Mini-chromosome maintenance complexes form a filament to remodel DNA structure and topology.

Deregulation of mini-chromosome maintenance (MCM) proteins is associated with genomic instability and cancer. MCM complexes are recruited to replication origins for genome duplication. Paradoxically, MCM proteins are in excess than the number of origins and are associated with chromatin regions away from the origins during G1 and S phases. Here, we report an unusually wide left-handed filament structure for an archaeal MCM, as determined by X-ray and electron microscopy. The crystal structure reveals that an α-helix bundle formed between two neighboring subunits plays a critical role in filament formation. The filament has a remarkably strong electro-positive surface spiraling along the inner filament channel for DNA binding. We show that this MCM filament binding to DNA causes dramatic DNA topology change. This newly identified function of MCM to change DNA topology may imply a wider functional role for MCM in DNA metabolisms beyond helicase function. Finally, using yeast genetics, we show that the inter-subunit interactions, important for MCM filament formation, play a role for cell growth and survival

Fibromodulin Reduces Scar Formation in Adult Cutaneous Wounds by Eliciting a Fetal-Like Phenotype

Blocking transforming growth factor (TGF)β1 signal transduction has been a central strategy for scar reduction; however, this approach appears to be minimally effective. Here, we show that fibromodulin (FMOD), a 59-kD small leucine-rich proteoglycan critical for normal collagen fibrillogenesis, significantly reduces scar formation while simultaneously increasing scar strength in both adult rodent models and porcine wounds, which simulate human cutaneous scar repair. Mechanistically, FMOD uncouples pro-migration/contraction cellular signals from pro-fibrotic signaling by selectively enhancing SMAD3-mediated signal transduction, while reducing AP-1-mediated TGFβ1 auto-induction and fibrotic extracellular matrix accumulation. Consequently, FMOD accelerates TGFβ1-responsive adult fibroblast migration, myofibroblast conversion, and function. Furthermore, our findings strongly indicate that, by delicately orchestrating TGFβ1 activities rather than indiscriminately blocking TGFβ1, FMOD elicits fetal-like cellular and molecular phenotypes in adult dermal fibroblasts in vitro and adult cutaneous wounds in vivo, which is a unique response of living system undescribed previously. Taken together, this study illuminates the signal modulating activities of FMOD beyond its structural support functions, and highlights the potential for FMOD-based therapies to be used in cutaneous wound repair. © The Author(s) 2017

Foregut microbiome in development of esophageal adenocarcinoma

Esophageal adenocarcinoma (EA), the type of cancer linked to heartburn due to gastroesophageal reflux diseases (GERD), has increased six fold in the past 30 years. This cannot currently be explained by the usual environmental or by host genetic factors. EA is the end result of a sequence of GERD-related diseases, preceded by reflux esophagitis (RE) and Barrett’s esophagus (BE). Preliminary studies by Pei and colleagues at NYU on elderly male veterans identified two types of microbiotas in the esophagus. Patients who carry the type II microbiota are >15 fold likely to have esophagitis and BE than those harboring the type I microbiota. In a small scale study, we also found that 3 of 3 cases of EA harbored the type II biota. The findings have opened a new approach to understanding the recent surge in the incidence of EA. 

Our long-term goal is to identify the cause of GERD sequence. The hypothesis to be tested is that changes in the foregut microbiome are associated with EA and its precursors, RE and BE in GERD sequence. We will conduct a case control study to demonstrate the microbiome disease association in every stage of GERD sequence, as well as analyze the trend in changes in the microbiome along disease progression toward EA, by two specific aims. Aim 1 is to conduct a comprehensive population survey of the foregut microbiome and demonstrate its association with GERD sequence. Furthermore, spatial relationship between the esophageal microbiota and upstream (mouth) and downstream (stomach) foregut microbiotas as well as temporal stability of the microbiome-disease association will also be examined. Aim 2 is to define the distal esophageal metagenome and demonstrate its association with GERD sequence. Detailed analyses will include pathway-disease and gene-disease associations. Archaea, fungi and viruses, if identified, also will be correlated with the diseases. A significant association between the foregut microbiome and GERD sequence, if demonstrated, will be the first step for eventually testing whether an abnormal microbiome is required for the development of the sequence of phenotypic changes toward EA. If EA and its precursors represent a microecological disease, treating the cause of GERD might become possible, for example, by normalizing the microbiota through use of antibiotics, probiotics, or prebiotics. Causative therapy of GERD could prevent its progression and reverse the current trend of increasing incidence of EA

Discovering Fine-grained RRC State Dynamics and Performance Impacts in Cellular Networks

ABSTRACT To conserve power while ensuring good performance on resourceconstrained mobile devices, devices transition between different Radio Resource Control (RRC) states in response to network traffic and according to parameters specific to network operators. As RRC states significantly affect application power consumption and performance, it is important to understand how RRC state timers interact with network traffic patterns. In this paper, we show that the impact of RRC states on performance is significantly more complex and diverse than found in previous work. To do so, we introduce an open-source tool that allows the impact of RRC states on network and application performance to be measured in a robust and accurate manner on unmodified user devices, and deploy the tool in 23 countries around the world to test a broad range of cellular network technologies. We detect previously unknown performance problems which increase network latencies by up to several seconds and for LTE, can increase packet losses by an order of magnitude. Through an in-depth cross-layer analysis of several carriers, we examine the lower-layer causes of these problems. We determine that the highly complex state transitions of certain carriers, and in particular poor interactions between state demotions and network traffic, can lead to substantial, unexpected latencies

Electrically Tunable Excitonic Light Emitting Diodes based on Monolayer WSe2 p-n Junctions

