bluuebunny/crossref_metadata_2025 huggingface dataset:
Binding mode of the side-by-side two-IgV molecule CD226/DNAM-1 to its ligand CD155/Necl-5
Authors: Wang Han , Qi Jianxun , Zhang Shuijun , Li Yan , Tan Shuguang , Gao George F.
Published: December 2018

Natural killer (NK) cells are important component of innate immunity and also contribute to activating and reshaping the adaptive immune responses. The functions of NK cells are modulated by multiple inhibitory and stimulatory receptors. Among these receptors, the activating receptor CD226 (DNAM-1) mediates NK cell activation via binding to its nectin-like (Necl) family ligand, CD155 (Necl-5). Here, we present a unique side-by-side arrangement pattern of two tandem immunoglobulin V-set (IgV) domains deriving from the ectodomains of both human CD226 (hCD226-ecto) and mouse CD226 (mCD226-ecto), which is substantially different from the conventional head-to-tail arrangement of other multiple Ig-like domain molecules. The hybrid complex structure of mCD226-ecto binding to the first domain of human CD155 (hCD155-D1) reveals a conserved binding interface with the first domain of CD226 (D1), whereas the second domain of CD226 (D2) both provides structural supports for the unique architecture of CD226 and forms direct interactions with CD155. In the absence of the D2 domain, CD226-D1 exhibited substantially reduced binding efficacy to CD155. Collectively, these findings would broaden our knowledge of the interaction between NK cell receptors and the nectin/Necl family ligands, as well as provide molecular basis for the development of CD226-targeted antitumor immunotherapeutics.
Imaging electron-density fluctuations by multidimensional X-ray photon-coincidence diffraction
Authors: Ye Lyuzhou , Rouxel Jérémy R. , Cho Daeheum , Mukamel Shaul
Published: December 2018

Significance

X-ray diffraction is routinely used to monitor the ground-state electronic charge density of molecules or the motion of nuclei. In this work, we propose a spectroscopic measurement based on multidimensional photon-coincidence X-ray diffraction, which probes the correlation functions of the charge densities in momentum space. The inverse Fourier-transformed signal in real space, which is a combination of correlation functions of transition charge densities, allows us to identify the various scattering pathways that dominate the signal in momentum space and provides most valuable information on spontaneous electronic fluctuations and correlations.
Two symmetric arginine residues play distinct roles in
Thermus thermophilus
Argonaute DNA guide strand-mediated DNA target cleavage
Authors: Lei Jinping , Sheng Gang , Cheung Peter Pak-Hang , Wang Shenglong , Li Yu , Gao Xin , Zhang Yingkai , Wang Yanli , Huang Xuhui
Published: December 2018

Significance

Argonaute (Ago) proteins function in host defense against foreign mRNA. The Ago-mediated mRNA target cleavage necessitates glutamate finger insertion. Two positively charged residues locate symmetrically around the plugged-in finger, but their functional roles are unclear for
Thermus thermophilus
Ago (
Tt
Ago), a prokaryotic Ago protein. Surprisingly, our simulations and site-mutagenesis experiments indicated that, in contrast to the equivalent roles of symmetrical positively charged residues in
Kluyveromyces polysporus
Ago (a eukaryotic Ago protein), in
Tt
Ago, only R545 is critical for mRNA cleavage as a structural anchor to stabilize the plugged-in conformation, whereas R486 plays a negligible role. These differences provide a molecular basis of the distinct glutamate finger functions of Ago proteins in different organisms.
Comparing mutagenesis and simulations as tools for identifying functionally important sequence changes for protein thermal adaptation
Authors: Liao Ming-ling , Somero George N. , Dong Yun-wei
Published: December 2018

Comparative studies of orthologous proteins of species evolved at different temperatures have revealed consistent patterns of temperature-related variation in thermal stabilities of structure and function. However, the precise mechanisms by which interspecific variations in sequence foster these adaptive changes remain largely unknown. Here, we compare orthologs of cytosolic malate dehydrogenase (cMDH) from marine molluscs adapted to temperatures ranging from −1.9 °C (Antarctica) to ∼55 °C (South China coast) and show how amino acid usage in different regions of the enzyme (surface, intermediate depth, and protein core) varies with adaptation temperature. This eukaryotic enzyme follows some but not all of the rules established in comparisons of archaeal and bacterial proteins. To link the effects of specific amino acid substitutions with adaptive variations in enzyme thermal stability, we combined site-directed mutagenesis (SDM) and in vitro protein experimentation with in silico mutagenesis using molecular dynamics simulation (MDS) techniques. SDM and MDS methods generally but not invariably yielded common effects on protein stability. MDS analysis is shown to provide insights into how specific amino acid substitutions affect the conformational flexibilities of mobile regions (MRs) of the enzyme that are essential for binding and catalysis. Whereas these substitutions invariably lie outside of the MRs, they effectively transmit their flexibility-modulating effects to the MRs through linked interactions among surface residues. This discovery illustrates that regions of the protein surface lying outside of the site of catalysis can help establish an enzyme’s thermal responses and foster evolutionary adaptation of function.
Prediagnostic levels of urinary 8-epi-prostaglandin F2α and prostaglandin E2 metabolite, biomarkers of oxidative damage and inflammation, and risk of hepatocellular carcinoma
Authors: Yuan Jian-Min , Grouls Menno , Carmella Steven G , Wang Renwei , Heskin Alisa , Jiang Yang , Tan Yu-Ting , Adams-Haduch Jennifer , Gao Yu-Tang , Hecht Stephen S
Published: December 2018

