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Bart Simpson Blastoff
Countdown to laughter. . .Bart Simpson will send you over the moon with high-octane hilarity as he leads the Springfield Elementary team to the state eating competition, does his best not to embarrass Marge on Mother's Day, learns a Kwik-E life lesson from Apu, gets a little bedtime assistance from Maggie, bonds with Grampa over a junky jalopy, and foils Mr. Burns' plan to sidestep Springfield's child labor laws. Then, Lisa gets some surprising competition as she squares off against Bart in a contest to win a prized pony, teenagers Homer and Barney encounter zombies, and much, much more! It's a supersonic, supercharged, Bart Simpson shebang!
Book
Leukemia: An Overview for Primary Care
Leukemia is a clonal proliferation of hematopoietic stem cells in the bone marrow. The four broad subtypes most likely to be encountered by primary care physicians are acute lymphoblastic, acute myelogenous, chronic lymphocytic, and chronic myelogenous. Acute lymphoblastic leukemia occurs more often in children, whereas the other subtypes are more common in adults. Risk factors include a genetic predisposition as well as environmental factors, such as exposure to ionizing radiation. Symptoms are nonspecific and include fever, fatigue, weight loss, bone pain, bruising, or bleeding. A complete blood count usually reveals leukocytosis and other abnormally elevated or depressed cell lines. Patients with suspected leukemia should be referred promptly to a hematologist-oncologist. The diagnosis is confirmed by further examination of the bone marrow or peripheral blood. Treatment may include chemotherapy, radiation, monoclonal antibodies, or hematopoietic stem cell transplantation. Complications of treatment include tumor lysis syndrome and serious infections from immunosuppression. Leukemia survivors should be monitored closely for secondary malignancies, cardiac complications, and endocrine disturbances such as metabolic syndrome, hypothyroidism, and hypogonadism. Five-year survival rates are highest in younger patients and in patients with chronic myelogenous leukemia or chronic lymphocytic leukemia.
Journal Article
Expansion of interferon inducible gene pool via USP18 inhibition promotes cancer cell pyroptosis
While immunotherapy has emerged as a breakthrough cancer therapy, it is only effective in some patients, indicating the need of alternative therapeutic strategies. Induction of cancer immunogenic cell death (ICD) is one promising way to elicit potent adaptive immune responses against tumor-associated antigens. Type I interferon (IFN) is well known to play important roles in different aspects of immune responses, including modulating ICD in anti-tumor action. However, how to expand IFN effect in promoting ICD responses has not been addressed. Here we show that depletion of ubiquitin specific protease 18 (USP18), a negative regulator of IFN signaling, selectively induces cancer cell ICD. Lower USP18 expression correlates with better survival across human selected cancer types and delays cancer progression in mouse models. Mechanistically, nuclear USP18 controls the enhancer landscape of cancer cells and diminishes STAT2-mediated transcription complex binding to IFN-responsive elements. Consequently, USP18 suppression not only enhances expression of canonical IFN-stimulated genes (ISGs), but also activates the expression of a set of atypical ISGs and NF-κB target genes, including genes such as Polo like kinase 2 (
PLK2
), that induce cancer pyroptosis. These findings may support the use of targeting USP18 as a potential cancer immunotherapy.
The induction of immunogenic cell death (ICD) can potentiate antitumour immunity. Here the authors show that USP18, a negative regulator of IFN signaling protects cancer cells from ICD by suppressing the expression of canonical and non-canonical IFN-stimulated genes.
Journal Article
Living Shorelines: Coastal Resilience with a Blue Carbon Benefit
Living shorelines are a type of estuarine shoreline erosion control that incorporates native vegetation and preserves native habitats. Because they provide the ecosystem services associated with natural coastal wetlands while also increasing shoreline resilience, living shorelines are part of the natural and hybrid infrastructure approach to coastal resiliency. Marshes created as living shorelines are typically narrow (< 30 m) fringing marshes with sandy substrates that are well flushed by tides. These characteristics distinguish living shorelines from the larger meadow marshes in which most of the current knowledge about created marshes was developed. The value of living shorelines for providing both erosion control and habitat for estuarine organisms has been documented but their capacity for carbon sequestration has not. We measured carbon sequestration rates in living shorelines and sandy transplanted Spartina alterniflora marshes in the Newport River Estuary, North Carolina. The marshes sampled here range in age from 12 to 38 years and represent a continuum of soil development. Carbon sequestration rates ranged from 58 to 283 g C m-2 yr-1 and decreased with marsh age. The pattern of lower sequestration rates in older marshes is hypothesized to be the result of a relative enrichment of labile organic matter in younger sites and illustrates the importance of choosing mature marshes for determination of long-term carbon sequestration potential. The data presented here are within the range of published carbon sequestration rates for S. alterniflora marshes and suggest that wide-scale use of the living shoreline approach to shoreline management may come with a substantial carbon benefit.
