Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA

In eukaryotes, the Cdt1-bound replicative helicase core MCM2-7 is loaded onto DNA by the ORC-Cdc6 ATPase to form a prereplicative complex (pre-RC) with an MCM2-7 double hexamer encircling DNA. Using purified components in the presence of ATP-γS, we have captured in vitro an intermediate in pre-RC assembly that contains a complex between the ORC-Cdc6 and Cdt1-MCM2-7 heteroheptamers called the OCCM. Cryo-EM studies of this 14-subunit complex reveal that the two separate heptameric complexes are engaged extensively, with the ORC-Cdc6 N-terminal AAA+ domains latching onto the C-terminal AAA+ motor domains of the MCM2-7 hexamer. The conformation of ORC-Cdc6 undergoes a concerted change into a right-handed spiral with helical symmetry that is identical to that of the DNA double helix. The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action

The Ctf18 RFC-like complex positions yeast telomeres but does not specify their replication time

Peer reviewedPreprin

Liquid-gas phase transition in nuclear multifragmentation

The equation of state of nuclear matter suggests that at suitable beam energies the disassembling hot system formed in heavy ion collisions will pass through a liquid-gas coexistence region. Searching for the signatures of the phase transition has been a very important focal point of experimental endeavours in heavy ion collisions, in the last fifteen years. Simultaneously theoretical models have been developed to provide information about the equation of state and reaction mechanisms consistent with the experimental observables. This article is a review of this endeavour.Comment: 63 pages, 27 figures, submitted to Adv. Nucl. Phys. Some typos corrected, minor text change

The Temporal Signature of Memories: Identification of a General Mechanism for Dynamic Memory Replay in Humans

Reinstatement of dynamic memories requires the replay of neural patterns that unfold over time in a similar manner as during perception. However, little is known about the mechanisms that guide such a temporally structured replay in humans, because previous studies used either unsuitable methods or paradigms to address this question. Here, we overcome these limitations by developing a new analysis method to detect the replay of temporal patterns in a paradigm that requires participants to mentally replay short sound or video clips. We show that memory reinstatement is accompanied by a decrease of low-frequency (8 Hz) power, which carries a temporal phase signature of the replayed stimulus. These replay effects were evident in the visual as well as in the auditory domain and were localized to sensory-specific regions. These results suggest low-frequency phase to be a domain-general mechanism that orchestrates dynamic memory replay in humans

Study Effort and Student Success: A MOOC Case Study

Learning was once defined as the function of efforts spent in relation to efforts needed [3]. Provided that effort is closely linked to time, previous research has found a positive relationship between student effort over time and student success, both in university education and Massive Open Online Courses (MOOCs). With the complex environment of tracing and identifying relevant data of student learning processes in MOOCs, this study employs learning analytics to examine this relationship for MITx 6.00x, an introductory programming and computer science MOOC hosted on the edX MOOC platform. A population sample from the MOOC (N = 32,621) was examined using logistic regression, controlling for variables that may also influence the outcome. Conversely, the outcome of this research study suggests that there is a curvilinear relationship between effort over time and student success, meaning those who exert effort for the longest amount of time in the MOOC actually have a lower probability of obtaining a certificate than others who exert effort over somewhat less time. Finally, research implications are discussed.acceptedVersio

Revisiting the B-cell compartment in mouse and humans: more than one B-cell subset exists in the marginal zone and beyond.

International audienceABSTRACT: The immunological roles of B-cells are being revealed as increasingly complex by functions that are largely beyond their commitment to differentiate into plasma cells and produce antibodies, the key molecular protagonists of innate immunity, and also by their compartmentalisation, a more recently acknowledged property of this immune cell category. For decades, B-cells have been recognised by their expression of an immunoglobulin that serves the function of an antigen receptor, which mediates intracellular signalling assisted by companion molecules. As such, B-cells were considered simple in their functioning compared to the other major type of immune cell, the T-lymphocytes, which comprise conventional T-lymphocyte subsets with seminal roles in homeostasis and pathology, and non-conventional T-lymphocyte subsets for which increasing knowledge is accumulating. Since the discovery that the B-cell family included two distinct categories - the non-conventional, or extrafollicular, B1 cells, that have mainly been characterised in the mouse; and the conventional, or lymph node type, B2 cells - plus the detailed description of the main B-cell regulator, FcγRIIb, and the function of CD40+ antigen presenting cells as committed/memory B-cells, progress in B-cell physiology has been slower than in other areas of immunology. Cellular and molecular tools have enabled the revival of innate immunity by allowing almost all aspects of cellular immunology to be re-visited. As such, B-cells were found to express "Pathogen Recognition Receptors" such as TLRs, and use them in concert with B-cell signalling during innate and adaptive immunity. An era of B-cell phenotypic and functional analysis thus began that encompassed the study of B-cell microanatomy principally in the lymph nodes, spleen and mucosae. The novel discovery of the differential localisation of B-cells with distinct phenotypes and functions revealed the compartmentalisation of B-cells. This review thus aims to describe novel findings regarding the B-cell compartments found in the mouse as a model organism, and in human physiology and pathology. It must be emphasised that some differences are noticeable between the mouse and human systems, thus increasing the complexity of B-cell compartmentalisation. Special attention will be given to the (lymph node and spleen) marginal zones, which represent major crossroads for B-cell types and functions and a challenge for understanding better the role of B-cell specificities in innate and adaptive immunology

