bluuebunny/crossref_metadata_2025 huggingface dataset:
Improving readability of informed consents for research at an academic medical institution
Authors: Hadden Kristie B. , Prince Latrina Y. , Moore Tina D. , James Laura P. , Holland Jennifer R. , Trudeau Christopher R.
Published: April 2018

Introduction

The final rule for the protection of human subjects requires that informed consent be “in language understandable to the subject” and mandates that “the informed consent must be organized in such a way that facilitates comprehension.” This study assessed the readability of Institutional Review Board-approved informed consent forms at our institution, implemented an intervention to improve the readability of consent forms, and measured the first year impact of the intervention.

Methods

Readability assessment was conducted on a sample of 217 Institutional Review Board-approved informed consents from 2013 to 2015. A plain language informed consent template was developed and implemented and readability was assessed again after 1 year.

Results

The mean readability of the baseline sample was 10th grade. The mean readability of the post-intervention sample (n=82) was seventh grade.

Conclusions

Providing investigators with a plain language informed consent template and training can promote improved readability of informed consents for research.
Effectiveness and cost of recruiting healthy volunteers for clinical research studies using an electronic patient portal: A randomized study
Authors: Samuels Mary H. , Schuff Robert , Beninato Peter , Gorsuch Adriel , Dursch James , Egan Sarah , Adams Bridget , Hollis Kate F. , Navarro Rachel , Burdick Timothy E.
Published: April 2018

Introduction

It is not clear how to effectively recruit healthy research volunteers.

Methods

We developed an electronic health record (EHR)-based algorithm to identify healthy subjects, who were randomly assigned to receive an invitation to join a research registry via the EHR’s patient portal, letters, or phone calls. A follow-up survey assessed contact preferences.

Results

The EHR algorithm accurately identified 858 healthy subjects. Recruitment rates were low, but occurred more quickly via the EHR patient portal than letters or phone calls (2.7 vs. 19.3 or 10.4 d). Effort and costs per enrolled subject were lower for the EHR patient portal (3.0 vs. 17.3 or 13.6 h, $113 vs. $559 or $435). Most healthy subjects indicated a preference for contact via electronic methods.

Conclusions

Healthy subjects can be accurately identified from EHR data, and it is faster and more cost-effective to recruit healthy research volunteers using an EHR patient portal.
Feasibility and Value of Developing a Regional Antibiogram for Community Hospitals
Authors: Hostler Christopher J. , Moehring Rebekah W. , Ashley Elizabeth S. Dodds , Johnson Melissa , Davis Angelina , Lewis Sarah S. , Sexton Daniel J. , Anderson Deverick J. ,   for the CDC Prevention Epicenters Program
Published: April 2018

OBJECTIVE

To determine the feasibility and value of developing a regional antibiogram for community hospitals.

DESIGN

Multicenter retrospective analysis of antibiograms.

SETTING AND PARTICIPANTS

A total of 20 community hospitals in central and eastern North Carolina and south central Virginia participated in this study.

METHODS

We combined antibiogram data from participating hospitals for 13 clinically relevant gram-negative pathogen–antibiotic combinations. From this combined antibiogram, we developed a regional antibiogram based on the mean susceptibilities of the combined data.

RESULTS

We combined a total of 69,778 bacterial isolates across 13 clinically relevant gram-negative pathogen–antibiotic combinations (median for each combination, 1100; range, 174–27,428). Across all pathogen–antibiotic combinations, 69% of local susceptibility rates fell within 1 SD of the regional mean susceptibility rate, and 97% of local susceptibilities fell within 2 SD of the regional mean susceptibility rate. No individual hospital had >1 pathogen–antibiotic combination with a local susceptibility rate >2 SD of the regional mean susceptibility rate. All hospitals’ local susceptibility rates were within 2 SD of the regional mean susceptibility rate for low-prevalence pathogens (<500 isolates cumulative for the region).

CONCLUSIONS

Small community hospitals frequently cannot develop an accurate antibiogram due to a paucity of local data. A regional antibiogram is likely to provide clinically useful information to community hospitals for low-prevalence pathogens.

Infect Control Hosp Epidemiol 2018;39:718–722
A NOTE ON THE ERDŐS–GRAHAM THEOREM
Authors: WANG WENHUI , TANG MIN
Published: April 2018

Let ${\mathcal{A}}=\{a_{1}<a_{2}<\cdots \,\}$ be a set of nonnegative integers. Put $D({\mathcal{A}})=\gcd \{a_{k+1}-a_{k}:k=1,2,\ldots \}$. The set ${\mathcal{A}}$ is an asymptotic basis if there exists $h$ such that every sufficiently large integer is a sum of at most $h$ (not necessarily distinct) elements of ${\mathcal{A}}$. We prove that if the difference of consecutive integers of ${\mathcal{A}}$ is bounded, then ${\mathcal{A}}$ is an asymptotic basis if and only if there exists an integer $a\in {\mathcal{A}}$ such that $(a,D({\mathcal{A}}))=1$.
Seed treatment with glycine betaine enhances tolerance of cotton to chilling stress
Authors: Cheng C. , Pei L. M. , Yin T. T. , Zhang K. W.
Published: April 2018

