxiv2022

An intranasal self-amplifying RNA SARS-CoV-2 vaccine produces durable respiratory and systemic immunity

While mRNA vaccines have been effective in combating SARS-CoV-2, waning of vaccine-induced antibody responses and lack of vaccine-induced respiratory tract immunity contribute to ongoing infection and transmission. In this work, we compare and contrast intranasal (i.n.) and intramuscular (i.m.) administration of a SARS-CoV-2 self-amplifying RNA (saRNA) vaccine delivered by a nanostructured lipid carrier (NLC). Both i.m. and i.n. vaccines induce potent systemic serum neutralizing antibodies, bone marrow-resident IgG-secreting cells, and splenic T cell responses. The i.n. vaccine additionally induces robust respiratory mucosal immune responses, including SARS-CoV-2-reactive lung-resident memory and lung-homing T cell populations. As a booster following previous i.m. vaccination, the i.n. vaccine also elicits the development of mucosal virus-specific T cells. Both the i.m. and i.n. administered vaccines durably protect hamsters from infection-associated morbidity upon viral challenge, significantly reducing viral loads and preventing challenged hamsters from transmitting virus to naive cagemates. This saRNA-NLC vaccines potent systemic immunogenicity, and additional mucosal immunogenicity when delivered i.n., may be key for combating SARS-CoV-2 and other respiratory pathogens.

immunology↗

bioRxiv2022

OpenPBTA: An Open Pediatric Brain Tumor Atlas

SummaryPediatric brain and spinal cancer are the leading disease-related cause of death in children, thus we urgently need curative therapeutic strategies for these tumors. To accelerate such discoveries, the Childrens Brain Tumor Network and Pacific Pediatric Neuro-Oncology Consortium created a systematic process for tumor biobanking, model generation, and sequencing with immediate access to harmonized data. We leverage these data to create OpenPBTA, an open collaborative project which establishes over 40 scalable analysis modules to genomically characterize 1,074 pediatric brain tumors. Transcriptomic classification reveals that TP53 loss is a significant marker for poor overall survival in ependymomas and H3 K28-altered diffuse midline gliomas and further identifies universal TP53 dysregulation in mismatch repair-deficient hypermutant high-grade gliomas. OpenPBTA is a foundational analysis platform actively being applied to other pediatric cancers and inform molecular tumor board decision-making, making it an invaluable resource to the pediatric oncology community. In BriefThe OpenPBTA is a global, collaborative open-science initiative which brought together researchers and clinicians to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Shapiro, et. al create over 40 open-source, scalable modules to perform cancer genomics analyses and provide a richly-annotated somatic dataset across 58 brain tumor histologies. The OpenPBTA framework can be used as a model for large-scale data integration to inform basic research, therapeutic target identification, and clinical translation. HighlightsOpenPBTA collaborative analyses establish resource for 1,074 pediatric brain tumors NGS-based WHO-aligned integrated diagnoses generated for 641 of 1,074 tumors RNA-Seq analysis infers medulloblastoma subtypes, TP53 status, and telomerase activity OpenPBTA will accelerate therapeutic translation of genomic insights

genomics↗

bioRxiv2022

A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability

mRNA vaccines were the first to be authorized for use against SARS-CoV-2 and have since demonstrated high efficacy against serious illness and death. However, limitations in these vaccines have been recognized due to their requirement for cold storage, short durability of protection, and lack of access in low-resource regions. We have developed an easily-manufactured, potent self-amplifying RNA (saRNA) vaccine against SARS-CoV-2 that is stable at room temperature. This saRNA vaccine is formulated with a nanostructured lipid carrier (NLC), providing enhanced stability, improved manufacturability, and protection against degradation. In preclinical studies, this saRNA/NLC vaccine induced strong humoral immunity, as demonstrated by high pseudovirus neutralization titers to the Alpha, Beta, and Delta variants of concern and induction of long-lived bone marrow-resident antibody secreting cells. Robust Th1-biased T-cell responses were also observed after prime or homologous prime-boost in mice. Notably, the saRNA/NLC platform demonstrated thermostability at room temperature for at least 6 months when lyophilized. Taken together, this saRNA delivered by NLC represents a potential improvement in RNA technology that could allow wider access to RNA vaccines for the current COVID-19 and future pandemics.

immunology↗

bioRxiv2020

Robust estimates of cuticle conductance on stomatous leaf surfaces during the light induction of photosynthesis

