2,097 research outputs found
Kripke Semantics for Martin-L\"of's Extensional Type Theory
It is well-known that simple type theory is complete with respect to
non-standard set-valued models. Completeness for standard models only holds
with respect to certain extended classes of models, e.g., the class of
cartesian closed categories. Similarly, dependent type theory is complete for
locally cartesian closed categories. However, it is usually difficult to
establish the coherence of interpretations of dependent type theory, i.e., to
show that the interpretations of equal expressions are indeed equal. Several
classes of models have been used to remedy this problem. We contribute to this
investigation by giving a semantics that is standard, coherent, and
sufficiently general for completeness while remaining relatively easy to
compute with. Our models interpret types of Martin-L\"of's extensional
dependent type theory as sets indexed over posets or, equivalently, as
fibrations over posets. This semantics can be seen as a generalization to
dependent type theory of the interpretation of intuitionistic first-order logic
in Kripke models. This yields a simple coherent model theory, with respect to
which simple and dependent type theory are sound and complete
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A drug-repositioning screen using splicing-sensitive fluorescent reporters identifies novel modulators of VEGF-A splicing with anti-angiogenic properties.
Alternative splicing of the vascular endothelial growth factor A (VEGF-A) terminal exon generates two protein families with differing functions. Pro-angiogenic VEGF-Axxxa isoforms are produced via selection of the proximal 3' splice site of the terminal exon. Use of an alternative distal splice site generates the anti-angiogenic VEGF-Axxxb proteins. A bichromatic splicing-sensitive reporter was designed to mimic VEGF-A alternative splicing and was used as a molecular tool to further investigate this alternative splicing event. Part of VEGF-A's terminal exon and preceding intron were inserted into a minigene construct followed by the coding sequences for two fluorescent proteins. A different fluorescent protein is expressed depending on which 3' splice site of the exon is used during splicing (dsRED denotes VEGF-Axxxa and EGFP denotes VEGF-Axxxb). The fluorescent output can be used to follow splicing decisions in vitro and in vivo. Following successful reporter validation in different cell lines and altering splicing using known modulators, a screen was performed using the LOPAC library of small molecules. Alterations to reporter splicing were measured using a fluorescent plate reader to detect dsRED and EGFP expression. Compounds of interest were further validated using flow cytometry and assessed for effects on endogenous VEGF-A alternative splicing at the mRNA and protein level. Ex vivo and in vitro angiogenesis assays were used to demonstrate the anti-angiogenic effect of the compounds. Furthermore, anti-angiogenic activity was investigated in a Matrigel in vivo model. To conclude, we have identified a set of compounds that have anti-angiogenic activity through modulation of VEGF-A terminal exon splicing
A drug-repositioning screen using splicing-sensitive fluorescent reporters identifies novel modulators of VEGF-A splicing with anti-angiogenic properties.
Alternative splicing of the vascular endothelial growth factor A (VEGF-A) terminal exon generates two protein families with differing functions. Pro-angiogenic VEGF-Axxxa isoforms are produced via selection of the proximal 3' splice site of the terminal exon. Use of an alternative distal splice site generates the anti-angiogenic VEGF-Axxxb proteins. A bichromatic splicing-sensitive reporter was designed to mimic VEGF-A alternative splicing and was used as a molecular tool to further investigate this alternative splicing event. Part of VEGF-A's terminal exon and preceding intron were inserted into a minigene construct followed by the coding sequences for two fluorescent proteins. A different fluorescent protein is expressed depending on which 3' splice site of the exon is used during splicing (dsRED denotes VEGF-Axxxa and EGFP denotes VEGF-Axxxb). The fluorescent output can be used to follow splicing decisions in vitro and in vivo. Following successful reporter validation in different cell lines and altering splicing using known modulators, a screen was performed using the LOPAC library of small molecules. Alterations to reporter splicing were measured using a fluorescent plate reader to detect dsRED and EGFP expression. Compounds of interest were further validated using flow cytometry and assessed for effects on endogenous VEGF-A alternative splicing at the mRNA and protein level. Ex vivo and in vitro angiogenesis assays were used to demonstrate the anti-angiogenic effect of the compounds. Furthermore, anti-angiogenic activity was investigated in a Matrigel in vivo model. To conclude, we have identified a set of compounds that have anti-angiogenic activity through modulation of VEGF-A terminal exon splicing
Certified DNA Reference Materials to Compare HER2 Gene Amplification Measurements Using Next-Generation Sequencing Methods
The National Institute of Standards and Technology (NIST) Standard Reference Materials 2373 is a set of genomic DNA samples prepared from five breast cancer cell lines with certified values for the ratio of the HER2 gene copy number to the copy numbers of reference genes determined by real-time quantitative PCR and digital PCR. Targeted-amplicon, whole-exome, and whole-genome sequencing measurements were used with the reference material to compare the performance of both the laboratory steps and the bioinformatic approaches of the different methods using a range of amplification ratios. Although good reproducibility was observed in each next-generation sequencing method, slightly different HER2 copy numbers associated with platform-specific biases were obtained. This study clearly demonstrates the value of Standard Reference Materials 2373 as reference material and as a calibrator for evaluating assay performance as well as for increasing confidence in reporting HER2 amplification for clinical applications
Carpenter-Coustan Compared With National Diabetes Data Group Criteria for Diagnosing Gestational Diabetes
Use of Carpenter-Coustan compared to National Diabetes Data Group (NDDG) criteria increases the number of women diagnosed with GDM by 30-50%, but whether treatment of this milder GDM reduces adverse outcomes is unknown. We explored the effects of the diagnostic criteria used on the benefits of GDM treatment
Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis
RATIONALE
Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-Aa and VEGF-Ab, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF.