Chilling injury is an important natural stress that can threaten cotton production, especially at the sowing and seedling stages in early spring. It is therefore important for cotton production to improve chilling tolerance at these stages. The current work examines the potential for glycine betaine (GB) treatment of seeds to increase the chilling tolerance of cotton at the seedling stage. Germination under cold stress was increased significantly by GB treatment. Under low temperature, the leaves of seedlings from treated seeds exhibited a higher net photosynthetic rate (PN), higher antioxidant enzyme activity including superoxide dismutase, ascorbate peroxidase and catalase, lower hydrogen peroxide (H2O2) content and less damage to the cell membrane. Enzyme activity was correlated negatively with H2O2 content and degree of damage to the cell membrane but correlated positively with GB content. The experimental results suggested that although GB was only used to treat cotton seed, the beneficial effect caused by the preliminary treatment of GB could play a significant role during germination that persisted to at least the four-leaf seedling stage. Therefore, it is crucial that this method is employed in agricultural production to improve chilling resistance in the seedling stage by soaking the seeds in GB.
Communicating health and wellness
Authors: Chen Lindsey N.
Published: April 2018

The late 1990s saw a rapid growth in green marketing and organic food markets in the United States (Ottman, 2011). Widespread environmental awareness could explain the rise in the popularity of eco-friendly household products. More people than ever are discovering that going green is not only good for the body but also for the planet, as ‘consumers are concerned about the environmental and social impacts of the products they buy’ (Bonini & Oppenheim, 2008: 56). Concurrently, marketing researchers have sought to understand different retail strategies concerning the branding of organic products (cf. Hall, 2008; Ottman, 2011; Smith & Brower, 2012).
Between the Labor Camp and the Clinic:Temaor the Shared Forms of Late Soviet Homosexual Subjectivities
Authors: Clech Arthur
Published: April 2018

Based on interviews with twenty-one women and fifteen men who expressed homosexual desires during the late Soviet period, this article seeks to shed light upon Soviet homosexual subjectivities in the Russian SFSR. As a result of the drive to “close off the entire topic of gay subjectivity to respectable inquiry, so as to prevent gayness from ever again being understood as a sickness,” queer studies has for a long time been “silent” on this topic (David Halperin). My objective here is to take into account both the effects produced by Soviet medical and penal discourse on the subjectification of individuals who experience homosexual desire and the room to maneuver open to individuals for constructing the subject of their sexuality from their experience. I suggest that men and women were able to construct homosexual subjectivities that cannot be reduced to binary stigmatization as either sickness or criminality. In reality, men and women rendered themselves the subjects of their homosexuality in confrontation simultaneously and non-exclusively with both the pathologizing and criminalizing definitions of homosexuality.
Soviet Legal and Criminological Debates on the Decriminalization of Homosexuality (1965–75)
Authors: Alexander Rustam
Published: April 2018

In the late 1950s and early 1960s, almost three decades after consensual sodomy was declared a crime in the USSR, voices began to speak out in favor of its decriminalization. This article traces the history of the ensuing debate on this issue, conducted between Soviet criminologists and legal academics in the period from 1965–75. Through a close reading of the related texts, I explore the evolution of the different positions put forward. These fall into two camps: on the one hand, legal scholars who, together with their graduate students, made the case for decriminalization, and on the other, criminologists affiliated with the Interior Ministry, who opposed their views. The article provides the first detailed historical account of this extraordinary discussion and contributes to expanding our scant knowledge on the history of homosexuality in the Soviet Union.
Three‐Dimensional Tomography of Ionospheric Anomalies Immediately Before the 2015 Illapel Earthquake, Central Chile
Authors: He Liming , Heki Kosuke
Published: April 2018

Using ionospheric total electron contents residual data from 146 Global Navigation Satellite System stations in South America, we conducted three‐dimensional tomography of ionospheric electron density anomalies immediately before the 2015 Illapel Mw8.3 earthquake, Central Chile. We used five GPS and five GLONASS satellites and applied continuity constraints to regularize the linear least squares inversion. The reconstructed anomalies are composed of positive and negative regions, at altitudes of ~200 km and ~400 km, respectively, distributed roughly along the geomagnetic field. This feature suggests that the observed anomalies occurred by the downward E × B drift of electrons due to electric fields within ionosphere, possibly caused by surface positive electric charges. We also discuss the existence of the mirror image anomalies near the geomagnetic conjugate point of the epicenter using stations in Colombia.
The Seismic History of the Pisia Fault (Eastern Corinth Rift, Greece) From Fault Plane Weathering Features and Cosmogenic36Cl Dating
Authors: Mechernich Silke , Schneiderwind Sascha , Mason Jack , Papanikolaou Ioannis D. , Deligiannakis Georgios , Pallikarakis Aggelos , Binnie Steven A. , Dunai Tibor J. , Reicherter Klaus
Published: April 2018

The deformation of the eastern Corinth rift (Greece) is distributed along several E‐W trending active normal faults. Here the 25‐km‐long Pisia fault experienced up to 150 cm of coseismic displacement during the 1981 Alkyonides earthquake sequence (M = 6.7, 6.4, 6.3). Using terrestrial laser scanning, coupled with analyses of color changes, lichen colonization, and karstic features, we identify differentially weathered horizontal stripes on the exposed Pisia fault plane. The stripe boundaries occur at scarp heights of 1.10, 2.05, 2.85, 3.60, 4.15, and 5.15 m, with two additional possible boundaries at 3.10 and 4.65 m (~±0.1 m, respectively). This indicates that six to eight paleoearthquakes have exhumed the fault plane in a series of distinct coseismic slip events. A vertical profile of cosmogenic36Cl measurements is used to constrain age models of the exhumation. The results imply that, in addition to the last earthquake of 1981 (EQ1), exhumation events occurred at ~2.0 kyr (EQ2), ~3.1 kyr (EQ3), ~4.5 kyr (EQ4/4a,b), ~6.0 kyr (EQ5), and ~7.3 kyr (EQ6/6a,b), with modeled age uncertainties of ~0.7 kyr. Bayesian modeling provides a middle and late Holocene slip rate of 0.5–0.6 mm/yr (last 7.3 ± 0.7 kyr), while the upper part of the 8.45‐m‐high fault plane was exhumed at a higher rate of 0.8–2.3 mm/yr (7.3 ± 0.7 kyr to 10.2 ± 1.9 kyr). This slip rate variability suggests an increased seismicity or larger slip events during the early Holocene.
Sinking of Dense North Atlantic Waters in a Global Ocean Model: Location and Controls
Authors: Katsman C. A. , Drijfhout S. S. , Dijkstra H. A. , Spall M. A.
Published: April 2018