Journal Article
Multiple metals influence distinct properties of the Arabidopsis circadian clock
Circadian rhythms coordinate endogenous events with external signals, and are essential to biological function. When environmental contaminants affect these rhythms, the organism may experience fitness consequences such as reduced growth or increased susceptibility to pathogens. In their natural environment plants may be exposed to a wide range of industrial and agricultural soil pollutants. Here, we investigate how the addition of various metal salts to the root-interaction environment can impact rhythms, measured via the promoter:luciferase system. The consequences of these environmental changes were found to be varied and complex. Therefore, in addition to traditional Fourier-based analyses, we additionally apply novel wavelet-based spectral hypothesis testing and clustering methodologies to organize and understand the data. We are able to classify broad sets of responses to these metal salts, including those that increase, and those that decrease, the period, or which induce a lack of precision or disrupt any meaningful periodicity. Our methods are general, and may be applied to discover common responses and hidden structures within a wide range of biological time series data.
Journal Article
The human memory T cell compartment changes across tissues of the female reproductive tract
Memory CD4 T cells in tissues fulfill numerous functions that are critical for local immune homeostasis and protection against pathogens. Previous studies have highlighted the phenotypic and functional heterogeneity of circulating and tissue-resident memory CD4 T cells across different human tissues such as skin, lung, liver, and colon. Comparatively little is known in regard to memory CD4 T cells across tissues of the female reproductive tract (FRT). We examined CD4 T cells in donor-matched vaginal, ecto- and endocervical tissues, which differ in mucosal structure and exposure to external environmental stimuli. We hypothesized that this could be reflected by tissue-specific differences in the memory CD4 T cell compartment. We found differences in CD4 subset distribution across these tissues. Specifically, CD69+CD103+ CD4 T cells were significantly more abundant in vaginal than cervical tissues. In contrast, the transcriptional profiles of CD4 subsets were fairly conserved across FRT tissues. CD69+CD103+ CD4 T cells showed a TH17 bias independent of tissue niche. Our data suggest that FRT tissues affect T cell subset distribution but have limited effects on the transcriptome of each subset. We discuss the implications for barrier immunity in the FRT.
Journal Article
Thyroid Nodules: Advances in Evaluation and Management
Thyroid nodules can be detected by ultrasonography in up to 68% of the general population. They are typically benign and are often discovered incidentally. The primary goal of thyroid nodule evaluation is to determine whether it is malignant. After thyroid ultrasonography has been performed, the next step is measurement of serum thyroid-stimulating hormone. If levels are low, a radionuclide thyroid uptake scan is indicated. Hyperfunctioning nodules are rarely malignant and do not require tissue sampling. Nonfunctioning nodules and nodules in a patient with a normal or high thyroid-stimulating hormone level may require fine-needle aspiration based on ultrasound characteristics and size. Nodules with suspicious features and solid hypoechoic nodules 1 cm or larger require aspiration. The Bethesda System (categories 1 through 6) is used to classify samples. Molecular testing can be used to guide treatment when aspiration yields an indeterminate result. Molecular testing detects mutations associated with thyroid cancer and can help inform decisions about surgical excision vs. continued ultrasound monitoring. Treatment of pregnant women with nonfunctioning thyroid nodules and of children with thyroid nodules is similar to that for nonpregnant adults, with the exception of molecular testing, which has not been validated in these populations.