OBJECTIVES
To establish VEGF-A isoform expression and functional effects in IPF.
METHODS
We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTATetoCreLoxP-VEGF-Ato conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice.
MEASUREMENTS AND MAIN RESULTS
IPF and normal lung fibroblasts differentially expressed and responded to VEGF-Aa and VEGF-Ab in terms of proliferation and matrix expression. Increased VEGF-Ab was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-Ab inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-Ab to wild-type mice.
CONCLUSIONS
These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-Aa to VEGF-Ab, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair
Global biochemical and structural analysis of the type IV pilus from the Gram-positive bacterium Streptococcus sanguinis
Type IV pili (Tfp) are functionally versatile filaments, widespread in prokaryotes, that belong to a large class of filamentous nanomachines known as type IV filaments (Tff). Although Tfp have been extensively studied in several Gram-negative pathogens where they function as key virulence factors, many aspects of their biology remain poorly understood. Here, we performed a global biochemical and structural analysis of Tfp in a recently emerged Gram-positive model, Streptococcus sanguinis. In particular, we focused on the five pilins and pilin-like proteins involved in Tfp biology in S. sanguinis. We found that the two major pilins, PilE1 and PilE2, (i) follow widely conserved principles for processing by the prepilin peptidase PilD and for assembly into filaments; (ii) display only one of the post-translational modifications frequently found in pilins, i.e. a methylatedN terminus; (iii) are found in the same heteropolymeric filaments; and (iv) are not functionally equivalent. The 3D structure of PilE1, solved byNMR,revealed a classical pilin-fold with a highly unusual flexible C terminus. Intriguingly, PilE1 more closely resembles pseudopilins forming shorter Tff than bona fide Tfp-forming major pilins, underlining the evolutionary relatedness among different Tff. Finally, we show that S. sanguinis Tfp contain a low abundance of three additional proteins processed by PilD, the minor pilins PilA, PilB, and PilC. These findings provide the first global biochemical and structural picture of a Gram-positive Tfp and have fundamental implications for our understanding of a widespread class of filamentous nanomachines
Repeated course antenatal steroids, inflammation gene polymorphisms, and neurodevelopmental outcomes at age 2
Evaluate the interaction between repeated course antenatal corticosteroids and inflammation gene polymorphisms with neurodevelopmental outcomes at age 2
SN 2021zny: an early flux excess combined with late-time oxygen emission suggests a double white dwarf merger event
We present a photometric and spectroscopic analysis of the ultra-luminous and
slowly evolving 03fg-like Type Ia SN 2021zny. Our observational campaign starts
from hours after explosion (making SN 2021zny one of the earliest
observed members of its class), with dense multi-wavelength coverage from a
variety of ground- and space-based telescopes, and is concluded with a nebular
spectrum months after peak brightness. SN 2021zny displayed several
characteristics of its class, such as the peak brightness ( mag),
the slow decline ( mag), the blue early-time colours,
the low ejecta velocities and the presence of significant unburned material
above the photosphere. However, a flux excess for the first days
after explosion is observed in four photometric bands, making SN 2021zny the
third 03fg-like event with this distinct behavior, while its d spectrum
shows prominent [O I] lines, a very unusual characteristic of thermonuclear
SNe. The early flux excess can be explained as the outcome of the interaction
of the ejecta with of H/He-poor circumstellar
material at a distance of cm, while the low ionization state of
the late-time spectrum reveals low abundances of stable iron-peak elements. All
our observations are in accordance with a progenitor system of two
carbon/oxygen white dwarfs that undergo a merger event, with the disrupted
white dwarf ejecting carbon-rich circumstellar material prior to the primary
white dwarf detonation.Comment: 19 pages, 16 figures, accepted for publication in MNRA
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