Choosing the Right Path toward Polio Eradication John, T. Jacob; Hirschhorn, Norbert; Dharmapalan, Dhanya ...
The New England journal of medicine,
05/2023, Letnik:
388, Številka:
19
Journal Article
Recenzirano
To the Editor:
The Perspective article by Chumakov et al. (Feb. 16 issue)
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articulates the discontent of many observers, including us. We agree that “the use of OPV oral polio vaccine must also be ...stopped” to eradicate polio. Eliminating wild poliovirus circulation with OPV and eliminating vaccine-virus polio with the use of inactivated polio vaccine (IPV) is a time-tested model, illustrated by Norway (1979), France (1988), Germany (1989), the United States (2000), New Zealand (2002), the United Kingdom (2004), and Malaysia (2008).
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We question two of the authors’ statements. The first is that “policy decisions must be based on solid . . .
A variety of protocols exist for producing whole genome run-on transcription datasets. However, little is known about how differences between these protocols affect the signal within the resulting ...libraries.
Using run-on transcription datasets generated from the same biological system, we show that a variety of GRO- and PRO-seq preparation methods leave identifiable signatures within each library. Specifically we show that the library preparation method results in differences in quality control metrics, as well as differences in the signal distribution at the 5
end of transcribed regions. These shifts lead to disparities in eRNA identification, but do not impact analyses aimed at inferring the key regulators involved in changes to transcription.
Run-on sequencing protocol variations result in technical signatures that can be used to identify both the enrichment and library preparation method of a particular data set. These technical signatures are batch effects that limit detailed comparisons of pausing ratios and eRNAs identified across protocols. However, these batch effects have only limited impact on our ability to infer which regulators underlie the observed transcriptional changes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Many cancers carry recurrent, change-of-function mutations affecting RNA splicing factors. Here, we describe a method to harness this abnormal splicing activity to drive splicing factor ...mutation-dependent gene expression to selectively eliminate tumor cells. We engineered synthetic introns that were efficiently spliced in cancer cells bearing SF3B1 mutations, but unspliced in otherwise isogenic wild-type cells, to yield mutation-dependent protein production. A massively parallel screen of 8,878 introns delineated ideal intronic size and mapped elements underlying mutation-dependent splicing. Synthetic introns enabled mutation-dependent expression of herpes simplex virus-thymidine kinase (HSV-TK) and subsequent ganciclovir (GCV)-mediated killing of SF3B1-mutant leukemia, breast cancer, uveal melanoma and pancreatic cancer cells in vitro, while leaving wild-type cells unaffected. Delivery of synthetic intron-containing HSV-TK constructs to leukemia, breast cancer and uveal melanoma cells and GCV treatment in vivo significantly suppressed the growth of these otherwise lethal xenografts and improved mouse host survival. Synthetic introns provide a means to exploit tumor-specific changes in RNA splicing for cancer gene therapy.
Chronic stress is epidemiologically correlated with physical and psychiatric disorders. Whereas many animal models of chronic stress induce symptoms of psychopathology, repeated homotypic stressors ...to moderate intensity stimuli typically reduce stress-related responses with fewer, if any, pathological symptoms. Recent results indicate that the rostral posterior hypothalamic (rPH) region is a significant component of the brain circuitry underlying response reductions (habituation) associated with repeated homotypic stress. To test whether posterior hypothalamic transcriptional regulation associates with the neuroendocrine modifications induced by repeated homotypic stress, RNA-seq was performed in the rPH dissected from adult male rats that experienced either no stress, 1, 3, or 7 stressful loud noise exposures. Plasma samples displayed reliable increases of corticosterone in all stressed groups, with the smallest increase in the group exposed to 7 loud noises, indicating significant habituation compared to the other stressed groups. While few or no differentially expressed genes were detected 24-h after one or three loud noise exposures, relatively large numbers of transcripts were differentially expressed between the group exposed to 7 loud noises when compared to the control or 3-stress groups, respectively, which correlated with the corticosterone response habituation observed. Gene ontology analyses indicated multiple significant functional terms related to neuron differentiation, neural membrane potential, pre- and post-synaptic elements, chemical synaptic transmission, vesicles, axon guidance and projection, glutamatergic and GABAergic neurotransmission. Some of the differentially expressed genes (Myt1l, Zmat4, Dlx6, Csrnp3) encode transcription factors that were independently predicted by transcription factor enrichment analysis to target other differentially regulated genes in this study. A similar experiment employing
hybridization histochemical analysis in additional animals validated the direction of change of the 5 transcripts investigated (Camk4, Gabrb2, Gad1, Grin2a and Slc32a) with a high level of temporal and regional specificity for the rPH. In aggregate, the results suggest that distinct patterns of gene regulation are obtained in response to a repeated homotypic stress regimen; they also point to a significant reorganization of the rPH region that may critically contribute to the phenotypic modifications associated with repeated homotypic stress habituation.
We investigate students' sense of ownership of multiweek final projects in an upper-division optics lab course. Using a multiple case study approach, we describe three student projects in detail. ...Within-case analyses focused on identifying key issues in each project, and constructing chronological descriptions of those events. Cross-case analysis focused on identifying emergent themes with respect to five dimensions of project ownership: student agency, instructor mentorship, peer collaboration, interest and value, and affective responses. Our within- and cross-case analyses yielded three major findings. First, coupling division of labor with collective brainstorming can help balance student agency, instructor mentorship, and peer collaboration. Second, students' interest in the project and perceptions of its value can increase over time; initial student interest in the project topic is not a necessary condition for student ownership of the project. Third, student ownership is characterized by a wide range of emotions that fluctuate as students alternate between extended periods of struggle and moments of success while working on their projects. These findings not only extend the literature on student ownership into a new educational domain--namely, upper-division physics labs--they also have concrete implications for the design of experimental physics projects in courses for which student ownership is a desired learning outcome. We describe the course and projects in sufficient detail that others can adapt our results to their particular contexts.