We investigate the characteristics of the sinking of dense waters in the North Atlantic Ocean that constitute the downwelling limb of the Atlantic Meridional Overturning Circulation (AMOC) as simulated by two global ocean models: an eddy‐permitting model at 1/4° resolution and its coarser 1° counterpart. In line with simple geostrophic considerations, it is shown that the sinking predominantly occurs in a narrow region close to the continental boundary in both model simulations. That is, the regions where convection is deepest do not coincide with regions where most dense waters sink. The amount of near‐boundary sinking that occurs varies regionally. For the 1/4° resolution model, these variations are in quantitative agreement with a relation based on geostrophy and a thermodynamic balance between buoyancy loss and alongshore advection of density, which links the amount of sinking to changes in density along the edge of the North Atlantic Ocean. In the 1° model, the amount and location of sinking appears not to be governed by this simple relation, possibly due to the large impact of overflows and nonnegligible cross‐shore density advection. If this poor representation of the processes governing the sinking of dense waters in the North Atlantic Ocean is a generic feature of such low‐resolution models, the response of the AMOC to changes in climate simulated by this type of models needs to be evaluated with care.
In Situ Microphysical Observations of the 29–30 May 2012 Kingfisher, OK, Supercell With a Balloon‐Borne Video Disdrometer
Authors: Waugh Sean M. , Ziegler Conrad L. , MacGorman Donald R.
Published: April 2018

The microphysical characteristics of deep convective storms are a critically important, yet difficult aspect of storm morphology to observe in situ. These observations play a large role in several areas of ongoing research, but detailed observations in key portions of clouds do not exist with the currently available measurement platforms. To facilitate these observations, a balloon‐borne particle imaging device known as the PArticle Size, Image, and Velocity (PASIV) probe was developed at the National Severe Storms Laboratory, which is capable of measuring particle counts on scales as small as 50 m. The videosonde observations from the PASIV showed that precipitation particle counts change rapidly between analysis layers, sometimes by as much as a few orders of magnitude (102–104 in adjacent layers), and radar reflectivities calculated directly from observed particle size distributions agree with mobile radar measurements. Furthermore, the observations allow the distributions to be partitioned into various particle types, which sheds light on which particles are dominating the radar signal at various times. These distributions per particle type, and their associated mixing ratios, agree with independent model analysis. Additionally, single‐, double‐, and triple‐moment parameterized particle size distribution functions are fit to various layers, with the general result that ice particles are easily represented by exponential distributions while rain is better fit with a gamma distribution. The parametric fits for ice and rain distributions found here support previous work and some portions of modeled microphysics, but also suggest room for improvement when deciding which schemes to use with cloud modeling.
Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors
Authors: Bey Alexandra L. , Wang Xiaoming , Yan Haidun , Kim Namsoo , Passman Rebecca L. , Yang Yilin , Cao Xinyu , Towers Aaron J. , Hulbert Samuel W. , Duffney Lara J. , Gaidis Erin , Rodriguiz Ramona M. , Wetsel William C. , Yin Henry H. , Jiang Yong-hui
Published: April 2018

We previously reported a new line of Shank3 mutant mice which led to a complete loss of Shank3 by deleting exons 4−22 (Δe4−22) globally. Δe4−22 mice display robust ASD-like behaviors including impaired social interaction and communication, increased stereotypical behavior and excessive grooming, and a profound deficit in instrumental learning. However, the anatomical and neural circuitry underlying these behaviors are unknown. We generated mice with Shank3 selectively deleted in forebrain, striatum, and striatal D1 and D2 cells. These mice were used to interrogate the circuit/brain-region and cell-type specific role of Shank3 in the expression of autism-related behaviors. Whole-cell patch recording and biochemical analyses were used to study the synaptic function and molecular changes in specific brain regions. We found perseverative exploratory behaviors in mice with deletion of Shank3 in striatal inhibitory neurons. Conversely, self-grooming induced lesions were observed in mice with deletion of Shank3 in excitatory neurons of forebrain. However, social, communicative, and instrumental learning behaviors were largely unaffected in these mice, unlike what is seen in global Δe4−22 mice. We discovered unique patterns of change for the biochemical and electrophysiological findings in respective brain regions that reflect the complex nature of transcriptional regulation of Shank3. Reductions in Homer1b/c and membrane hyper-excitability were observed in striatal loss of Shank3. By comparison, Shank3 deletion in hippocampal neurons resulted in increased NMDAR-currents and GluN2B-containing NMDARs. These results together suggest that Shank3 may differentially regulate neural circuits that control behavior. Our study supports a dissociation of Shank3 functions in cortical and striatal neurons in ASD-related behaviors, and it illustrates the complexity of neural circuit mechanisms underlying these behaviors.
FoxM1 drives ADAM17/EGFR activation loop to promote mesenchymal transition in glioblastoma
Authors: Zhang Chunli , Han Xiu , Xu Xiao , Zhou Zhengrong , Chen Xi , Tang Yu , Cheng Jie , Moazzam Nida Fatima , Liu Fei , Xu Jing , Peng Wanxin , Du Fengyi , Zhang Bin , Song Zhiwen , Zeng Jian , Gong Aihua
Published: April 2018

