Atomic Resolution Cryo-EM Structure Of A Nativelike CENP-A Nucleosome Aided By An Antibody Fragment

Genomic DNA in eukaryotes is organized into chromatin through association with core histones to form nucleosomes, each distinguished by their DNA sequences and histone variants. Here, we used a single-chain antibody fragment (scFv) derived from the anti-nucleosome antibody mAb PL2-6 to stabilize human CENP-A nucleosome containing a native α-satellite DNA and solved its structure by the cryo-electron microscopy (cryo-EM) to 2.6 Å resolution. In comparison, the corresponding cryo-EM structure of the free CENP-A nucleosome could only reach 3.4 Å resolution. We find that scFv binds to a conserved acidic patch on the histone H2A-H2B dimer without perturbing the nucleosome structure. Our results provide an atomic resolution cryo-EM structure of a nucleosome and insight into the structure and function of the CENP-A nucleosome. The scFv approach is applicable to the structural determination of other native-like nucleosomes with distinct DNA sequences

The Insulator Binding Protein CTCF Positions 20 Nucleosomes around Its Binding Sites across the Human Genome

Chromatin structure plays an important role in modulating the accessibility of genomic DNA to regulatory proteins in eukaryotic cells. We performed an integrative analysis on dozens of recent datasets generated by deep-sequencing and high-density tiling arrays, and we discovered an array of well-positioned nucleosomes flanking sites occupied by the insulator binding protein CTCF across the human genome. These nucleosomes are highly enriched for the histone variant H2A.Z and 11 histone modifications. The distances between the center positions of the neighboring nucleosomes are largely invariant, and we estimate them to be 185 bp on average. Surprisingly, subsets of nucleosomes that are enriched in different histone modifications vary greatly in the lengths of DNA protected from micrococcal nuclease cleavage (106–164 bp). The nucleosomes enriched in those histone modifications previously implicated to be correlated with active transcription tend to contain less protected DNA, indicating that these modifications are correlated with greater DNA accessibility. Another striking result obtained from our analysis is that nucleosomes flanking CTCF sites are much better positioned than those downstream of transcription start sites, the only genomic feature previously known to position nucleosomes genome-wide. This nucleosome-positioning phenomenon is not observed for other transcriptional factors for which we had genome-wide binding data. We suggest that binding of CTCF provides an anchor point for positioning nucleosomes, and chromatin remodeling is an important component of CTCF function

Teaching the science of learning

The science of learning has made a considerable contribution to our understanding of effective teaching and learning strategies. However, few instructors outside of the field are privy to this research. In this Tutorial Review, we focus on six specific cognitive strategies that have received robust support from decades of research: spaced practice, interleaving, retrieval practice, elaboration, concrete examples, and dual coding. We describe the basic research behind each strategy and relevant applied research, present examples of existing and suggested implementation, and make recommendations for further research that would broaden the reach of these strategies

Towards a framework for attention cueing in instructional animations: Guidelines for research and design

This paper examines the transferability of successful cueing approaches from text and static visualization research to animations. Theories of visual attention and learning as well as empirical evidence for the instructional effectiveness of attention cueing are reviewed and, based on Mayer’s theory of multimedia learning, a framework was developed for classifying three functions for cueing: (1) selection—cues guide attention to specific locations, (2) organization—cues emphasize structure, and (3) integration—cues explicate relations between and within elements. The framework was used to structure the discussion of studies on cueing in animations. It is concluded that attentional cues may facilitate the selection of information in animations and sometimes improve learning, whereas organizational and relational cueing requires more consideration on how to enhance understanding. Consequently, it is suggested to develop cues that work in animations rather than borrowing effective cues from static representations. Guidelines for future research on attention cueing in animations are presented

Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis

Nanotechnology advances towards development of targeted-treatment for obesity

Obesity through its association with type 2 diabetes (T2D), cancer and cardiovascular diseases (CVDs), poses a serious health threat, as these diseases contribute to high mortality rates. Pharmacotherapy alone or in combination with either lifestyle modifcation or surgery, is reliable in maintaining a healthy body weight, and preventing progression to obesity-induced diseases. However, the anti-obesity drugs are limited by non-specifcity and unsustainable weight loss efects. As such, novel and improved approaches for treatment of obesity are urgently needed. Nanotechnology-based therapies are investigated as an alternative strategy that can treat obesity and be able to overcome the drawbacks associated with conventional therapies. The review presents three nanotechnology-based anti-obesity strategies that target the white adipose tissues (WATs) and its vasculature for the reversal of obesity. These include inhibition of angiogenesis in the WATs, transformation of WATs to brown adipose tissues (BATs), and photothermal lipolysis of WATs. Compared to conventional therapy, the targeted-nanosystems have high tolerability, reduced side efects, and enhanced efcacy. These efects are reproducible using various nanocarriers (liposomes, polymeric and gold nanoparticles), thus providing a proof of concept that targeted nanotherapy can be a feasible strategy that can combat obesity and prevent its comorbiditie

