Abstract
The PathoSystems Resource Integration Center (PATRIC) is the bacterial Bioinformatics Resource Center funded by the National Institute of Allergy and Infectious Diseases ...(https://www.patricbrc.org). PATRIC supports bioinformatic analyses of all bacteria with a special emphasis on pathogens, offering a rich comparative analysis environment that provides users with access to over 250 000 uniformly annotated and publicly available genomes with curated metadata. PATRIC offers web-based visualization and comparative analysis tools, a private workspace in which users can analyze their own data in the context of the public collections, services that streamline complex bioinformatic workflows and command-line tools for bulk data analysis. Over the past several years, as genomic and other omics-related experiments have become more cost-effective and widespread, we have observed considerable growth in the usage of and demand for easy-to-use, publicly available bioinformatic tools and services. Here we report the recent updates to the PATRIC resource, including new web-based comparative analysis tools, eight new services and the release of a command-line interface to access, query and analyze data.
The Pathosystems Resource Integration Center (PATRIC) is the bacterial Bioinformatics Resource Center (https://www.patricbrc.org). Recent changes to PATRIC include a redesign of the web interface and ...some new services that provide users with a platform that takes them from raw reads to an integrated analysis experience. The redesigned interface allows researchers direct access to tools and data, and the emphasis has changed to user-created genome-groups, with detailed summaries and views of the data that researchers have selected. Perhaps the biggest change has been the enhanced capability for researchers to analyze their private data and compare it to the available public data. Researchers can assemble their raw sequence reads and annotate the contigs using RASTtk. PATRIC also provides services for RNA-Seq, variation, model reconstruction and differential expression analysis, all delivered through an updated private workspace. Private data can be compared by 'virtual integration' to any of PATRIC's public data. The number of genomes available for comparison in PATRIC has expanded to over 80 000, with a special emphasis on genomes with antimicrobial resistance data. PATRIC uses this data to improve both subsystem annotation and k-mer classification, and tags new genomes as having signatures that indicate susceptibility or resistance to specific antibiotics.
AS1411 is a 26-mer G-rich DNA oligonucleotide that forms a variety of G-quadruplex structures. It was identified based on its cancer-selective antiproliferative activity and subsequently determined ...to be an aptamer to nucleolin, a multifunctional protein that preferentially binds quadruplex nucleic acids and which is present at high levels on the surface of cancer cells. AS1411 has exceptionally efficient cellular internalization compared to non-quadruplex DNA sequences.
Recent developments related to AS1411 will be examined, with a focus on its use for targeted delivery of therapeutic and imaging agents.
Numerous research groups have used AS1411 as a targeting agent to deliver nanoparticles, oligonucleotides, and small molecules into cancer cells. Studies in animal models have demonstrated that AS1411-linked materials can accumulate selectively in tumors following systemic administration. The mechanism underlying the cancer-targeting ability of AS1411 is not completely understood, but recent studies suggest a model that involves: (1) initial uptake by macropinocytosis, a form of endocytosis prevalent in cancer cells; (2) stimulation of macropinocytosis by a nucleolin-dependent mechanism resulting in further uptake; and (3) disruption of nucleolin-mediated trafficking and efflux leading to cargoes becoming trapped inside cancer cells.
Human trials have indicated that AS1411 is safe and can induce durable remissions in a few patients, but new strategies are needed to maximize its clinical impact. A better understanding of the mechanisms by which AS1411 targets and kills cancer cells may hasten the development of promising technologies using AS1411-linked nanoparticles or conjugates for cancer-targeted therapy and imaging. This article is part of a Special Issue entitled "G-quadruplex" Guest Editor: Dr. Concetta Giancola and Dr. Daniela Montesarchio.
•AS1411 is a G-quadruplex DNA oligonucleotide that is also a nucleolin aptamer.•This review covers the structure, clinical status, uses, and mechanism of AS1411.•AS1411 is being widely used to deliver therapeutic and imaging agents to cancer cells.•Its cancer-targeting activity has been demonstrated in at least 30 animal studies.•Its targeting mechanism is not fully understood but may involve macropinocytosis.
