363 research outputs found
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The RIR motif in the scaffold protein XRCC1 mediates a low-affinity interaction with polynucleotide kinase/phosphatase (PNKP) during DNA single-strand break repair
The scaffold protein X-ray repair cross-complementing 1 (XRCC1)interacts with multiple enzymes involved in DNA base excision repair and single-strand break repair(SSBR) and is important for genetic integrity and normal neurological
function. One of the most important interactions of XRCC1 is that with polynucleotide kinase/phosphatase(PNKP), a dual-function DNA kinase/phosphatase that processes damaged DNA termini and that, if mutated, results in ataxia with oculomotor apraxia 4 (AOA4) and microcephaly with early-onset seizures and developmental delay(MCSZ). XRCC1 and PNKP interact via a high-affinity phosphorylationdependent
interaction site in XRCC1 and a fork-head associated domain
in PNKP. Here, we identified using biochemical and biophysical approaches a second PNKP interaction site in XRCC1 that binds PNKP with lower affinity and independently of XRCC1 phosphorylation. However, this interaction nevertheless stimulated PNKP activity and promoted SSBR
and cell survival. The low-affinity interaction site required the highly conserved REV1-interacting (RIR)
motif in XRCC1 and included three critical and evolutionarily invariant phenylalanine residues. We propose
a bipartite interaction model in which the previously identified highaffinity interaction acts as a molecular tether, holding XRCC1 and PNKP together and thereby
promoting the low-affinity interaction identified here, which then stimulates PNKP directly
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Research priorities of women at risk for preterm birth: findings and a call to action.
BACKGROUND:Traditional hierarchical approaches to research give privilege to small groups with decision-making power, without direct input from those with lived experience of illness who bear the burden of disease. A Research Justice framework values the expertise of patients and communities as well as their power in creating knowledge and in decisions about what research is conducted. Preterm birth has persisted at epidemic levels in the United States for decades and disproportionately affects women of color, especially Black women. Women of color have not been included in setting the agenda regarding preterm birth research. METHODS:We used the Research Priorities of Affected Communities protocol to elicit and prioritize potential research questions and topics directly from women of color living in three communities that experience disproportionately high rates of preterm birth. Women participated in two focus group sessions, first describing their healthcare experiences and generating lists of uncertainties about their health and/or healthcare during pregnancy. Women then participated in consensus activities to achieve 'top-priority' research questions and topic lists. The priority research questions and topics produced by each group were examined within and across the three regions for similarities and differences. RESULTS:Fifty-four women participated in seven groups (14 sessions) and generated 375 researchable questions, clustered within 22 topics and four overarching themes: Maternal Health and Care Before, During, and After Pregnancy; Newborn Health and Care of the Preterm Baby; Understanding Stress and Interventions to Prevent or Reduce Stress; and Interpersonal and Structural Health Inequities. The questions and topics represent a wide range of research domains, from basic science, translational, clinical, health and social care delivery to policy and economic research. There were many similarities and some unique differences in the questions, topics and priorities across the regions. CONCLUSIONS:These findings can be used to design and fund research addressing unanswered questions that matter most to women at high risk for preterm birth. Investigators and funders are strongly encouraged to incorporate women at the front lines of the preterm birth epidemic in research design and funding decisions, and more broadly, to advance methods to deepen healthcare research partnerships with affected communities
Pharmacological inhibition of c-Abl compromises genetic stability and DNA repair in Bcr-Abl-negative cells
Imatinib inhibits the kinase activity of Bcr-Abl and is currently the most effective drug for treatment of chronic myeloid leukemia (CML). Imatinib also blocks c-Abl, a physiological tyrosine kinase activated by a variety of stress signals including damaged DNA. We investigated the effect of pharmacological inhibition of c-Abl on the processing of irradiation-induced DNA damage in Bcr-Abl-negative cells. Cell lines and peripheral blood mononuclear cells (PBMCs) from healthy volunteers were treated with imatinib or dasatinib before gamma-irradiation. Inhibition of c-Abl caused an enhanced irradiation-induced mutation frequency and slowdown of DNA repair, whereas imatinib was ineffective in cells expressing a T315I variant of c-Abl. Mutation frequency and repair kinetics were also studied in c-Abl-/- murine embryonic fibroblasts (MEFs) retransfected with wild-type c-Abl (wt-Abl) or a kinase-defect variant of Abl (KD-Abl). Enhanced mutation frequency as well as delayed DNA repair was observed in cells expressing KD-Abl. These data indicate that pharmacological inhibition of c-Abl compromises DNA-damage response
"Forget" the Forget Gate: Estimating Anomalies in Videos using Self-contained Long Short-Term Memory Networks
Abnormal event detection is a challenging task that requires effectively
handling intricate features of appearance and motion. In this paper, we present
an approach of detecting anomalies in videos by learning a novel LSTM based
self-contained network on normal dense optical flow. Due to their sigmoid
implementations, standard LSTM's forget gate is susceptible to overlooking and
dismissing relevant content in long sequence tasks like abnormality detection.