Chronic inflammation and oxidative stress play pivotal roles in the pathogenesis of hepatocellular carcinoma (HCC). We conducted a nested case–control study of 347 HCC cases and 691 matched controls within a prospective cohort of 18 244 Chinese men in Shanghai, China. The concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α), a biomarker of oxidative stress, and prostaglandin E2 (PGE2) metabolite (PGE-M), a biomarker of the inflammation mediator PGE2, were determined in baseline urine samples using validated mass spectrometry assays. 8-epi-PGF2α levels were significantly higher in HCC cases than control subjects (geometric means 0.92 versus 0.80 pmol/mg creatinine, P < 0.001). The relative risks of developing HCC for the highest relative to the lowest quartile of 8-epi-PGF2α were 2.55 (95% confidence interval = 1.62–4.01, Ptrend < 0.001). This positive 8-epi-PGF2α–HCC risk association was independent of smoking status, alcohol consumption and hepatitis B or liver cirrhosis and was present 10 years before the clinical manifestation of HCC. This study did not find any significant association between urinary PEG-M and HCC risk. This study provides direct evidence in support of the critical role of oxidative stress in the development of HCC regardless of its underlying causes.
Noninferiority of Simplified Dolutegravir Monotherapy Compared to Continued Combination Antiretroviral Therapy That Was Initiated During Primary Human Immunodeficiency Virus Infection: A Randomized, Controlled, Multisite, Open-label, Noninferiority Trial
Authors: Braun Dominique L , Turk Teja , Tschumi Fabian , Grube Christina , Hampel Benjamin , Depmeier Carsten , Schreiber Peter W , Brugger Silvio D , Greiner Michael , Steffens Daniela , De Torrenté-Bayard Cornelia , Courlet Perrine , Neumann Kathrin , Kuster Herbert , Flepp Markus , Bertisch Barbara , Decosterd Laurent , Böni Jürg , Metzner Karin J , Kouyos Roger D , Günthard Huldrych F
Published: December 2018

Background

Patients who start combination antiretroviral therapy (cART) during primary human immunodeficiency virus type 1 (HIV-1) infection show a smaller HIV-1 latent reservoir, less immune activation, and less viral diversity compared to patients who start cART during chronic infection. We conducted a pilot study to determine whether these properties would allow sustained virological suppression after simplification of cART to dolutegravir monotherapy.

Methods

EARLY-SIMPLIFIED is a randomized, open-label, noninferiority trial. Patients who started cART <180 days after a documented primary HIV-1 infection and had an HIV-1 RNA <50 copies/mL plasma for at least 48 weeks were randomized (2:1) to monotherapy with dolutegravir 50 mg once daily or to continuation of cART. The primary efficacy endpoint was the proportion of patients with <50 HIV-1 RNA copies/mL on or before week 48; noninferiority margin 10%.

Results

Of the 101 patients randomized, 68 were assigned to simplification to dolutegravir monotherapy and 33 to continuation of cART. At week 48 in the per-protocol population, 67/67 (100%) had virological response in the dolutegravir monotherapy group vs 32/32 (100%) in the cART group (difference, 0.00%; 95% confidence interval, –100%, 4.76%). This showed noninferiority of the dolutegravir monotherapy at the prespecified level.

Conclusion

In this pilot study consisting of patients who initiated cART during primary HIV-1 infection and had <50 HIV-1 RNA copies/mL for at least 48 weeks, monotherapy with once-daily dolutegravir was noninferior to cART. Our results suggest that future simplification studies should use a stratification according to time of HIV infection and start of first cART.