To protect the aquatic living resources of Chesapeake Bay, the Chesapeake Bay Program partnership has developed guidance for state water quality standards, which include ambient water quality ...criteria to protect designated uses (DUs), and associated assessment procedures for dissolved oxygen (DO), water clarity/underwater bay grasses, and chlorophyll-a. For measuring progress toward meeting the respective states' water quality standards, a multimetric attainment indicator approach was developed to estimate combined standards attainment. We applied this approach to three decades of monitoring data of DO, water clarity/underwater bay grasses, and chlorophyll-a data on annually updated moving 3-year periods to track the progress in all 92 management segments of tidal waters in Chesapeake Bay. In 2014–2016, 40% of tidal water segment-DU-criterion combinations in the Bay (n = 291) are estimated to meet thresholds for attainment of their water quality criteria. This index score marks the best 3-year status in the entire record. Since 1985–1987, the indicator has followed a nonlinear trajectory, consistent with impacts from extreme weather events and subsequent recoveries. Over the period of record (1985–2016), the indicator exhibited a positive and statistically significant trend (p < 0.05), indicating that the Bay has been recovering since 1985. Patterns of attainment of individual DUs are variable, but improvements in open water DO, deep channel DO, and water clarity/submerged aquatic vegetation have combined to drive the improvement in the Baywide indicator in 2014–2016 relative to its long-term median. Finally, the improvement in estimated Baywide attainment was statistically linked to the decline of total nitrogen, indicating responsiveness of attainment status to the reduction of nutrient load through various management actions since at least the 1980s.
•Chesapeake Bay's water quality history was assessed by using an indicator framework.•The indicator has a positive long-term trend (p < 0.05) and reached its peak in 2014–2016.•The indicator was responsive to extreme weather events but can recover afterwards.•Improvement of indicator score in 2014–2016 over its long-term average was driven by open water and deep channel dissolved oxygen.•The improvement in Baywide attainment was statistically linked to the decline of total nitrogen input.
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Systemic delivery of conventional chemotherapies can cause negative systemic toxicity, including reduced immunity and damage to organs such as the heart and kidneys-limiting the maximum dose that can ...be administered. Targeted therapies appear to address this problem by having a specific target while mitigating off-target effects. Biocompatible perfluorocarbon-based nanodroplet emulsions encapsulated by a phospholipid shell are in development for delivery of molecular compounds and hold promise as vehicles for targeted delivery of chemotherapeutics to tumors. When ultrasound is applied, perfluorocarbon will undergo a phase change-ultimately inducing transient perforation of the cell membrane when in close proximity, which is more commonly known as "sonoporation." Sonoporation allows enhanced intracellular delivery of molecular compounds and will reseal to encapsulate the molecular compound intracellularly. In this study, we investigated delivery of thymoquinone (TQ), a natural hydrophobic phytochemical compound with bioactivity in cancer cells. In addition, we conjugated a G-quadruplex aptamer, 'AS1411', to TQ-loaded nanodroplets and explored their effects on multiple human cancer cell lines. AS1411 binds nucleolin, which is over-expressed on the surface of cancer cells, and in addition to its tumor-targeting properties AS1411 has also been shown to induce anti-cancer effects. Thymoquinone was loaded onto AS1411-conjugated nanodroplet emulsion to assess activity against cancer cells. Confocal microscopy indicated uptake of AS1411-conjugated nanodroplets by cancer cells. Furthermore, AS1411-conjugated nanoemulsions loaded with TQ significantly enhanced cytotoxicity in cancer cells compared to free compound. These results demonstrate that AS1411 can be conjugated onto nanodroplet emulsions for targeted delivery to human cancer cells. This novel formulation offers significant potential for targeted delivery of hydrophobic chemotherapeutics to tumors for cancer treatment.
Plerixafor for the Treatment of WHIM Syndrome McDermott, David H; Pastrana, Diana V; Calvo, Katherine R ...
The New England journal of medicine,
01/2019, Letnik:
380, Številka:
2
Journal Article
Recenzirano
Odprti dostop
WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in ...CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).
Abstract
Objectives
To investigate the slowdown in mortality improvement in the United States, United Kingdom, and comparator countries observed in the first decade of the twenty-first century and ...critically evaluate proposed explanations.
Methods
Change-point analysis to identify the year of change in comparison of national mortality trends and linear spline models in the investigation of subnational differences using data from the Human Mortality Database, Global Burden of Disease cause-specific data, and, for the United Kingdom, national statistics data. Consideration of the impact of using different methods to estimate overall mortality is also concluded together with a review of methodological assumptions made in previous studies.
Results
The results confirm the slowdown in mortality improvement observed in the early twenty-first century but indicate that proposed explanations for this are inadequate on a range of counts.
Discussion
Mortality improvement slowed down in the early twenty-first century but the explanations advanced, such as opioid use in the United States or influenza epidemics and austerity programs in the United Kingdom, seem unlikely to account for this. Further research considering longer-term life course and cohort influences is needed.