Post-irradiation characterization of a high burnup mixed oxide fuel rod with minor actinides

The Advanced Fuels Campaign performed a series of irradiation tests of minor actinide-bearing mixed oxide fuel (MA-MOX), the so-called AFC-2C&D experiments, to investigate the transmutation of long-lived transuranic actinide isotopes contained in spent nuclear fuel via fast reactor technology at burnups exceeding 10 % fission of initial metallic atoms. This manuscript reports the test results derived from one of the five MA-MOX rodlets taken to higher burnup in the AFC-2D irradiation. This includes both non-destructive investigations, such as gamma and neutron spectrometry, and destructive investigations, such as fission gas release, ceramography, and chemical burnup analysis. In addition, the microstructure of the fuel was investigated using advanced electron microscopy techniques including electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM). It was observed with EBSD that the pellet had subdivision of the grains and the TEM observed migration of cladding material into the 5 metal precipitates in the fuel which could have been from the higher than desired oxygen/metal ratio. The TEM also showed an enrichment of Cr in fuel clad chemical interaction (FCCI) layer

A new classification of earthquake-induced landslide event sizes based on seismotectonic, topographic, climatic and geologic factors

Background This paper reviews the classical and some particular factors contributing to earthquake-triggered landslide activity. This analysis should help predict more accurately landslide event sizes, both in terms of potential numbers and affected area. It also highlights that some occurrences, especially those very far from the hypocentre/activated fault, cannot be predicted by state-of-the-art methods. Particular attention will be paid to the effects of deep focal earthquakes in Central Asia and to other extremely distant landslide activations in other regions of the world (e.g. Saguenay earthquake 1988, Canada). Results The classification of seismically induced landslides and the related ‘event sizes’ is based on five main factors: ‘Intensity’, ‘Fault factor’, ‘Topographic energy’, ‘Climatic background conditions’, ‘Lithological factor’. Most of these data were extracted from papers, but topographic inputs were checked by analyzing the affected region in Google Earth. The combination and relative weight of the factors was tested through comparison with well documented events and complemented by our studies of earthquake-triggered landslides in Central Asia. The highest relative weight (6) was attributed to the ‘Fault factor’; the other factors all received a smaller relative weight (2–4). The high weight of the ‘Fault factor’ (based on the location in/outside the mountain range, the fault type and length) is strongly constrained by the importance of the Wenchuan earthquake that, for example, triggered far more landslides in 2008 than the Nepal earthquake in 2015: the main difference is that the fault activated by the Wenchuan earthquake created an extensive surface rupture within the Longmenshan Range marked by a very high topographic energy while the one activated by the Nepal earthquake ruptured the surface in the frontal part of the Himalayas where the slopes are less steep and high. Finally, the calibrated factor combination was applied to almost 100 other earthquake events for which some landslide information was available. This comparison revealed the ability of the classification to provide a reasonable estimate of the number of triggered landslides and of the size of the affected area. According to this prediction, the most severe earthquake-triggered landslide event of the last one hundred years would actually be the Wenchuan earthquake in 2008 followed by the 1950 Assam earthquake in India – considering that the dominating role of the Wenchuan earthquake data (including the availability of a complete landslide inventory) for the weighting of the factors strongly influences and may even bias this result. The strongest landslide impacts on human life in recent history were caused by the Haiyuan-Gansu earthquake in 1920 – ranked as third most severe event according to our classification: its size is due to a combination of high shaking intensity, an important ‘Fault factor’ and the extreme susceptibility of the regional loess cover to slope failure, while the surface morphology of the affected area is much smoother than the one affected by the Wenchuan 2008 or the Nepal 2015 earthquakes. Conclusions The main goal of the classification of earthquake-triggered landslide events is to help improve total seismic hazard assessment over short and longer terms. Considering the general performance of the classification-prediction, it can be seen that the prediction either fits or overestimates the known/observed number of triggered landslides for a series of earthquakes, while it often underestimates the size of the affected area. For several events (especially the older ones), the overestimation of the number of landslides can be partly explained by the incompleteness of the published catalogues. The underestimation of the extension of the area, however, is real – as some particularities cannot be taken into account by such a general approach: notably, we used the same seismic intensity attenuation for all events, while attenuation laws are dependent on regional tectonic and geological conditions. In this regard, it is likely that the far-distant triggering of landslides, e.g., by the 1988 Saguenay earthquake (and the related extreme extension of affected area) is due to a very low attenuation of seismic energy within the North American plate. Far-distant triggering of landslides in Central Asia can be explained by the susceptibility of slopes covered by thick soft soils to failure under the effect of low-frequency shaking induced by distant earthquakes, especially by the deep focal earthquakes in the Pamir – Hindukush seismic region. Such deep focal and high magnitude (> > 7) earthquakes are also found in Europe, first of all in the Vrancea region (Romania). For this area as well as for the South Tien Shan we computed possible landslide event sizes related to some future earthquake scenarios