O_LICuticle conductance (gcw) can bias calculations of intercellular CO2 concentration inside the leaf (Ci) when stomatal conductance (gsw) is small. C_LIO_LIWe examined how the light induction of photosynthesis impacts calculations by directly measuring Ci along with standard gas exchange in sunflower and tobacco leaves. C_LIO_LIWhen photosynthesis was induced from dark to saturating light (1200 mol m-2 s-1 PAR) the calculated Ci was significantly larger than measured Ci and the difference decreased as gsw increased. This difference could lead to over-estimation of rubisco deactivation by limited CO2 supply during early induction of photosynthesis. However, only small differences in Ci were observed during the induction from shade (50 mol m-2 s-1 PAR) because gsw was sufficiently large. The induction from dark also allowed robust estimations of gcw when combined with direct Ci measurements. These gcw estimates succeeded in correcting the calculation, suggesting that the cuticle was the major source of error. C_LIO_LIDespite a technical restriction to amphi-stomatous leaves, the presented technique has a potential to provide insights into the cuticle conductance on intact stomatous leaf surfaces. C_LI

plant biology↗

bioRxiv2020

Minimum conductance in leaves-cuticle, leaky stomata, or water vapor saturation?

O_LIMinimum conductance (gw,min) in leaves is important for water relations in land plants. Yet, its regulation is unclear due to measurement constraints. C_LIO_LICuticle conductance to water vapor (gcw) was estimated from the difference between calculated and direct measurement of CO2 concentration in the leaf airspace (Ci) of amphi-stomatous tobacco and sunflower. We estimated gcw in a series of light and dark experiments, and partitioned gw,min into cuticle and stomatal components. Some leaves were detached to simulate severe drought through desiccation conditions where gw,min is generally determined. C_LIO_LIBetween light and dark experiments each gcw was in close agreement, and successfully corrected the discrepancies of calculations from direct measurements. In the dark, either stomatal or cuticle conductance dominated the gw,min, suggesting either of them can control the minimum water loss. In the detached leaves, gcw could not be estimated likely due to unsaturation in the leaf airspace, and gw,min was progressively underestimated. C_LIO_LIBesides cuticle, leaf water status is a potential pitfall of the standard gas exchange model. Our technique is useful to study the minimal gas exchange as well as to refine the model. C_LI

plant biology↗

bioRxiv2019

Repeatability of adaptive radiation depends on spatial scale: regional versus global replicates of stickleback in lake versus stream habitats

The repeatability of adaptive radiation is expected to be scale dependent, with determinism decreasing as greater spatial separation among "replicates" leads to their increased genetic and ecological independence. Threespine stickleback (Gasterosteus aculeatus) provide an opportunity to test whether this expectation holds for the early stages of adaptive radiation - their diversification in freshwater ecosystems has been replicated many times. To better understand the repeatability of that adaptive radiation, we examined the influence of geographic scale on levels of parallel evolution by quantifying phenotypic and genetic divergence between lake and stream stickleback pairs sampled at regional (Vancouver Island) and global (North America and Europe) scales. We measured phenotypes known to show lake-stream divergence and used reduced representation genome-wide sequencing to estimate genetic divergence. We assessed the scale-dependence of parallel evolution by comparing effect sizes from multivariate models and also the direction and magnitude of lake-stream divergence vectors. At the phenotypic level, parallelism was greater at the regional than the global scale. At the genetic level, putative selected loci showed greater lake-stream parallelism at the regional than the global scale. Generally, the level of parallel evolution was low at both scales, except for some key univariate traits. Divergence vectors were often orthogonal, highlighting possible ecological and genetic constraints on parallel evolution at both scales. Overall, our results confirm that the repeatability of adaptive radiation decreases at increasing spatial scales. We suggest that greater environmental heterogeneity at larger scales imposes different selection regimes, thus generating lower repeatability of adaptive radiation at larger spatial scales.

evolutionary biology↗

bioRxiv2017

Copy number heterogeneity, large origin tandem repeats, and interspecies recombination in HHV-6A and HHV-6B reference strains