Tuberous sclerosis is a developmental genetic disorder caused by mutations in TSC1, which results in epilepsy, autism, and intellectual disability. The cause of these neurological deficits remains ...unresolved. Imaging studies suggest that the thalamus may be affected in tuberous sclerosis patients, but this has not been experimentally interrogated. We hypothesized that thalamic deletion of Tsc1 at distinct stages of mouse brain development would produce differential phenotypes. We show that mosaic Tsc1 deletion within thalamic precursors at embryonic day (E) 12.5 disrupts thalamic circuitry and alters neuronal physiology. Tsc1 deletion at this early stage is unique in causing both seizures and compulsive grooming in adult mice. In contrast, only a subset of these phenotypes occurs when thalamic Tsc1 is deleted at a later embryonic stage. Our findings demonstrate that abnormalities in a discrete population of neurons can cause global brain dysfunction and that phenotype severity depends on developmental timing and degree of genetic mosaicism.
•Spatially and temporally controlled Tsc1 deletion mimics genetic mosaicism•Early Tsc1 deletion causes abnormal thalamic neuron physiology•Tsc1 mutant thalamic circuits alter somatosensory cortex patterning and function•Tsc1 deletion within developing thalamus causes abnormal grooming and seizures
Tuberous sclerosis is a genetic disorder involving autism, epilepsy, and intellectual disability. Using genetic mouse models, Normand et al. show how developmental timing of gene deletion, number of mutant neurons, and the brain regions affected contribute to these complex disease phenotypes.
The Association of American Medical Colleges identifies telemedicine competence as an important skill for graduating medical students, but which educational methods are effective in improving student ...performance is unclear. We aimed to assess the impact of two educational interventions on student performance in telemedicine standardized patient encounters.
Sixty second-year medical students participated in the telemedicine curriculum during their required longitudinal ambulatory clerkship. Students first completed a preintervention telemedicine standardized patient (SP) encounter in October 2020. They subsequently were assigned to two intervention groups (ie, a role-play intervention, N=30; a faculty demonstration, N=30) and completed a teaching case. In December 2020, they completed a postintervention telemedicine SP encounter. Each case was a unique clinical scenario. SPs scored the encounters across six domains based on a standardized performance checklist. We compared the median scores for these domains and the median total score pre- and postintervention (using Wilcoxon signed rank and rank-sum tests) and the difference in median score by intervention type.
Students scored highly in history-taking and communication performance but had low physical exam (PE) and assessment/plan scores. Postintervention, median scores in PE (ie, median score difference 2, interquartile ranges IQR 1-3.5, P<.001), assessment/plan (ie, median score difference 0.5, IQR 0-2, P=.005), and overall performance improved significantly (ie, median score difference 3, IQR 0-5, P<.001).
Early medical students had low performance at baseline in telemedicine PE and assessment/plan skills, but both a role-play intervention and faculty demonstration led to significant increases in student performance.
Background
Security emergency responses (SERs) are utilized by hospitals to ensure the safety of patients and staff but can cause unintended morbidity. The presence of racial and ethnic inequities in ...SER utilization has not been clearly elucidated.
Objective
To determine whether Black and Hispanic patients experience higher rates of SER and physical restraints in a non-psychiatric inpatient setting.
Design
Retrospective cohort study.
Participants
All patients discharged from September 2018 through December 2019.
Exposure
Race and ethnicity, as reported by patients at time of registration.
Main Outcomes
The primary outcome was whether a SER was called on a patient. The secondary outcome was the incidence of physical restraints among patients who experienced a SER.
Key Results
Among 24,212 patients, 18,755 (77.5%) patients identified as white, 2,346 (9.7%) as Black, and 2,425 (10.0%) identified with another race. Among all patients, 1,827 (7.6%) identified as Hispanic and 21,554 (89.0%) as non-Hispanic. Sixty-six (2.8%) Black patients had a SER activated during their first admission, compared to 295 (1.6%) white patients. In a Firth logit multivariable model, Black patients had higher adjusted odds of a SER than white patients (adjusted odds ratio (aOR) 1.37 95% confidence interval: 1.02, 1.81,
p
= 0.037). Hispanic patients did not have higher odds of having a SER called than non-Hispanic patients. In a Poisson multivariable model among patients who had a SER called, race and ethnicity were not found to be significant predictors of restraint.
Conclusion
Black patients had higher odds of a SER compared to white patients. No significant differences were found between Hispanic and non-Hispanic patients. Future efforts should focus on assessing the generalizability of these findings, the underlying mechanisms driving these inequities, and effective interventions to address them.
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