2-Oxoglutarate and iron dependent oxygenases are therapeutic targets for human diseases. Using a representative 2OG oxygenase panel, we compare the inhibitory activities of ...5-carboxy-8-hydroxyquinoline (IOX1) and 4-carboxy-8-hydroxyquinoline (4C8HQ) with that of two other commonly used 2OG oxygenase inhibitors,
-oxalylglycine (NOG) and 2,4-pyridinedicarboxylic acid (2,4-PDCA). The results reveal that IOX1 has a broad spectrum of activity, as demonstrated by the inhibition of transcription factor hydroxylases, representatives of all 2OG dependent histone demethylase subfamilies, nucleic acid demethylases and γ-butyrobetaine hydroxylase. Cellular assays show that, unlike NOG and 2,4-PDCA, IOX1 is active against both cytosolic and nuclear 2OG oxygenases without ester derivatisation. Unexpectedly, crystallographic studies on these oxygenases demonstrate that IOX1, but not 4C8HQ, can cause translocation of the active site metal, revealing a rare example of protein ligand-induced metal movement.
The use of lab notebooks for scientific documentation is a ubiquitous part of physics research. However, it is common for undergraduate physics laboratory courses not to emphasize the development of ...documentation skills, despite the fact that such courses are some of the earliest opportunities for students to start engaging in this practice. One potential impediment to the inclusion of explicit documentation training is that it may be unclear to instructors which features of authentic documentation practice are efficacious to teach and how to incorporate these features into the lab class environment. In this work, we outline some of the salient features of authentic documentation, informed by interviews with physics researchers, and provide recommendations for how these can be incorporated into the lab curriculum. We do not focus on structural details or templates for notebooks. Instead, we address holistic considerations for the purpose of scientific documentation that can guide students to develop their own documentation style. While taking into consideration all the aspects that can help improve students' documentation, it is also important to consider the design of the lab activities themselves. Students should have experience with implementing these authentic features of documentation during lab activities in order for them to find practice with documentation beneficial.
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•Intermetallic Ni–Zn catalysts were employed for acetylene semi-hydrogenation.•Isotopic labeling was used to evaluate reaction pathways.•Ethylene selectivity increases with increasing ...zinc content.•Zinc addition to nickel reduces the propensity for carbon–carbon bond formation.
Isotopic labeling and density functional theory (DFT) were used to determine the mechanism for acetylene hydrogenation and oligomerization on well-defined intermetallic nickel–zinc catalysts. The primary benefit of adding zinc to nickel is a reduction in oligomeric species formation which leads to higher ethylene selectivity. The production of ethane is not highly dependent on zinc content; therefore, ethane production is not a good descriptor of ethylene selectivity since acetylene may also be converted to higher molecular weight products. Analysis using DFT and Langmuir–Hinshelwood kinetics shows that the large decrease in the adsorption energy of acetylene on intermetallic NiZn compared to pure Ni is responsible for the observed increase in ethylene selectivity. The adsorption energy of acetylene appears to be a descriptor for carbon–carbon bond formation since a high adsorption energy leads to an increased coverage of C2 species and an increased rate of carbon–carbon bond formation.
We demonstrate how students' use of modeling can be examined and assessed using student notebooks collected from an upper-division electronics lab course. The use of models is a ubiquitous practice ...in undergraduate physics education, but the process of constructing, testing, and refining these models is much less common. We focus our attention on a lab course that has been transformed to engage students in this modeling process during lab activities. The design of the lab activities was guided by a framework that captures the different components of model-based reasoning, called the Modeling Framework for Experimental Physics. We demonstrate how this framework can be used to assess students' written work and to identify how students' model-based reasoning differed from activity to activity. Broadly speaking, we were able to identify the different steps of students' model-based reasoning and assess the completeness of their reasoning. Varying degrees of scaffolding present across the activities had an impact on how thoroughly students would engage in the full modeling process, with more scaffolded activities resulting in more thorough engagement with the process. Finally, we identified that the step in the process with which students had the most difficulty was the comparison between their interpreted data and their model prediction. Students did not use sufficiently sophisticated criteria in evaluating such comparisons, which had the effect of halting the modeling process. This may indicate that in order to engage students further in using model-based reasoning during lab activities, the instructor needs to provide further scaffolding for how students make these types of experimental comparisons. This is an important design consideration for other such courses attempting to incorporate modeling as a learning goal.
In experimental physics, lab notebooks play an essential role in the research process. For all of the ubiquity of lab notebooks, little formal attention has been paid to addressing what is considered ..."best practice" for scientific documentation and how researchers come to learn these practices in experimental physics. Using interviews with practicing researchers, namely, physics graduate students, we explore the different experiences researchers had in learning how to effectively use a notebook for scientific documentation. We find that very few of those interviewed thought that their undergraduate lab classes successfully taught them the benefit of maintaining a lab notebook. Most described training in lab notebook use as either ineffective or outright missing from their undergraduate lab course experience. Furthermore, a large majority of those interviewed explained that they did not receive any formal training in maintaining a lab notebook during their graduate school experience and received little to no feedback from their advisors on these records. Many of the interviewees describe learning the purpose of, and how to maintain, these kinds of lab records only after having a period of trial and error, having already started doing research in their graduate program. Despite the central role of scientific documentation in the research enterprise, these physics graduate students did not gain skills in documentation through formal instruction, but rather through informal hands-on practice.
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