Mesenchymal transition (MES transition) is a hallmark of glioblastoma multiforme (GBM), however, the mechanism regulating the process remains to be elucidated. Here we report that FoxM1 drives ADAM17/EGFR activation loop to promote MES transition in GBM. Firstly, FoxM1 expression was positively associated with ADAM17 expression, and their expression was correlated with the mesenchymal features and overall patient survival of GBM. Overexpressing FoxM1 or ADAM17 increased the mesenchymal phenotype of glioma cells, which could be reversed by silencing FoxM1 or ADAM17. Importantly, FoxM1 bound to the ADAM17 promoter to transcriptionally upregulate its expression. Using gain- and loss-of-function studies, we showed that FoxM1/ADAM17 axis promoted the MES transition in glioma cells. Moreover, tissue microarray analysis and orthotopic xenograft model further confirmed that FoxM1/ADAM17 axis played key roles in malignancy of GBM. Mechanistically, FoxM1/ADAM17 axis activated the EGFR/AKT/GSK3β signaling pathway and ADAM17/EGFR/GSK3β axis could maintain FoxM1 stability in glioma cells. Taken together, our study demonstrated that FoxM1/ADAM17 feedback loop controlled the MES transition and regulated the progression of GBM, raising the possibility that deregulation of this loop might improve the durability of therapies in GBM.
Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes
Authors: Bhatta Maulasri , Chatpar Krishna , Hu Zihua , Wang Joshua J. , Zhang Sarah X.
Published: April 2018

Persistent vascular injury and degeneration in diabetes are attributed in part to defective reparatory function of angiogenic cells. Our recent work implicates endoplasmic reticulum (ER) stress in high-glucose-induced bone marrow (BM) progenitor dysfunction. Herein, we investigated the in vivo role of ER stress in angiogenic abnormalities of streptozotocin-induced diabetic mice. Our data demonstrate that ER stress markers and inflammatory gene expression in BM mononuclear cells and hematopoietic progenitor cells increase dynamically with disease progression. Increased CHOP and cleaved caspase­ 3 levels were observed in BM­-derived early outgrowth cells (EOCs) after 3 months of diabetes. Inhibition of ER stress by ex vivo or in vivo chemical chaperone treatment significantly improved the generation and migration of diabetic EOCs while reducing apoptosis of these cells. Chemical chaperone treatment also increased the number of circulating angiogenic cells in peripheral blood, alleviated BM pathology, and enhanced retinal vascular repair following ischemia/reperfusion in diabetic mice. Mechanistically, knockdown of CHOP alleviated high-glucose-induced EOC dysfunction and mitigated apoptosis, suggesting a pivotal role of CHOP in mediating ER stress-associated angiogenic cell injury in diabetes. Together, our study suggests that targeting ER signaling may provide a promising and novel approach to enhancing angiogenic function in diabetes.
Requirement of GSK-3 for PUMA induction upon loss of pro-survival PI3K signaling
Authors: Schubert Florian , Rapp Juliane , Brauns-Schubert Prisca , Schlicher Lisa , Stock Kerstin , Wissler Manuela , Weiß Martina , Charvet Céline , Borner Christoph , Maurer Ulrich
Published: April 2018

Growth factor withdrawal induces rapid apoptosis via mitochondrial outer membrane permeabilization. We had previously observed that cell death of IL-3-dependent Ba/F3 cells, induced by removal of the growth factor, required the activity of the kinase GSK-3. Employing CRISPR/Cas9-mediated gene knockout, we aimed to identify pro-apoptotic GSK-3 regulated factors in this process. Knockout of either Puma or Bim demonstrated that the induction of Puma, but not Bim, was crucial for apoptosis induced by IL-3 deprivation. Thus, we aimed at identifying the GSK-3-dependent PUMA regulator. Loss of FOXO3A reduced the induction of Puma, while additional loss of p53 completely repressed induction upon growth factor withdrawal. A constitutively active mutant of FOXO3A, which cannot be controlled by AKT directly, still required active GSK-3 for the full transcriptional induction of Puma and cell death upon IL-3 withdrawal. Thus, the suppression of GSK-3 is the key function of PI3K signaling in order to prevent the induction of Puma by FOXO3A and p53 and thereby apoptosis upon growth factor withdrawal.
ZBTB20 regulates EGFR expression and hepatocyte proliferation in mouse liver regeneration
Authors: Zhang Hai , Shi Jian-Hui , Jiang Hui , Wang Kejia , Lu Jun-Yu , Jiang Xuchao , Ma Xianhua , Chen Yu-Xia , Ren An-Jing , Zheng Jianming , Xie Zhifang , Guo Shaodong , Xu Xiongfei , Zhang Weiping J.
Published: April 2018