Quantitative PCR is the diagnostic pillar for clinical virology testing, and reference materials are necessary for accurate, comparable quantitation between clinical laboratories. Accurate quantitation of HHV-6 is important for detection of viral reactivation and inherited chromosomally integrated HHV-6 in immunocompromised patients. Reference materials in clinical virology commonly consist of laboratory-adapted viral strains that may be affected by the culture process. We performed next-generation sequencing to make relative copy number measurements at single nucleotide resolution of eight candidate HHV-6A and seven HHV-6B reference strains and DNA materials from the HHV-6 Foundation and Advanced Biotechnologies. 11 of 17 (65%) HHV6 candidate reference materials showed multiple copies of the origin of replication upstream of the U41 gene by next-generation sequencing. These large tandem repeats arose independently in culture-adapted HHV-6A and HHV-6B strains, measuring 1254 bp and 983 bp, respectively. Copy number measured between 4-10X copies relative to the rest of the genome. We also report the first interspecies recombinant HHV-6 strain with a HHV-6A GS backbone and >5.5kb region from HHV-6B Z29 from U41-U43 that covered the origin tandem repeat. Specific HHV-6A reference strains demonstrated duplication of regions at UL1/UL2, U87, and U89, as well as deletion in the U12-U24 region and U94/95 genes. HHV-6 strains derived from cord blood mononuclear cells from different labs on different continents revealed no copy number differences throughout the viral genome. These data indicate large origin tandem duplications are an adaptation of both HHV-6A and HHV-6B in culture and show interspecies recombination is possible within the Betaherpesvirinae.\n\nImportanceAnything in science that needs to be quantitated requires a standard unit of measurement. This includes viruses, for which quantitation increasingly determines definitions of pathology and guidelines for treatment. However, the act of making standard or reference material in virology can alter its very usefulness through genomic duplications, insertions, and rearrangements. We used deep sequencing to examine candidate reference strains for HHV-6, a ubiquitous human virus that can reactivate in the immunocompromised population and is integrated into the human genome in every cell of the body for 1% of people worldwide. We found large tandem repeats in the origin of replication for both HHV-6A and HHV-6B that are selected for in culture. We also found the first interspecies recombinant between HHV-6A and HHV-6B, a phenomenon that is well-known in alphaherpesviruses but to date has not been seen in betaherpesviruses. These data critically inform HHV-6 biology and the standard selection process.

genomics↗

bioRxiv2017

Genomic and proteomic analysis of Human herpesvirus 6 reveals distinct clustering of acute versus inherited forms and reannotation of reference strain

Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach >90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). To date, only two complete genomes are available for HHV-6B. Using a custom capture panel for HHV-6B, we report near-complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). We also report partial genome sequences from 10 strains of iciHHV-6A. Although the overall sequence diversity of HHV-6 is limited relative to other human herpesviruses, our sequencing identified geographical clustering of HHV-6B sequences from active infections, as well as evidence of recombination among HHV-6B strains. One strain of active HHV-6B was more divergent than any other HHV-6B previously sequenced. In contrast to the active infections, sequences from iciHHV-6 cases showed reduced sequence diversity. Strikingly, multiple iciHHV-6B sequences from unrelated individuals were found to be completely identical, consistent with a founder effect. However, several iciHHV-6B strains intermingled with strains from active pediatric infection, consistent with the hypothesis that intermittent de novo integration into host germline cells can occur during active infection Comparative genomic analysis of the newly sequenced strains revealed numerous instances where conflicting annotations between the two existing reference genomes could be resolved. Combining these findings with transcriptome sequencing and shotgun proteomics, we reannotated the HHV-6B genome and found multiple instances of novel splicing and genes that hitherto had gone unannotated. The results presented here constitute a significant genomic resource for future studies on the detection, diversity, and control of HHV-6.\n\nAuthor SummaryHHV-6 is a ubiquitous large DNA virus that is the most common cause of febrile seizures and reactivates in allogeneic stem cell patients. It also has the unique ability among human herpesviruses to be integrated into the genome of every cell via integration in the germ line, a condition called inherited chromosomally integrated (ici)HHV-6, which affects approximately 1% of the population. To date, very little is known about the comparative genomics of HHV-6. We sequenced 61 isolates of HHV-6B from active infections, 64 strains of iciHHV-6B, and 10 strains of iciHHV-6A. We found geographic clustering of HHV-6B strains from active infections. In contrast, iciHHV-6B had reduced sequence diversity, with many identical sequences of iciHHV-6 found in individuals not known to share recent common ancestry, consistent with a founder effect from a remote common ancestor with iciHHV-6. We also combined our genomic analysis with transcriptome sequencing and shotgun proteomics to correct previous misannotations of the HHV-6 genome.

microbiology↗