Clinical Trials Registration

NCT02551523.
Derived Picard Groups of Preprojective Algebras of Dynkin Type
Authors: Mizuno Yuya
Published: December 2018

In this paper, we study two-sided tilting complexes of preprojective algebras of Dynkin type. We construct the most fundamental class of two-sided tilting complexes, which has a group structure by derived tensor products and induces a group of auto-equivalences of the derived category. We show that the group structure of the two-sided tilting complexes is isomorphic to the braid group of the corresponding folded graph. Moreover, we show that these two-sided tilting complexes induce tilting mutation and any tilting complex is given as the derived tensor products of them. Using these results, we determine the derived Picard group of preprojective algebras for type $A$ and $D$.
Factors impacting physician use of information charted by others
Authors: Zozus Meredith N , Penning Melody , Hammond William E
Published: December 2018

Objectives

To identify factors impacting physician use of information charted by others.

Materials and methods

A 4-round Delphi process was conducted with physicians and non-physicians publishing in the healthcare data quality literature to identify and characterize factors impacting physician use of information charted by others (other people or devices), either within or external to their organization. Factors with high average importance and reliability were categorized according to similarity of topic.

Results

Thirty-nine factors were ultimately identified as impacting physician use of information charted by others. Five categories of factors included aspects of: the information source, the information itself, the information user, the information system, and aspects of healthcare as an institution. In addition, 4 themes were identified: (1) value of narrative text in providing context, (2) importance of mental models and personal heuristics in deciding whether, and how to use information, (3) loss of confidence in, and decreased use of information due to errors encountered, and (4) existence of a trust hierarchy potentially influencing information use.

Discussion

Five similarly focused studies have recently probed clinician willingness to use information in decision-making. Our results mostly confirmed factors identified by prior studies, and uniquely identified aspects of the information user as important.

Conclusion

According to the participants in this study, information quality is prominent among factors impacting physician use of information charted by others. Based on this and similar studies, it appears that despite concerns about information quality, physicians use information charted by others.
Is the Refugee Health Screener a Useful Tool when Screening 14- to 18-Year-Old Refugee Adolescents for Emotional Distress?
Authors: Sarkadi Anna , Bjärtå Anna , Leiler Anna , Salari Raziye
Published: December 2018

The high number of asylum seekers in Sweden has highlighted the need for structured assessment tools to screen for refugee mental health problems in clinical services. We examined the utility of the Refugee Health Screener (RHS) in refugee adolescents, aged 14–18, attending routine clinical examinations or staying in group homes/refugee centres (N = 29). Participants completed a survey, including the RHS, administered through iPads in their native language. The RHS showed excellent internal consistency (α = 0.96) and correlated moderately with symptoms of post-traumatic stress disorder (r = 0.41, p = 0.025). Mean scores and prevalence rates were comparable to a study of adult refugees in Sweden. Unaccompanied refugee minors (URMs) scored significantly higher (M = 32.0, SD = 12.9) compared to youth staying with their families (M = 7.5, SD = 8.2, p < 0.001, d = 2.27). Our findings confirm that the RHS can be used in the adolescent population in Sweden. These findings moreover suggest that URMs are a particularly vulnerable group with a large burden of mental health problems.

In 2015, 162,877 persons sought asylum in Sweden, 35,369 of whom were unaccompanied refugee minors (URMs) and another 35,015 children in families (Swedish Migration Agency, 2017). Most URMs (86 per cent) are boys, mainly from Afghanistan, Syria, Somalia and Eritrea, whereas children in families (accompanied refugee minors) more often come from Syria and Iraq with an equal gender distribution. During the asylum process, lasting up to 30 months, children have access to free education and health care. URMs are under the care of the social services and are assigned a legal guardian until they turn 18. Adults are entitled to acute health care and housing but cannot work and have no access to studies. If granted asylum, the person/family is assigned to a municipality that assumes responsibility for them. Thus, on top of adverse events before and during migration, the asylum and resettlement process per se involves stressors and a lack of control for refugees, which increases the risk of developing mental health problems.
DAZL is a master translational regulator of murine spermatogenesis
Authors: Li Haixin , Liang Zhuqing , Yang Jian , Wang Dan , Wang Hanben , Zhu Mengyi , Geng Baobao , Xu Eugene Yujun
Published: December 2018

Expression of DAZ-like (DAZL) is a hallmark of vertebrate germ cells, and is essential for embryonic germ cell development and differentiation, yet the gametogenic function of DAZL has not been fully characterized and most of its in vivo direct targets remain unknown. We showed that postnatal stage-specific deletion of Dazl in mouse germ cells did not affect female fertility, but caused complete male sterility with gradual loss of spermatogonial stem cells, meiotic arrest and spermatid arrest. Using the genome-wide high-throughput sequencing of RNAs isolated by cross-linking immunoprecipitation and mass spectrometry approach, we found that DAZL bound to a large number of testicular mRNA transcripts (at least 3008) at the 3′-untranslated region and interacted with translation proteins including poly(A) binding protein. In the absence of DAZL, polysome-associated target transcripts, but not their total transcripts, were significantly decreased, resulting in a drastic reduction of an array of spermatogenic proteins and thus developmental arrest. Thus, DAZL is a master translational regulator essential for spermatogenesis.
High-resolution CO images of the Galactic central molecular zone
Authors: Tokuyama Sekito , Oka Tomoharu , Takekawa Shunya , Iwata Yuhei , Tsujimoto Shiho , Yamada Masaya , Furusawa Maiko , Nomura Mariko
Published: December 2018