Liver has a unique regenerative capacity, however, its regulatory mechanism is not fully defined. We have established the zinc-finger protein ZBTB20 as a key transcriptional repressor for alpha-fetoprotein (AFP) gene in liver. As a marker of hepatic differentiation, AFP expression is closely associated with hepatocyte proliferation. Unexpectedly, here we showed that ZBTB20 acts as a positive regulator of hepatic replication and is required for efficient liver regeneration. The mice specifically lacking ZBTB20 in hepatocytes exhibited a remarkable defect in liver regeneration after partial hepatectomy, which was characterized by impaired hepatocyte proliferation along with delayed cyclin D1 induction and diminished AKT activation. Furthermore, we found that epithelial growth factor receptor (EGFR) expression was dramatically reduced in the liver in the absence of ZBTB20, thereby substantially attenuating the activation of EGFR signaling pathway in regenerating liver. Adenovirus-mediated EGFR overexpression in ZBTB20-deficient hepatocytes could largely restore AKT activation in response to EGFR ligands in vitro, as well as hepatocyte replication in liver regeneration. Furthermore, ZBTB20 overexpression could significantly restore hepatic EGFR expression and cell proliferation after hepatectomy in ZBTB20-deficient liver. Taken together, our data point to ZBTB20 as a critical regulator of EGFR expression and hepatocyte proliferation in mouse liver regeneration, and may serve as a potential therapeutic target in clinical settings of liver regeneration.
KPT-330 inhibition of chromosome region maintenance 1 is cytotoxic and sensitizes chronic myeloid leukemia to Imatinib
Authors: Nie Danian , Huang Kezhi , Yin Songmei , Li Yiqing , Xie Shuangfeng , Ma Liping , Wang Xiuju , Wu Yudan , Xiao Jie , Wang Jieyu , Yang Wenjuan , Liu Hongyun
Published: April 2018

As tyrosine kinase inhibitors (e.g., Imatinib, IM) fail to induce long-term response in some chronic myeloid leukemia (CML), novel therapies targeting leukemia-dysregulated pathways are necessary. Nuclear-cytoplasmic trafficking of proteins play a key role in the development of leukemia and drug resistance. KPT-330 (Selinexor), an inhibitor of chromosome region maintenance 1 (CRM1, nuclear receptor exportin 1, XPO1), demonstrated activities against a few hematological malignancies. We examined the anti-leukemic efficacy of KPT-330 in IM-resistant CML. Cell viability was examined by MTS assay. Apoptosis and cell cycle were assessed by flow cytometry. CRM1 mRNA was detected by PCR. Expression of CRM1 protein and its cargo proteins were determined by western blot or immunofluorescent staining. Furthermore, we engrafted nude mice subcutaneously with IM-resistant CML K562G. Mice were treated with IM, KPT-330 alone or in combination. Expression of CRM1 in CML were markedly higher than control. KPT-330 inhibited proliferation, induced cell cycle arrest and apoptosis of K562 and K562G. IC50 of IM on K562G was reduced by KPT-330. Mechanistically, KPT-330 inhibited CRM1 and increased the nuclear/cytoplasm ratio of BCR-ABL and P27. p-AKT was downregulated while p-STAT1 and caspase-3 were upregulated. Furthermore, KPT-330 showed anti-leukemic effect in primary IM-resistant CML with T315I mutation in CRM1-dependent manner. In K562G xenograft mice model, KPT-330 inhibited tumor growth and sensitized K562G to IM in vivo. To conclude, KPT-330 showed anti-leukemic activity and sensitized CML to IM in CRM1-dependent manner in vitro and in vivo. KPT-330 represents an alternative therapy for IM-refractory CML, warranting further investigation of CRM1 as therapeutic target.
Bayesian nonparametric discovery of isoforms and individual specific quantification
Authors: Aguiar Derek , Cheng Li-Fang , Dumitrascu Bianca , Mordelet Fantine , Pai Athma A. , Engelhardt Barbara E.
Published: April 2018

Most human protein-coding genes can be transcribed into multiple distinct mRNA isoforms. These alternative splicing patterns encourage molecular diversity, and dysregulation of isoform expression plays an important role in disease etiology. However, isoforms are difficult to characterize from short-read RNA-seq data because they share identical subsequences and occur in different frequencies across tissues and samples. Here, we develop biisq, a Bayesian nonparametric model for isoform discovery and individual specific quantification from short-read RNA-seq data. biisq does not require isoform reference sequences but instead estimates an isoform catalog shared across samples. We use stochastic variational inference for efficient posterior estimates and demonstrate superior precision and recall for simulations compared to state-of-the-art isoform reconstruction methods. biisq shows the most gains for low abundance isoforms, with 36% more isoforms correctly inferred at low coverage versus a multi-sample method and 170% more versus single-sample methods. We estimate isoforms in the GEUVADIS RNA-seq data and validate inferred isoforms by associating genetic variants with isoform ratios.
Dynamic tuneable G protein-coupled receptor monomer-dimer populations
Authors: Dijkman Patricia M. , Castell Oliver K. , Goddard Alan D. , Munoz-Garcia Juan C. , de Graaf Chris , Wallace Mark I. , Watts Anthony
Published: April 2018

G protein-coupled receptors (GPCRs) are the largest class of membrane receptors, playing a key role in the regulation of processes as varied as neurotransmission and immune response. Evidence for GPCR oligomerisation has been accumulating that challenges the idea that GPCRs function solely as monomeric receptors; however, GPCR oligomerisation remains controversial primarily due to the difficulties in comparing evidence from very different types of structural and dynamic data. Using a combination of single-molecule and ensemble FRET, double electron–electron resonance spectroscopy, and simulations, we show that dimerisation of the GPCR neurotensin receptor 1 is regulated by receptor density and is dynamically tuneable over the physiological range. We propose a “rolling dimer” interface model in which multiple dimer conformations co-exist and interconvert. These findings unite previous seemingly conflicting observations, provide a compelling mechanism for regulating receptor signalling, and act as a guide for future physiological studies.
A modular synthetic approach for band-gap engineering of armchair graphene nanoribbons
Authors: Li Gang , Yoon Ki-Young , Zhong Xinjue , Wang Jianchun , Zhang Rui , Guest Jeffrey R. , Wen Jianguo , Zhu X.-Y. , Dong Guangbin
Published: April 2018