Nothing Lasts Forever: Environmental Discourses on the Collapse of Past Societies

The study of the collapse of past societies raises many questions for the theory and practice of archaeology. Interest in collapse extends as well into the natural sciences and environmental and sustainability policy. Despite a range of approaches to collapse, the predominant paradigm is environmental collapse, which I argue obscures recognition of the dynamic role of social processes that lie at the heart of human communities. These environmental discourses, together with confusion over terminology and the concepts of collapse, have created widespread aporia about collapse and resulted in the creation of mixed messages about complex historical and social processes

Computer-based technology and student engagement: a critical review of the literature

Computer-based technology has infiltrated many aspects of life and industry, yet there is little understanding of how it can be used to promote student engagement, a concept receiving strong attention in higher education due to its association with a number of positive academic outcomes. The purpose of this article is to present a critical review of the literature from the past 5 years related to how web-conferencing software, blogs, wikis, social networking sites (Facebook and Twitter), and digital games influence student engagement. We prefaced the findings with a substantive overview of student engagement definitions and indicators, which revealed three types of engagement (behavioral, emotional, and cognitive) that informed how we classified articles. Our findings suggest that digital games provide the most far-reaching influence across different types of student engagement, followed by web-conferencing and Facebook. Findings regarding wikis, blogs, and Twitter are less conclusive and significantly limited in number of studies conducted within the past 5 years. Overall, the findings provide preliminary support that computer-based technology influences student engagement, however, additional research is needed to confirm and build on these findings. We conclude the article by providing a list of recommendations for practice, with the intent of increasing understanding of how computer-based technology may be purposefully implemented to achieve the greatest gains in student engagement. © 2017, The Author(s)

Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurode- generative disorders are very complicated and multifacto- rial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very di cult to be interpretated and often useless. Mouse models could be condiderated a ‘pathway models’, rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high eld Magnetic resonance, Optical Imaging scanners and of highly speci c contrast agents. Behavioral test are useful tool to characterize di erent ani- mal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the di erent neurodegenerative disorders. Aim of this review is to focus on the di erent existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases

Up-regulation of bone marrow stromal protein 2 (BST2) in breast cancer with bone metastasis

<p>Abstract</p> <p>Background</p> <p>Bone metastases are frequent complications of breast cancer. Recent literature implicates multiple chemokines in the formation of bone metastases in breast cancer. However, the molecular mechanism of metastatic bone disease in breast cancer remains unknown. We have recently made the novel observation of the BST2 protein expression in human breast cancer cell lines. The purpose of our present study is to investigate the expression and the role of BST2 in bone metastatic breast cancer.</p> <p>Methods</p> <p>cDNA microarray analysis was used to compare the BST2 gene expression between a metastatic to bone human breast cancer cell line (MDA-231BO) and a primary human breast cancer cell line (MDA-231). The BST2 expression in one bone metastatic breast cancer and seven non-bone metastatic breast cancer cell lines were also determined using real-time RT-PCR and Western blot assays. We then employed tissue array to further study the BST2 expression in human breast cancer using array slides containing 20 independent breast cancer tumors that formed metastatic bone lesions, 30 non-metastasis-forming breast cancer tumors, and 8 normal breast tissues. In order to test the feasibility of utilizing BST2 as a serum marker for the presence of bone metastasis in breast cancer, we had measured the BST2 expression levels in human serums by using ELISA on 43 breast cancer patients with bone metastasis, 43 breast cancer patients without bone metastasis, and 14 normal healthy controls. The relationship between cell migration and proliferation and BST2 expression was also studied in a human breast recombinant model system using migration and FACS analysis.</p> <p>Results</p> <p>The microarray demonstrated over expression of the BST2 gene in the bone metastatic breast cancer cell line (MDA-231BO) compared to the primary human breast cancer cell line (MDA-231). The expression of the BST2 gene was significantly increased in the bone metastatic breast cancer cell lines and tumor tissues compared to non-bone metastatic breast cancer cell lines and tumor tissues by real time RT-PCR, Western blot and TMA. Furthermore, serum levels of BST2 measured by ELISA were also significantly higher among patients with breast cancer metastatic to bone compared to breast cancer patients without metastatic to bone (P < .0001). Most importantly, the breast cancer cell line that transfected with BST2 demonstrated increased BST2 expressions, which was associated with increased cancer cell migration and cell proliferation.</p> <p>Conclusion</p> <p>These results provide novel data indicating the BST2 protein expression is associated with the formation of bone metastases in human breast cancer. We believe that BST2 may be a potential biomarker in breast cancer with bone metastasis.</p