We performed Nyquist-sampled mapping observations of the central molecular zone of our Galaxy in the J = 1–0 lines of CO, 13CO, and C18O using the 45 m telescope at the Nobeyama Radio Observatory. The newly obtained data sets were an improvement by a factor of four in spatial resolution of the CO data previously obtained with the same telescope 22 years ago, providing the highest angular resolution CO atlas of this special area of the Galaxy. The data cover the area: −0${^{\circ}_{.}}$8 ≤ l ≤ +1${^{\circ}_{.}}$4 and −0${^{\circ}_{.}}$35 ≤ b ≤ +0${^{\circ}_{.}}$35 with a 15″ beamwidth. Total intensity ratios for CO J = 3–2/J = 1–0, 13CO/CO J = 1–0 and C18O/13CO J = 1–0, are 0.70 ± 0.06, 0.12 ± 0.01, and 0.14 ± 0.01, respectively. The high-resolution CO images show the fine structure of the molecular gas and enable us to identify a number of compact clouds with broad velocity widths, i.e., high-velocity compact clouds. We conducted a detailed comparison of our CO J = 1–0 data with the CO J = 3–2 data obtained with the James Clerk Maxwell Telescope to derive the distribution and kinematics of the highly excited gas. Three, out of four, of the previously identified high CO J = 3–2/J = 1–0 ratio areas at l = +1${^{\circ}_{.}}$3, 0${^{\circ}_{.}}$0, and −0${^{\circ}_{.}}$4 were confirmed with a higher spatial resolution. In addition to these, we identified several very compact, high CO J = 3–2/J = 1–0 spots with broad velocity widths for the first time. These are candidates for accelerated gas in the vicinity of invisible, point-like massive objects.
OCCUPATIONAL EXPOSURE TO EXTERNAL IONISING RADIATION IN TANZANIA (2011–17)
Authors: Muhogora Wilbroad Edward , Banzi Firm Paul , Ngaile Justin Emanuel , Ngoye Wilson Maliyatabu , Lema Usha Sara , Shao Didas , Chuma Furaha , Masoud Ali Omar , Kileo Abdallah , Mikidadi Salehe , Salum Salum K
Published: December 2018

The objectives of this paper were to evaluate the occupational radiation exposure data from 2011 to 2017 and to compare the results with status in 1996–2010 periods. The evaluation was performed in terms of annual collective effective dose, the average annual effective dose, the individual dose distribution ratio and the annual collective effective dose distribution ratio. Irrespective of work category, the results indicate that the average effective dose ranged from 0.64 to 1.55 mSv and broadly comparable to data in the previous analysis. Over seven year period, the maximum annual individual dose was 4 mSv and therefore below the dose limit of 20 mSv y−1. The impact of radiological practice on the exposed population was <1.1 person.Sv. The results demonstrate satisfactory radiation protection conditions at workplaces, a situation which is mainly explained by the existing effective regulatory enforcement and improved workers’ awareness.
Draft Genome Resources of Two Strains (“ESVL” and “IVIA5901”) of Xylella fastidiosa Associated with Almond Leaf Scorch Disease in Alicante, Spain
Authors: Giampetruzzi Annalisa , Velasco-Amo María Pilar , Marco-Noales Ester , Montes-Borrego Miguel , Román-Écija Miguel , Navarro Inmaculada , Monterde Adela , Barbé Silvia , Almeida Rodrigo P. P. , Saldarelli Pasquale , Saponari Maria , Montilon Vito , Savino Vito Nicola , Boscia Donato , Landa Blanca B.
Published: December 2018

An outbreak of Xylella fastidiosa subsp. multiplex sequence type ST6 was discovered in 2017 in mainland Spain affecting almond trees. Two cultured almond strains, “ESVL” and “IVIA5901,” were subjected to high throughput sequencing and the draft genomes assembled. Phylogenetic analysis conclusively indicated they belong to the subspecies multiplex, and pairwise comparisons of the chromosomal genomes showed an average nucleotide identity higher than 99%. Interestingly, the two strains differ for the presence of the plasmids pXF64-Hb_ESVL and pUCLA-ESVL detected only in the ESVL strain. The availability of these draft genomes contribute to extend the European genomic sequence dataset, a first step toward setting new research to elucidate the pathway of introduction and spread of the numerous strains of this subspecies so far detected in Europe.
How People Initiate Energy Optimization and Converge on Their Optimal Gaits
Authors: Selinger Jessica , Wong Jeremy , Simha Surabhi , Donelan Maxwell
Published: December 2018