Despite the great promise of armchair graphene nanoribbons (aGNRs) as high-performance semiconductors, practical band-gap engineering of aGNRs remains an unmet challenge. Given that width and edge structures are the two key factors for modulating band-gaps of aGNRs, a reliable synthetic method that allows control of both factors would be highly desirable. Here we report a simple modular strategy for efficient preparation of N = 6 aGNR, the narrowest member in the N = 3p (p: natural number) aGNR family, and two unsymmetrically edge-functionalized GNRs that contain benzothiadiazole and benzotriazole moieties. The trend of band-gap transitions among these GNRs parallels those in donor–acceptor alternating conjugated polymers. In addition, post-functionalization of the unsymmetrical heterocyclic edge via C–H borylation permits further band-gap tuning. Therefore, this method opens the door for convenient band-gap engineering of aGNRs through modifying the heteroarenes on the edge.
Selective far-field addressing of coupled quantum dots in a plasmonic nanocavity
Authors: Tang Jianwei , Xia Juan , Fang Maodong , Bao Fanglin , Cao Guanjun , Shen Jianqi , Evans Julian , He Sailing
Published: April 2018

Plasmon–emitter hybrid nanocavity systems exhibit strong plasmon–exciton interactions at the single-emitter level, showing great potential as testbeds and building blocks for quantum optics and informatics. However, reported experiments involve only one addressable emitting site, which limits their relevance for many fundamental questions and devices involving interactions among emitters. Here we open up this critical degree of freedom by demonstrating selective far-field excitation and detection of two coupled quantum dot emitters in a U-shaped gold nanostructure. The gold nanostructure functions as a nanocavity to enhance emitter interactions and a nanoantenna to make the emitters selectively excitable and detectable. When we selectively excite or detect either emitter, we observe photon emission predominantly from the target emitter with up to 132-fold Purcell-enhanced emission rate, indicating individual addressability and strong plasmon–exciton interactions. Our work represents a step towards a broad class of plasmonic devices that will enable faster, more compact optics, communication and computation.
Genome-wide association study in 176,678 Europeans reveals genetic loci for tanning response to sun exposure
Authors: Visconti Alessia , Duffy David L. , Liu Fan , Zhu Gu , Wu Wenting , Chen Yan , Hysi Pirro G. , Zeng Changqing , Sanna Marianna , Iles Mark M. , Kanetsky Peter A. , Demenais Florence , Hamer Merel A. , Uitterlinden Andre G. , Ikram M. Arfan , Nijsten Tamar , Martin Nicholas G. , Kayser Manfred , Spector Tim D. , Han Jiali , Bataille Veronique , Falchi Mario
Published: April 2018

The skin’s tendency to sunburn rather than tan is a major risk factor for skin cancer. Here we report a large genome-wide association study of ease of skin tanning in 176,678 subjects of European ancestry. We identify significant association with tanning ability at 20 loci. We confirm previously identified associations at six of these loci, and report 14 novel loci, of which ten have never been associated with pigmentation-related phenotypes. Our results also suggest that variants at the AHR/AGR3 locus, previously associated with cutaneous malignant melanoma the underlying mechanism of which is poorly understood, might act on disease risk through modulation of tanning ability.
Plasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs
Authors: Scharer Christopher D. , Barwick Benjamin G. , Guo Muyao , Bally Alexander P. R. , Boss Jeremy M.
Published: April 2018

The genomic loci associated with B cell differentiation that are subject to transcriptional and epigenetic regulation in vivo are not well defined, leaving a gap in our understanding of the development of humoral immune responses. Here, using an in vivo T cell independent B cell differentiation model, we define a cellular division-dependent cis-regulatory element road map using ATAC-seq. Chromatin accessibility changes correlate with gene expression and reveal the reprogramming of transcriptional networks and the genes they regulate at specific cell divisions. A subset of genes in naive B cells display accessible promoters in the absence of transcription and are marked by H3K27me3, an EZH2 catalyzed repressive modification. Such genes encode regulators of cell division and metabolism and include the essential plasma cell transcription factor Blimp-1. Chemical inhibition of EZH2 results in enhanced plasma cell formation, increased expression of the above gene set, and premature expression of Blimp-1 ex vivo. These data provide insights into cell-division coupled epigenetic and transcriptional processes that program plasma cells.
A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing
Authors: Kato Masaki , Takemoto Keiko , Shinkai Yoichi
Published: April 2018

Subsets of endogenous retroviruses (ERVs) are derepressed in mouse embryonic stem cells (mESCs) deficient for Setdb1, which catalyzes histone H3 lysine 9 trimethylation (H3K9me3). Most of those ERVs, including IAPs, remain silent if Setdb1 is deleted in differentiated embryonic cells; however they are derepressed when deficient for Dnmt1, suggesting that Setdb1 is dispensable for ERV silencing in somatic cells. However, H3K9me3 enrichment on ERVs is maintained in differentiated cells and is mostly diminished in mouse embryonic fibroblasts (MEFs) lacking Setdb1. Here we find that distinctive sets of ERVs are reactivated in different types of Setdb1-deficient somatic cells, including the VL30-class of ERVs in MEFs, whose derepression is dependent on cell-type-specific transcription factors (TFs). These data suggest a more general role for Setdb1 in ERV silencing, which provides an additional layer of epigenetic silencing through the H3K9me3 modification.
Unexpected behaviors in molecular transport through size-controlled nanochannels down to the ultra-nanoscale
Authors: Bruno Giacomo , Di Trani Nicola , Hood R. Lyle , Zabre Erika , Filgueira Carly Sue , Canavese Giancarlo , Jain Priya , Smith Zachary , Demarchi Danilo , Hosali Sharath , Pimpinelli Alberto , Ferrari Mauro , Grattoni Alessandro
Published: April 2018