The forget gate mitigates participation of previous hidden state for
computation of cell state prioritizing current input. In addition, the
hyperbolic tangent activation of standard LSTMs sacrifices performance when a
network gets deeper. To tackle these two limitations, we introduce a bi-gated,
light LSTM cell by discarding the forget gate and introducing sigmoid
activation. Specifically, the LSTM architecture we come up with fully sustains
content from previous hidden state thereby enabling the trained model to be
robust and make context-independent decision during evaluation. Removing the
forget gate results in a simplified and undemanding LSTM cell with improved
performance effectiveness and computational efficiency. Empirical evaluations
show that the proposed bi-gated LSTM based network outperforms various LSTM
based models verifying its effectiveness for abnormality detection and
generalization tasks on CUHK Avenue and UCSD datasets.Comment: 16 pages, 7 figures, Computer Graphics International (CGI) 202
Mineral magnetism of dusty olivine:A credible recorder of pre-accretionary remanence
The magnetic properties of olivine-hosted Fe-Ni particles have been studied to assess the potential of âdusty olivineâ to retain a pre-accretionary remanence in chondritic meteorites. Both body-centered (bcc) and face-centered cubic (fcc) Fe-Ni phases were formed by reduction of a terrestrial olivine precursor. The presence of Ni complicates the magnetic properties during heating and cooling due to the fcc-bcc martensitic transition. First-order reversal curve (FORC) diagrams contain a central ridge with a broad coercivity distribution extending to 600 mT, attributed to non-interacting single-domain (SD) particles, and a âbutterflyâ structure extending to 250 mT, attributed to single-vortex (SV) states. SD and SV states were imaged directly using electron holography. The location of the SD/SV boundary is broadly consistent with theoretical predictions. A method to measure the volume of individual SD particles using electron holography is presented. Combining the volume information with constraints on coercivity, we calculate the thermal relaxation characteristics of the particles and demonstrate that the high-coercivity component of remanance would remain stable for 4.6 Ga, even at temperatures approaching the Curie temperature of pure Fe. The high coercivity of the particles, together with the chemical protection offered by the surrounding olivine, is likely to make them resistant to shock remagnetization, isothermal remagnetization and terrestrial weathering, making dusty olivine a credible recorder of pre-accretionary magnetic fields
A mitochondria-targeted mass spectrometry probe to detect glyoxals: implications for diabetes
The glycation of protein and nucleic acids that occurs as a consequence of hyperglycaemia disrupts cell function and contributes to many pathologies, including those associated with diabetes and aging. Intracellular glycation occurs following the generation of the reactive 1,2-dicarbonyls methylglyoxal and glyoxal and disruption to mitochondrial function is associated with hyperglycemia. However, the contribution of these reactive dicarbonyls to mitochondrial damage in pathology is unclear due to uncertainties about their levels within mitochondria in cells and in vivo. To address this we have developed a mitochondria-targeted reagent (MitoG) designed to assess the levels of mitochondrial dicarbonyls within cells. MitoG comprises a lipophilic triphenylphosphonium cationic function, which directs the molecules to mitochondria within cells and an o-phenylenediamine moiety that reacts with dicarbonyls to give distinctive and stable products. The extent of accumulation of these diagnostic heterocyclic products can be readily and sensitively quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS), enabling changes to be determined. Using the MitoG-based analysis we assessed the formation of methylglyoxal and glyoxal in response to hyperglycaemia in cells in culture and in the Akita mouse model of diabetes in vivo. These findings indicated that the levels of methylglyoxal and glyoxal within mitochondria increase during hyperglycaemia in both cells and in vivo, suggesting that they can contribute to the pathological mitochondrial dysfunction that occurs in diabetes and aging
Time-of-Flight Three Dimensional Neutron Diffraction in Transmission Mode for Mapping Crystal Grain Structures
The physical properties of polycrystalline materials depend on their microstructure, which is the nano-to centimeter scale arrangement of phases and defects in their interior. Such microstructure depends on the shape, crystallographic phase and orientation, and interfacing of the grains constituting the material. This article presents a new non-destructive 3D technique to study centimeter-sized bulk samples with a spatial resolution of hundred micrometers: time-of-flight three-dimensional neutron diffraction (ToF 3DND). Compared to existing analogous X-ray diffraction techniques, ToF 3DND enables studies of samples that can be both larger in size and made of heavier elements. Moreover, ToF 3DND facilitates the use of complicated sample environments. The basic ToF 3DND setup, utilizing an imaging detector with high spatial and temporal resolution, can easily be implemented at a time-of-flight neutron beamline. The technique was developed and tested with data collected at the Materials and Life Science Experimental Facility of the Japan Proton Accelerator Complex (J-PARC) for an iron sample. We successfully reconstructed the shape of 108 grains and developed an indexing procedure. The reconstruction algorithms have been validated by reconstructing two stacked Co-Ni-Ga single crystals, and by comparison with a grain map obtained by post-mortem electron backscatter diffraction (EBSD)
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