A central principle in motor control is that the coordination strategies learned by our nervous system are often optimal. Here we combined human experiments with computational reinforcement learning models to study how the nervous system navigates possible movements to arrive at an optimal coordination. Our experiments used robotic exoskeletons to reshape the relationship between how participants walk and how much energy they consume. We found that while some participants used their relatively high natural gait variability to explore the new energetic landscape and spontaneously initiate energy optimization, most participants preferred to exploit their originally preferred, but now suboptimal, gait. We could nevertheless reliably initiate optimization in these exploiters by providing them with the experience of lower cost gaits suggesting that the nervous system benefits from cues about the relevant dimensions along which to re-optimize its coordination. Once optimization was initiated, we found that the nervous system employed a local search process to converge on the new optimum gait over tens of seconds. Once optimization was completed, the nervous system learned to predict this new optimal gait and rapidly returned to it within a few steps if perturbed away. We model this optimization process as reinforcement learning and find behavior that closely matches these experimental observations. We conclude that the nervous system optimizes for energy using a prediction of the optimal gait, and then refines this prediction with the cost of each new walking step.
Insights into the genetic basis of predator-induced response inDaphnia galeata
Authors: Tams Verena , Nickel Jana Helene , Ehring Anne , Cordellier Mathilde
Published: December 2018

Phenotypic plastic responses allow organisms to rapidly adjust when facing environmental challenges - these responses comprise morphological, behavioral but also life-history changes. Alteration of life-history traits when exposed to predation risk have been reported often in the ecological and genomic model organismDaphnia. However, the molecular basis of this response is not well understood, especially in the context of fish predation. Here, we characterized the transcriptional profiles of twoDaphnia galeataclonal lines with opposed life histories when exposed to fish kairomones. First, we conducted a differential gene expression, identifying a total of 125 candidate transcripts involved in the predator-induced response, uncovering substantial intra-specific variation. Second, we applied a gene co-expression network analysis to find clusters of tightly linked transcripts revealing the functional relations of transcripts underlying the predator-induced response. Our results showed that transcripts involved in remodeling of the cuticle, growth and digestion correlated with the response to environmental change inD. galeata. Furthermore, we used an orthology-based approach to gain functional information for transcripts lacking gene ontology (GO) information, as well as insights into the evolutionary conservation of transcripts. We could show that our candidate transcripts have orthologs in otherDaphniaspecies but almost none in other arthropods. The unique combination of methods allowed us to identify candidate transcripts, their putative functions and evolutionary history associated with predator-induced responses inDaphnia. Our study opens up to the question as to whether the same molecular signature is associated fish kairomones-mediated life-history changes in otherDaphniaspecies.
Conditions for numerically accurate TMS electric field simulation
Authors: Gomez Luis , Dannhauer Moritz , Koponen Lari , Peterchev Angel V
Published: December 2018

Background: Computational simulations of the E-field induced by transcranial magnetic stimulation (TMS) are increasingly used to understand its mechanisms and to inform its administration. However, characterization of the accuracy of the simulation methods and the factors that affect it is lacking.
Objective: To ensure the accuracy of TMS E-field simulations, we systematically quantify their numerical error and provide guidelines for their setup.
Method: We benchmark the accuracy of computational approaches that are commonly used for TMS E-field simulations, including the finite element method (FEM), boundary element method (BEM), finite difference method (FDM), and coil modeling methods.
Results: To achieve cortical E-field error levels below 2%, the commonly used FDM and 1st order FEM require meshes with an average edge length below 0.4 mm, whereas BEM and 2nd (or higher) order FEM require edge lengths below 1.5 mm, which is more practical. Coil models employing magnetic and current dipoles require at least 200 and 3,000 dipoles, respectively. For thick solid-conductor coils and frequencies above 3 kHz, winding eddy currents may have to be modeled.
Conclusion: BEM, FDM, and FEM methods converge to the same solution. However, FDM and 1st order FEM converge slowly with increasing mesh resolution; therefore, the use of BEM or 2nd (or higher) order FEM is recommended. In some cases, coil eddy currents must be modeled. Both electric current dipole and magnetic dipole models of the coil current can be accurate with sufficiently fine discretization.
Affective flexibility without perceptual awareness
Authors: Homan Philipp , Lau H. Lee , Levy Ifat , Raio Candace M. , Bach Dominik R. , Carmel David , Schiller Daniela
Published: December 2018

