TFCONES: A database of vertebrate transcription factor-encoding genes and their associated conserved noncoding elements

<p>Abstract</p> <p>Background</p> <p>Transcription factors (TFs) regulate gene transcription and play pivotal roles in various biological processes such as development, cell cycle progression, cell differentiation and tumor suppression. Identifying <it>cis</it>-regulatory elements associated with TF-encoding genes is a crucial step in understanding gene regulatory networks. To this end, we have used a comparative genomics approach to identify putative <it>cis</it>-regulatory elements associated with TF-encoding genes in vertebrates.</p> <p>Description</p> <p>We have created a database named TFCONES (Transcription Factor Genes & Associated COnserved Noncoding ElementS) (<url>http://tfcones.fugu-sg.org</url>) which contains all human, mouse and fugu TF-encoding genes and conserved noncoding elements (CNEs) associated with them. The CNEs were identified by gene-by-gene alignments of orthologous TF-encoding gene loci using MLAGAN. We also predicted putative transcription factor binding sites within the CNEs. A significant proportion of human-fugu CNEs contain experimentally defined binding sites for transcriptional activators and repressors, indicating that a majority of the CNEs may function as transcriptional regulatory elements. The TF-encoding genes that are involved in nervous system development are generally enriched for human-fugu CNEs. Users can retrieve TF-encoding genes and their associated CNEs by conducting a keyword search or by selecting a family of DNA-binding proteins.</p> <p>Conclusion</p> <p>The conserved noncoding elements identified in TFCONES represent a catalog of highly prioritized putative <it>cis</it>-regulatory elements of TF-encoding genes and are candidates for functional assay.</p

Spatial heterogeneity in projected leprosy trends in India

Background: Leprosy is caused by infection with Mycobacterium leprae and is characterized by peripheral nerve damage and skin lesions. The disease is classified into paucibacillary (PB) and multibacillary (MB) leprosy. The 2012 London Declaration formulated the following targets for leprosy control: (1) global interruption of transmission or elimination by 2020, and (2) reduction of grade-2 disabilities in newly detected cases to below 1 per million population at a global level by 2020. Leprosy is treatable, but diagnosis, access to treatment and treatment adherence (all necessary to curtail transmission) represent major challenges. Globally, new case detection rates for leprosy have remained fairly stable in the past decade, with India responsible for more than half of cases reported annually. Methods: We analyzed publicly available data from the Indian Ministry of Health and Family Welfare, and fit linear mixed-effects regression models to leprosy case detection trends reported at the district level. We assessed correlation of the new district-level case detection rate for leprosy with several state-level regressors: TB incidence, BCG coverage, fraction of cases exhibiting grade 2 disability at diagnosis, fraction of cases in children, and fraction multibacillary. Results: Our analyses suggest an endemic disease in very slow decline, with substantial spatial heterogeneity at both district and state levels. Enhanced active case finding was associated with a higher case detection rate. Conclusions: Trend analysis of reported new detection rates from India does not support a thesis of rapid progress in leprosy control

Plankton imagery data inform satellite-based estimates of diatom carbon

© The Author(s), 2022. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Chase, A. P., Boss, E. S., Haentjens, N., Culhane, E., Roesler, C., & Karp-Boss, L. Plankton imagery data inform satellite-based estimates of diatom carbon. Geophysical Research Letters, 49(13), (2022): e2022GL098076, https://doi.org/10.1029/2022GL098076.Estimating the biomass of phytoplankton communities via remote sensing is a key requirement for understanding global ocean ecosystems. Of particular interest is the carbon associated with diatoms given their unequivocal ecological and biogeochemical roles. Satellite-based algorithms often rely on accessory pigment proxies to define diatom biomass, despite a lack of validation against independent diatom biomass measurements. We used imaging-in-flow cytometry to quantify diatom carbon in the western North Atlantic, and compared results to those obtained from accessory pigment-based approximations. Based on this analysis, we offer a new empirical formula to estimate diatom carbon concentrations from chlorophyll a. Additionally, we developed a neural network model in which we integrated chlorophyll a and environmental information to estimate diatom carbon distributions in the western North Atlantic. The potential for improving satellite-based diatom carbon estimates by integrating environmental information into a model, compared to models that are based solely on chlorophyll a, is discussed.Funding for this work was provided by NASA grants #NNX15AE67G and #80NSSC20M0202. A. Chase is supported by a Washington Research Foundation Postdoctoral Fellowship

Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome, characterized by hamartomatous growths in the brain, skin, kidneys, lungs, and heart, which lead to significant morbidity. TSC is caused by mutations in the TSC1 or TSC2 genes, whose products, hamartin and tuberin, form a tumor suppressor complex that regulates the PI3K/Akt/mTOR pathway. Early clinical trials show that TSC-related kidney tumors (angiomyolipomas) regress when treated with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (also known as sirolimus). Although side effects are tolerable, responses are incomplete, and tumor regrowth is common when rapamycin is stopped. Strategies for future clinical trials may include the investigation of longer treatment duration and combination therapy of other effective drug classes. RESULTS: Here, we examine the efficacy of a prolonged maintenance dose of rapamycin in Tsc2+/- mice with TSC-related kidney tumors. Cohorts were treated with rapamycin alone or in combination with interferon-gamma (IFN-g). The schedule of rapamycin included one month of daily doses before and after five months of weekly doses. We observed a 94.5% reduction in kidney tumor burden in Tsc2+/- mice treated (part one) daily with rapamycin (8 mg/kg) at 6 months ≤ age \u3c 7 months, (part 2) weekly with rapamycin (16 mg/kg) at 7 months ≤ age \u3c 12 months, and (part 3) daily with rapamycin (8 mg/kg) at 12 months ≤ age \u3c 13 months; but we did not observe any improvement with combination IFN-g plus rapamycin in this study. We also used a Tsc2-/- subcutaneous tumor model to evaluate other classes of drugs including sorafenib, atorvastatin, and doxycycline. These drugs were tested as single agents and in combination with rapamycin. Our results demonstrate that the combination of rapamycin and sorafenib increased survival and may decrease tumor volume as compared to rapamycin treatment alone while sorafenib as a single agent was no different than control. Atorvastatin and doxycycline, either as single agents or in combination with rapamycin, did not improve outcomes as compared with controls. CONCLUSION: Our results indicate that prolonged treatment with low doses of mTOR inhibitors may result in more complete and durable TSC-related tumor responses, and it would be reasonable to evaluate this strategy in a clinical trial. Targeting the Raf/Mek/Erk and/or VEGF pathways in combination with inhibiting the mTOR pathway may be another useful strategy for the treatment of TSC-related tumors

The bovine paranasal sinuses: Bacterial flora, epithelial expression of nitric oxide and potential role in the in-herd persistence of respiratory disease pathogens

peer-reviewedThe bovine paranasal sinuses are a group of complex cavernous air-filled spaces, lined by respiratory epithelium, the exact function of which is unclear. While lesions affecting these sinuses are occasionally reported in cattle, their microbial flora has not been defined. Furthermore, given that the various bacterial and viral pathogens causing bovine respiratory disease (BRD) persist within herds, we speculated that the paranasal sinuses may serve as a refuge for such infectious agents. The paranasal sinuses of clinically normal cattle (n = 99) and of cattle submitted for post-mortem examination (PME: n = 34) were examined by microbial culture, PCR and serology to include bacterial and viral pathogens typically associated with BRD: Mycoplasma bovis, Histophilus somni, Mannheimia haemolytica and Pasteurella multocida, bovine respiratory syncytial virus (BRSV) and bovine parainfluenza-3 virus (BPIV-3). Overall, the paranasal sinuses were either predominantly sterile or did not contain detectable microbes (83.5%: 94.9% of clinically normal and 50.0% of cattle submitted for PME). Bacteria, including BRD causing pathogens, were identified in relatively small numbers of cattle (<10%). While serology indicated widespread exposure of both clinically normal and cattle submitted for PME to BPIV-3 and BRSV (seroprevalences of 91.6% and 84.7%, respectively), PCR identified BPIV-3 in only one animal. To further explore these findings we investigated the potential role of the antimicrobial molecule nitric oxide (NO) within paranasal sinus epithelium using immunohistochemistry. Expression of the enzyme responsible for NO synthesis, inducible nitric oxide synthase (iNOS), was detected to varying degrees in 76.5% of a sub-sample of animals suggesting production of this compound plays a similar protective role in the bovine sinus as it does in humans

Evaluation of diagnostic pigments to estimate phytoplankton size classes

Limnology and Oceanography: Methods published by Wiley Periodicals LLC. on behalf of Association for the Sciences of Limnology and Oceanography. Phytoplankton accessory pigments are commonly used to estimate phytoplankton size classes, particularly during development and validation of biogeochemical models and satellite ocean color-based algorithms. The diagnostic pigment analysis (DPA) is based on bulk measurements of pigment concentrations and relies on assumptions regarding the presence of specific pigments in different phytoplankton taxonomic groups. Three size classes are defined by the DPA: picoplankton, nanoplankton, and microplankton. Until now, the DPA has not been evaluated against an independent approach that provides phytoplankton size calculated on a per-cell basis. Automated quantitative cell imagery of microplankton and some nanoplankton, used in combination with conventional flow cytometry for enumeration of picoplankton and nanoplankton, provide a novel opportunity to perform an independent evaluation of the DPA. Here, we use a data set from the North Atlantic Ocean that encompasses all seasons and a wide range of chlorophyll concentrations (0.18–5.14 mg m−3). Results show that the DPA overestimates microplankton and picoplankton when compared to cytometry data, and subsequently underestimates the contribution of nanoplankton to total biomass. In contrast to the assumption made by the DPA that the microplankton size class is largely made up of diatoms and dinoflagellates, imaging-in-flow cytometry shows significant presence of diatoms and dinoflagellates in the nanoplankton size class. Additionally, chlorophyll b is commonly attributed solely to picoplankton by the DPA, but Chl b-containing phytoplankton are observed with imaging in both nanoplankton and microplankton size classes. We suggest revisions to the DPA equations and application of uncertainties when calculating size classes from diagnostic pigments

Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons

Alternative splicing—the production of multiple messenger RNA isoforms from a single gene—is regulated in part by RNA binding proteins. While the RBPs transformer2 alpha (Tra2α) and Tra2β have both been implicated in the regulation of alternative splicing, their relative contributions to this process are not well understood. Here we find simultaneous—but not individual—depletion of Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α–Tra2β control. Target exons are enriched in genes associated with chromosome biology including CHEK1, which encodes a key DNA damage response protein. Dual Tra2 protein depletion reduces expression of full-length CHK1 protein, results in the accumulation of the DNA damage marker γH2AX and decreased cell viability. We conclude Tra2 proteins jointly control constitutive and alternative splicing patterns via paralog compensation to control pathways essential to the maintenance of cell viability