Light-emitting diodes are of importance for lighting, displays, optical interconnects, logic and sensors. Hence the development of new systems that allow improvements in their efficiency, spectral properties, compactness and integrability could have significant ramifications. Monolayer transition metal dichalcogenides have recently emerged as interesting candidates for optoelectronic applications due to their unique optical properties. Electroluminescence has already been observed from monolayer MoS2 devices. However, the electroluminescence efficiency was low and the linewidth broad due both to the poor optical quality of MoS2 and to ineffective contacts. Here, we report electroluminescence from lateral p-n junctions in monolayer WSe2 induced electrostatically using a thin boron nitride support as a dielectric layer with multiple metal gates beneath. This structure allows effective injection of electrons and holes, and combined with the high optical quality of WSe2 it yields bright electroluminescence with 1000 times smaller injection current and 10 times smaller linewidth than in MoS2. Furthermore, by increasing the injection bias we can tune the electroluminescence between regimes of impurity-bound, charged, and neutral excitons. This system has the required ingredients for new kinds of optoelectronic devices such as spin- and valley-polarized light-emitting diodes, on-chip lasers, and two-dimensional electro-optic modulators.Comment: 13 pages main text with 4 figures + 4 pages upplemental material

Relativistic Corrections to the Triton Binding Energy

The influence of relativity on the triton binding energy is investigated. The relativistic three-dimensional version of the Bethe-Salpeter equation proposed by Blankenbecler and Sugar (BbS) is used. Relativistic (non-separable) one-boson-exchange potentials (constructed in the BbS framework) are employed for the two-nucleon interaction. In a 34-channel Faddeev calculation, it is found that relativistic effects increase the triton binding energy by about 0.2 MeV. Including charge-dependence (besides relativity), the final triton binding energy predictions are 8.33 and 8.16 MeV for the Bonn A and B potential, respectively.Comment: 25 pages of text (latex), 1 figure (not included, available upon request

Educating a New Generation of Doctors to Improve the Health of Populations in Low- and Middle-Income Countries

Francesca Celletti and colleagues from WHO argue that a transformation in the scale-up of medical education in low- and middle-income countries is needed, and detail what this might look like

Productive Parvovirus B19 Infection of Primary Human Erythroid Progenitor Cells at Hypoxia Is Regulated by STAT5A and MEK Signaling but not HIFα

Human parvovirus B19 (B19V) causes a variety of human diseases. Disease outcomes of bone marrow failure in patients with high turnover of red blood cells and immunocompromised conditions, and fetal hydrops in pregnant women are resulted from the targeting and destruction of specifically erythroid progenitors of the human bone marrow by B19V. Although the ex vivo expanded erythroid progenitor cells recently used for studies of B19V infection are highly permissive, they produce progeny viruses inefficiently. In the current study, we aimed to identify the mechanism that underlies productive B19V infection of erythroid progenitor cells cultured in a physiologically relevant environment. Here, we demonstrate an effective reverse genetic system of B19V, and that B19V infection of ex vivo expanded erythroid progenitor cells at 1% O2 (hypoxia) produces progeny viruses continuously and efficiently at a level of approximately 10 times higher than that seen in the context of normoxia. With regard to mechanism, we show that hypoxia promotes replication of the B19V genome within the nucleus, and that this is independent of the canonical PHD/HIFα pathway, but dependent on STAT5A and MEK/ERK signaling. We further show that simultaneous upregulation of STAT5A signaling and down-regulation of MEK/ERK signaling boosts the level of B19V infection in erythroid progenitor cells under normoxia to that in cells under hypoxia. We conclude that B19V infection of ex vivo expanded erythroid progenitor cells at hypoxia closely mimics native infection of erythroid progenitors in human bone marrow, maintains erythroid progenitors at a stage conducive to efficient production of progeny viruses, and is regulated by the STAT5A and MEK/ERK pathways

Impacts of air pollutants from rural Chinese households under the rapid residential energy transition

Rural residential energy consumption in China is experiencing a rapid transition towards clean energy, nevertheless, solid fuel combustion remains an important emission source. Here we quantitatively evaluate the contribution of rural residential emissions to PM2.5 (particulate matter with an aerodynamic diameter less than 2.5 μm) and the impacts on health and climate. The clean energy transitions result in remarkable reductions in the contributions to ambient PM2.5, avoiding 130,000 (90,000-160,000) premature deaths associated with PM2.5 exposure. The climate forcing associated with this sector declines from 0.057 ± 0.016 W/m2 in 1992 to 0.031 ± 0.008 W/m2 in 2012. Despite this, the large remaining quantities of solid fuels still contributed 14 ± 10 μg/m3 to population-weighted PM2.5 in 2012, which comprises 21 ± 14% of the overall population-weighted PM2.5 from all sources. Rural residential emissions affect not only rural but urban air quality, and the impacts are highly seasonal and location dependent

Sum rules and dualities for generalized parton distributions: is there a holographic principle?

To leading order approximation, the physical content of generalized parton distributions (GPDs) that is accessible in deep virtual electroproduction of photons or mesons is contained in their value on the cross-over trajectory. This trajectory separates the t-channel and s-channel dominated GPD regions. The underlying Lorentz covariance implies correspondence between these two regions through their relation to GPDs on the cross-over trajectory. This point of view leads to a family of GPD sum rules which are a quark analogue of finite energy sum rules and it guides us to a new phenomenological GPD concept. As an example, we discuss the constraints from the JLab/Hall A data on the dominant u-quark GPD H. The question arises whether GPDs are governed by some kind of holographic principle.Comment: 45 pages, 4 figures, Sect. 2 reorganized for clarity. Typos in Eq. (20) corrected. 4 new refs. Matches published versio