In an ever-changing environment, survival depends on learning which stimuli represent threat, and also on updating such associations when circumstances shift. Humans can acquire physiological responses to threat-associated stimuli even when they are unaware of them, but the role of awareness in updating threat contingencies remains unknown. This complex process – generating novel responses while simultaneously suppressing learned ones – relies on distinct neural mechanisms from initial learning, and has only been shown with awareness. Can it occur unconsciously? Here we show that it can. Participants underwent classical threat conditioning to visual stimuli that were suppressed from their awareness. One of two images was paired with an electric shock; halfway through the experiment, contingencies were reversed and the shock was paired with the other image. We found that physiological responses reflected changes in stimulus-threat pairings independently of stimulus awareness, demonstrating the sophistication of unconscious affective flexibility.
Machine-learning for cluster analysis of localization microscopy data.
Authors: Williamson David J , Burn Garth L , Griffie Juliette , Davis Daniel M , Owen Dylan M
Published: December 2018

Quantifying the clustering of points within single-molecule localization microscopy data is useful to understanding the spatial relationships of the molecules in the underlying sample. The conversion of point pattern data into a meaningful description of clustering is difficult, especially for biologically derived data, as the definitions of clustering are often subjective or simplistic. Many existing computational approaches are also limited in their ability to process large-scale data-sets or to deal effectively with inhomogeneities in clustering. Here we have developed a supervised machine-learning approach to cluster analysis which is fast and accurate. Trained on a variety of simulated clustered data, the network can then classify all points from a typical localization microscopy data-set (several million points from the entire field of view) as being either clustered or not-clustered, with the potential to include additional classifiers to describe different types of clusters. Clustered points can then be further refined into like-clusters for the measurement of cluster area, shape, and point-density. We demonstrate the performance on simulated data and experimental data of the kinase Csk and the adaptor PAG in both naive and pre-stimulated primary human T cell synapses.
The Genomic Landscape of Centromeres in Cancers
Authors: Saha Anjan K. , Mourad Mohamad , Kaplan Mark H. , Chefetz Ilana , Malek Sami N. , Buckanovich Ronald , Markovitz David M. , Contreras-Galindo Rafael
Published: December 2018

Centromere genomics remain poorly characterized in cancer, due to technologic limitations in sequencing and bioinformatics methodologies that make high-resolution delineation of centromeric loci difficult to achieve. We here leverage a highly specific and targeted rapid PCR methodology to quantitatively assess the genomic landscape of centromeres in cancer cell lines and primary tissue. PCR-based profiling of centromeres revealed widespread heterogeneity of centromeric and pericentromeric sequences in cancer cells and tissue as compared to healthy counterparts. Quantitative reductions in select centromeric core and pericentromeric markers were observed in neoplastic samples as compared to healthy counterparts. Subsequent phylogenetic analysis of a pericentromeric endogenous retrovirus amplified by PCR revealed possible gene conversion events occurring at numerous pericentromeric loci in the setting of malignancy. Our findings collectively represent the first look into centromere genetics in the setting of malignancy, providing valuable insight into the evolution and reshuffling of centromeric sequences in cancer development and progression.
ADHD Symptoms are Associated with the Modular Structure of Intrinsic Brain Networks in a Representative Sample of Healthy Adults
Authors: Hilger Kirsten , Fiebach Christian J.
Published: December 2018

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders with significant and often lifelong effects on social, emotional, and cognitive functioning. Influential neurocognitive models of ADHD link behavioral symptoms to altered connections between and within functional brain networks. Here, we investigate whether network-based theories of ADHD can be generalized to understanding variations in ADHD-related behaviors within the normal (i.e., clinically unaffected) adult population. In a large and representative sample, self-rated presence of ADHD symptoms varied widely; only eight out of 291 participants scored in the clinical range. Subject-specific brain-network graphs were modeled from functional MRI resting-state data and revealed significant associations between (non-clinical) ADHD symptoms and region-specific profiles of between-module and within-module connectivity. Effects were located in brain regions associated with multiple neuronal systems including the default-mode network, the salience network, and the central executive system. Our results are consistent with network perspectives of ADHD and provide further evidence for the relevance of an appropriate information transfer between task-negative (default-mode) and task-positive brain regions. More generally, our findings support a dimensional conceptualization of ADHD and contribute to a growing understanding of cognition as an emerging property of functional brain networks.