Ionic transport through nanofluidic systems is a problem of fundamental interest in transport physics and has broad relevance in desalination, fuel cells, batteries, filtration, and drug delivery. When the dimension of the fluidic system approaches the size of molecules in solution, fluid properties are not homogeneous and a departure in behavior is observed with respect to continuum-based theories. Here we present a systematic study of the transport of charged and neutral small molecules in an ideal nanofluidic platform with precise channels from the sub-microscale to the ultra-nanoscale (<5 nm). Surprisingly, we find that diffusive transport of nano-confined neutral molecules matches that of charged molecules, as though the former carry an effective charge. Further, approaching the ultra-nanoscale molecular diffusivities suddenly drop by up to an order of magnitude for all molecules, irrespective of their electric charge. New theoretical investigations will be required to shed light onto these intriguing results.
Structural analysis of human ARS2 as a platform for co-transcriptional RNA sorting
Authors: Schulze Wiebke Manuela , Stein Frank , Rettel Mandy , Nanao Max , Cusack Stephen
Published: April 2018

ARS2 is a highly conserved metazoan protein involved in numerous aspects of nuclear RNA metabolism. As a direct partner of the nuclear cap-binding complex (CBC), it mediates interactions with diverse RNA processing and transport machineries in a transcript-dependent manner. Here, we present the human ARS2 crystal structure, which exhibits similarities and metazoan-specific differences to the plant homologue SERRATE, most notably an additional RRM domain. We present biochemical, biophysical and cellular interactome data comparing wild type and mutant ARS2 that identify regions critical for interactions with FLASH (involved in histone mRNA biogenesis), NCBP3 (a putative cap-binding protein involved in mRNA export) and single-stranded RNA. We show that FLASH and NCBP3 have overlapping binding sites on ARS2 and that CBC–ARS2–NCBP3 form a ternary complex that is mutually exclusive with CBC–ARS–PHAX (involved in snRNA export). Our results support that mutually exclusive higher-order CBC–ARS2 complexes are critical in determining Pol II transcript fate.
Supramolecular latching system based on ultrastable synthetic binding pairs as versatile tools for protein imaging
Authors: Kim Kyung Lock , Sung Gihyun , Sim Jaehwan , Murray James , Li Meng , Lee Ara , Shrinidhi Annadka , Park Kyeng Min , Kim Kimoon
Published: April 2018

Here we report ultrastable synthetic binding pairs between cucurbit[7]uril (CB[7]) and adamantyl- (AdA) or ferrocenyl-ammonium (FcA) as a supramolecular latching system for protein imaging, overcoming the limitations of protein-based binding pairs. Cyanine 3-conjugated CB[7] (Cy3-CB[7]) can visualize AdA- or FcA-labeled proteins to provide clear fluorescence images for accurate and precise analysis of proteins. Furthermore, controllability of the system is demonstrated by treating with a stronger competitor guest. At low temperature, this allows us to selectively detach Cy3-CB[7] from guest-labeled proteins on the cell surface, while leaving Cy3-CB[7] latched to the cytosolic proteins for spatially conditional visualization of target proteins. This work represents a non-protein-based bioimaging tool which has inherent advantages over the widely used protein-based techniques, thereby demonstrating the great potential of this synthetic system.
Towards ultrafast dynamics with split-pulse X-ray photon correlation spectroscopy at free electron laser sources
Authors: Roseker W. , Hruszkewycz S. O. , Lehmkühler F. , Walther M. , Schulte-Schrepping H. , Lee S. , Osaka T. , Strüder L. , Hartmann R. , Sikorski M. , Song S. , Robert A. , Fuoss P. H. , Sutton M. , Stephenson G. B. , Grübel G.
Published: April 2018

One of the important challenges in condensed matter science is to understand ultrafast, atomic-scale fluctuations that dictate dynamic processes in equilibrium and non-equilibrium materials. Here, we report an important step towards reaching that goal by using a state-of-the-art perfect crystal based split-and-delay system, capable of splitting individual X-ray pulses and introducing femtosecond to nanosecond time delays. We show the results of an ultrafast hard X-ray photon correlation spectroscopy experiment at LCLS where split X-ray pulses were used to measure the dynamics of gold nanoparticles suspended in hexane. We show how reliable speckle contrast values can be extracted even from very low intensity free electron laser (FEL) speckle patterns by applying maximum likelihood fitting, thus demonstrating the potential of a split-and-delay approach for dynamics measurements at FEL sources. This will enable the characterization of equilibrium and, importantly also reversible non-equilibrium processes in atomically disordered materials.
Measurement of the atomic orbital composition of the near-fermi-level electronic states in the lanthanum monopnictides LaBi, LaSb, and LaAs
Authors: Nummy Thomas J. , Waugh Justin A. , Parham Stephen P. , Liu Qihang , Yang Hung-Yu , Li Haoxiang , Zhou Xiaoqing , Plumb Nicholas C. , Tafti Fazel F. , Dessau Daniel S.
Published: April 2018