Journal Article
A degron-based strategy reveals new insights into Aurora B function in C. elegans
The widely conserved kinase Aurora B regulates important events during cell division. Surprisingly, recent work has uncovered a few functions of Aurora-family kinases that do not require kinase activity. Thus, understanding this important class of cell cycle regulators will require strategies to distinguish kinase-dependent from independent functions. Here, we address this need in C . elegans by combining germline-specific, auxin-induced Aurora B (AIR-2) degradation with the transgenic expression of kinase-inactive AIR-2. Through this approach, we find that kinase activity is essential for AIR-2’s major meiotic functions and also for mitotic chromosome segregation. Moreover, our analysis revealed insight into the assembly of the ring complex (RC), a structure that is essential for chromosome congression in C . elegans oocytes. AIR-2 localizes to chromosomes and recruits other components to form the RC. However, we found that while kinase-dead AIR-2 could load onto chromosomes, other components were not recruited. This failure in RC assembly appeared to be due to a loss of RC SUMOylation, suggesting that there is crosstalk between SUMOylation and phosphorylation in building the RC and implicating AIR-2 in regulating the SUMO pathway in oocytes. Similar conditional depletion approaches may reveal new insights into other cell cycle regulators.
Journal Article
Neutralization profiles of HIV-1 viruses from the VRC01 Antibody Mediated Prevention (AMP) trials
The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. HIV-1 viruses isolated from AMP participants who acquired infection during the study in the sub-Saharan African (HVTN 703/HPTN 081) and the Americas/European (HVTN 704/HPTN 085) trials represent a panel of currently circulating strains of HIV-1 and offer a unique opportunity to investigate the sensitivity of the virus to broadly neutralizing antibodies (bnAbs) being considered for clinical development. Pseudoviruses were constructed using envelope sequences from 218 individuals. The majority of viruses identified were clade B and C; with clades A, D, F and G and recombinants AC and BF detected at lower frequencies. We tested eight bnAbs in clinical development (VRC01, VRC07-523LS, 3BNC117, CAP256.25, PGDM1400, PGT121, 10–1074 and 10E8v4) for neutralization against all AMP placebo viruses (n = 76). Compared to older clade C viruses (1998–2010), the HVTN703/HPTN081 clade C viruses showed increased resistance to VRC07-523LS and CAP256.25. At a concentration of 1μg/ml (IC80), predictive modeling identified the triple combination of V3/V2-glycan/CD4bs-targeting bnAbs (10-1074/PGDM1400/VRC07-523LS) as the best against clade C viruses and a combination of MPER/V3/CD4bs-targeting bnAbs (10E8v4/10-1074/VRC07-523LS) as the best against clade B viruses, due to low coverage of V2-glycan directed bnAbs against clade B viruses. Overall, the AMP placebo viruses represent a valuable resource for defining the sensitivity of contemporaneous circulating viral strains to bnAbs and highlight the need to update reference panels regularly. Our data also suggests that combining bnAbs in passive immunization trials would improve coverage of global viruses.
Journal Article
Single-cell RNA sequencing of a new transgenic t(8;21) preleukemia mouse model reveals regulatory networks promoting leukemic transformation
T(8;21)(q22;q22), which generates the AML1-ETO fusion oncoprotein, is a common chromosomal abnormality in acute myeloid leukemia (AML) patients. Despite having favorable prognosis, 40% of patients will relapse, highlighting the need for innovative models and application of the newest technologies to study t(8;21) leukemogenesis. Currently, available AML1-ETO mouse models have limited utility for studying the pre-leukemic stage because AML1-ETO produces mild hematopoietic phenotypes and no leukemic transformation. Conversely, overexpression of a truncated variant, AML1-ETO9a (AE9a), promotes fully penetrant leukemia and is too potent for studying pre-leukemic changes. To overcome these limitations, we devised a germline-transmitted Rosa26 locus AE9a knock-in mouse model that moderately overexpressed AE9a and developed leukemia with long latency and low penetrance. We observed pre-leukemic alterations in AE9a mice, including skewing of progenitors towards granulocyte/monocyte lineages and replating of stem and progenitor cells. Next, we performed single-cell RNA sequencing to identify specific cell populations that contribute to these pre-leukemic phenotypes. We discovered a subset of common myeloid progenitors that have heightened granulocyte/monocyte bias in AE9a mice. We also observed dysregulation of key hematopoietic transcription factor target gene networks, blocking cellular differentiation. Finally, we identified Sox4 activation as a potential contributor to stem cell self-renewal during the pre-leukemic stage.
Journal Article