Author Summary

Neurocognitive models of ADHD link behavioral symptoms to altered connections between and within functional brain networks. We investigate whether these network-based theories of ADHD can be generalized to ADHD-related behaviors within the normal adult population. Subject-specific brain graphs were modeled from functional MRI resting-state data of a large and representative sample (N = 291). Significant associations between ADHD-related behaviors and region-specific profiles of between-module and within-module connectivity were observed in brain regions associated with multiple functional systems including the default-mode network, the salience network, and the central executive system. Our results support a dimensional conceptualization of ADHD and enforce network-based models of ADHD by providing further evidence for the relevance of an appropriate information transfer between task-negative (default-mode) and task-positive brain regions.
RNA Polymerase II Independent Recruitment of SPT6 at Transcription Start Sites in Arabidopsis
Authors: Chen Chen , Shu Jie , Li Chenlong , Thapa Raj K. , Nguyen Vi , Yu Kangfu , Yuan Zechun , Kohalmi Susanne E. , Liu Jun , Marsolais Frédéric , Huang Shangzhi , Cui Yuhai
Published: December 2018

SPT6 is a conserved transcription regulator that is generally viewed as an elongation factor. However, emerging evidence show its potential role in the control of transcription initiation at genic and intragenic promoters. Here we first present the genome-wide occupancy of Arabidopsis SPT6-like (SPT6L) and demonstrate its conserved role in facilitating RNA Polymerase II (RNAPII) occupancy across transcribed genes. Further, we show that SPT6L enrichment is shifted, unexpectedly, from gene body to the transcription starting site (TSS) when its association with RNAPII is disrupted. Finally, we demonstrate that recruitment of SPT6L starts at TSS, and then spreads to the gene body during transcription. These findings refine the mechanisms underlying SPT6L recruitment in transcription and shed light on the role of SPT6L in transcription initiation.
Activation of NIX-mediated mitophagy and replication by an interferon regulatory factor homologue of human herpesvirus
Authors: Vo Mai Tram , Smith Barbara J , Nicholas John , Choi Young Bong
Published: December 2018

Viral control of mitochondrial quality and content has emerged as an important mechanism for counteracting the host response to virus infection. Despite the knowledge of this crucial function of some viruses, little is known about how herpesviruses regulate mitochondrial homeostasis during infection. Human herpesvirus 8 (HHV-8) is an oncogenic virus causally related to AIDS-associated malignancies. Here, we found that HHV-8-encoded viral interferon regulatory factor 1 (vIRF-1) promotes mitochondrial clearance by activating mitophagy to support virus replication. Genetic interference with vIRF-1 expression or targeting to the mitochondria inhibits HHV-8 replication-induced mitophagy and leads to an accumulation of mitochondria. Moreover, vIRF-1 binds directly to a mitophagy receptor, NIX, on the mitochondria and activates NIX-mediated mitophagy to promote mitochondrial clearance. Genetic and pharmacological interruption of vIRF-1/NIX-activated mitophagy inhibits HHV-8 productive replication. In short, our findings uncover an essential role of vIRF-1 in mitophagy activation for successful lytic replication of HHV-8.
RNA sequencing identifies dysregulated circular RNAs in early-stage breast cancer
Authors: Arvinden Vittal Rangan , Magendhra Rao Arunagiri Kuha Deva , Meenakumari Balaiah , Ramanathan Priya , Sundersingh Shirley , Sridevi Velusami , Rajkumar Thangarajan , Herceg Zdenko , Mani Samson
Published: December 2018

Background:

Breast cancer is a major cause of cancer related death in women worldwide. Molecular diagnostic markers that are detectable in early-stage breast cancer can aid in effective clinical intervention. Circular RNAs are a recently identified group of non-coding RNA with potential role in cancer development and progression. In this study, we aimed to identify circular RNAs specific for early stage breast cancer.

Method:

Circular RNA expression profile was analyzed in early-stage breast cancer tissues (N=5), matched normal counterparts (N=5) and absolute normal samples (N=5) by RNA-sequencing that enables a comprehensive analysis of RNA expression across the transcriptome. Two different algorithms, find_circ and DCC were used to identify the differentially expressed circular RNAs.

Results:

A total of 58 and 87 circular RNAs were found to be differentially expressed by find_circ and DCC algorithms, respectively, among which 26 circular RNAs were common. Hsa_circ_0001946 (CDR1-as) was found to be upregulated in early stage breast cancer along with other novel circular RNAs (hsa_circ_0008225, hsa_circ_0007766, hsa_circ_0016601). We also found that a few of the identified circular RNAs harbor microRNA binding sites which can lead to microRNA sponging activity and pre-microRNA sequences which can generate mature microRNAs. The identified circular RNAs that are differentially regulated in early stage breast cancer can be of potential diagnostic/prognostic importance.