Recent debates in the literature over the relationship between topology and Extreme Magnetoresistance (XMR) have drawn attention to the Lanthanum Monopnictide family of binary compounds. Angle resolved photoemission spectroscopy (ARPES) is used to measure the electronic structure of the XMR topological semimetal candidates LaBi, LaSb, and LaAs. The orbital content of the near-E
F
states in LaBi and LaSb are extracted using varying photon polarizations and both dominant d and p bands are observed near X. The measured bulk bands are shifted in energy when compared to the results of Density Functional Calculations. This disagreement is minor in LaBi, but large in LaSb and LaAs. The measured bulk band structure of LaBi shows a clear band inversion and puts LaBi in the υ = 1 class of Topological Insulators (or semimetals), as predicted by calculations and consistent with the measured Dirac-like surface states. LaSb is on the verge of a band inversion with a less-clear case for any distinctly topological surface states and in disagreement with calculations. Lastly, these same bands in LaAs are clearly non-inverted implying its topological triviality and demonstrating a topological phase transition in the Lanthanum monopnictides. Using a wide range of photon energies the true bulk states are cleanly disentangled from the various types of surface states which are present. These surface states exist due to surface projections of bulk states in LaSb and for topological reasons in LaBi.
Public perception of genetically-modified (GM) food: A Nationwide Chinese Consumer Study
Authors: Cui Kai , Shoemaker Sharon P.
Published: April 2018

After more than 25 years of research and development on the genetic modification of a wide range of crops for food and fodder, China has reached a decision point as to whether it should accept, reject, or go slow with the use of genetically modified (GM) technology to produce the food and feed needed to sustain its population growth and economic renaissance. Here, we report a consumer survey on GM food that includes input from all provinces in China. Chinese consumers were surveyed for their awareness, knowledge, and opinion on GM food. The survey resulted in 11.9, 41.4, and 46.7% of respondents having a positive, neutral, or negative view on GM food, respectively. A minority of respondents (11.7%) claimed they understood the basic principles of GM technology, while most were either “neutral” or “unfamiliar with GM technology”. Most respondents (69.3%) obtained their information on GM food through the Internet and 64.3% of respondents thought that media coverage was predominately negative on GM food. The reasons given by consumers in favor of, or against, the use of GM food, were complex, as seen by the response of 13.8% of respondents who felt GM technology was a form of bioterrorism targeted at China. China’s Ministry of Agriculture and the science community generally expressed a positive attitude toward GM food, but the percentage of respondents that trusted the government and scientists was only 11.7 and 23.2%, respectively. Post-survey comments of respondents made suggestions on how the industrialization of GM technology might impact the future of China’s food supply and value chains. Finally, the impact of emerging technologies like genome editing and genome-edited organisms (GEOs) on the GM food debate is discussed.
Couple serostatus patterns in sub-Saharan Africa illuminate the relative roles of transmission rates and sexual network characteristics in HIV epidemiology
Authors: Bellan Steven E. , Champredon David , Dushoff Jonathan , Meyers Lauren Ancel
Published: April 2018

HIV prevalence has surpassed 30% in some African countries while peaking at less than 1% in others. The extent to which this variation is driven by biological factors influencing the HIV transmission rate or by variation in sexual network characteristics remains widely debated. Here, we leverage couple serostatus patterns to address this question. HIV prevalence is strongly correlated with couple serostatus patterns across the continent; in particular, high prevalence countries tend to have a lower ratio of serodiscordancy to concordant positivity. To investigate the drivers of this continental pattern, we fit an HIV transmission model to Demographic and Health Survey data from 45,041 cohabiting couples in 25 countries. In doing so, we estimated country-specific HIV transmission rates and sexual network characteristics reflective of pre-couple and extra-couple sexual contact patterns. We found that variation in the transmission rate could parsimoniously explain between-country variation in both couple serostatus patterns and prevalence. In contrast, between-country variation in pre-couple or extra-couple sexual contact rates could not explain the observed patterns. Sensitivity analyses suggest that future work should examine the robustness of this result to between-country variation in how heterogeneous infection risk is within a country, or to assortativity, i.e. the extent to which individuals at higher risk are likely to partner with each other.
A Plasma Biomarker Panel of Four MicroRNAs for the Diagnosis of Prostate Cancer
Authors: Matin Farhana , Jeet Varinder , Moya Leire , Selth Luke A. , Chambers Suzanne ,   Australian Prostate Cancer BioResource, Yeadon T. , Saunders P. , Eckert A. , Heathcote P. , Wood G. , Malone G. , Samaratunga H. , Collins A. , Turner M. , Kerr K. , Clements Judith A. , Batra Jyotsna
Published: April 2018

Prostate cancer is diagnosed in over 1 million men every year globally, yet current diagnostic modalities are inadequate for identification of significant cancer and more reliable early diagnostic biomarkers are necessary for improved clinical management of prostate cancer patients. MicroRNAs (miRNAs) modulate important cellular processes/pathways contributing to cancer and are stably present in body fluids. In this study we profiled 372 cancer-associated miRNAs in plasma collected before (~60% patients) and after/during commencement of treatment (~40% patients), from age-matched prostate cancer patients and healthy controls, and observed elevated levels of 4 miRNAs - miR-4289, miR-326, miR-152-3p and miR-98-5p, which were validated in an independent cohort. The miRNA panel was able to differentiate between prostate cancer patients and controls (AUC = 0.88). Analysis of published miRNA transcriptomic data from clinical samples demonstrated low expression of miR-152-3p in tumour compared to adjacent non-malignant tissues. Overexpression of miR-152-3p increased proliferation and migration of prostate cancer cells, suggesting a role for this miRNA in prostate cancer pathogenesis, a concept that was supported by pathway analysis of predicted miR-152-3p target genes. In summary, a four miRNA panel, including miR-152-3p which likely targets genes with key roles in prostate cancer pathogenesis, has the potential to improve early prostate cancer diagnosis.