Conclusion:

Circular RNA are differentially expressed in the early-stage breast cancer with potential application in early diagnosis and prognosis. The differentially expressed circular RNA can sequester microRNA and can act as microRNA precursor as well.
Identification of TTN as a novel candidate gene for atrioventricular block in a Chinese pedigree by whole-exome sequencing
Authors: Liu Guohui , Yang Ziying , Chen Weiwei , Xu Junguang , Mao Liangwei , Yu Qinlin , Guo Jian , Xu Hui , Liu Fengxia , Sun Yan , Huang Hui , Peng Zhiyu , Sun Jun , Li Wei , Yang Ping
Published: December 2018

Purpose

Cardiovascular diseases are the most common cause of death globally. In which atrioventricular block (AVB) is a common disorder with genetic causes, but the responsible genes have not been fully identified yet. To determine the underlying causative genes involved in cardiac AVB, here we report a three-generation Chinese family with severe autosomal dominant cardiac AVB that has been ruled out as being caused by known genes mutations.

Methods

Whole-exome sequencing was performed in five affected family members across three generations, and co-segregation analysis was validated on other members of this family.

Results

Whole-exome sequencing and subsequent co-segregation validation identified a novel germline heterozygous point missense mutation, c.49287C>A (p.N16429K), in the titin (TTN, NM_001267550.2) gene in all 5 affected family members, but not in the unaffected family members. The point mutation is predicted to be functionally deleterious by in-silico software tools. Our finding was further supported by the conservative analysis across species.

Conclusion

Based on this study, TTN was identified as a potential novel candidate gene for autosomal dominant AVB; this study expands the mutational spectrum of TTN gene and is the first to implicate TTN mutations as AVB disease causing in a Chinese pedigree.
Two-way assessment of key performance indicators to vaccine supply chain system in India
Authors: Chandra Dheeraj , Kumar Dinesh
Published: December 2018

Purpose

The purpose of this paper is to identify the key performance indicators (KPIs) of vaccine supply chain of Universal Immunization Program (UIP) India, and measure their impact on vaccine supply chain performance improvement, so that results of this study can help the decision makers manage the activity and effectiveness of their resources in order to improve vaccine delivery performance and child immunization coverage.

Design/methodology/approach

The 41 KPIs in terms of four dimension of the balanced scorecard (BSC), i.e. financial, customer, internal process and learning and growth have been identified and validated from the literature and expert’s opinions. Further, the impact of internal process and learning and growth performance indicators on the vaccine supply chain performance improvement have been evaluated using two-way assessment. The rankings obtained using two-way assessment are then compared to DEMATEL approach to validate the results.

Findings

The results from the analysis reveal that “Enhancement in employee work satisfaction” (LG3=10.08 percent), “Enhancement in professional vaccine supply chain managers and leaders” (LG2 = 6.70 percent) “Improvement in planning and coordination in the supply chain” (LG9 = 6.57 percent) are the three critical performance indicators having maximum impact on vaccine supply chain performance improvement. The decision makers should give priority to these performance indicators to improve delivery performance and immunization coverage.

Social implications

This study focuses on the improvement in vaccine delivery performance, therefore, analysis and findings can be useful to government immunization programs of India to other developing nations to improve child immunization coverage.

Originality/value

To our knowledge, this paper is first to attempt to provide a direction to improve immunization coverage through vaccine supply chain performance indicators.
Filter rule performance in an emerging market: evidence from Qatari listed companies
Authors: Almujamed Hesham I.
Published: December 2018

Purpose

The purpose of this paper is to examine the predictability of nine filter rules and test the validity of the weak form of the efficient market hypothesis for the Qatar Stock Exchange (QSE).

Design/methodology/approach

This study adopts the filter rule strategy employed by Fifieldet al.(2005), which suggests that a buy signal occurs when a share’s price increases by X percent from the previous price. This strategy recommends that the share is held until its price declines by X percent from the subsequent high price. Any price changes below X percent are ignored. Additionally, using the theory of weak-form efficiency, this paper suggests that, if a stock market is efficient, an investor cannot achieve superior results by using these trading rules. However, if market inefficiencies are present, profitable opportunities may arise. To this end, the daily closing share prices of 44 companies listed on QSE are explored for 2004–2017.

Findings

The findings propose that QSE is not weak-form efficient because security prices are predictable. As such, investors who followed filter strategies based on past price information could have made profit. Sectoral analysis findings further suggest that firms in the consumer goods and services, industrial and insurance sectors are most efficiently priced amongst the QSE-traded companies.

Practical implications

The evidence may be plausibly helpful as supporting market participants and academics that suggest that selecting filter strategy is extremely important for determining the overall profitability of the trading strategy.

Originality/value

To the best of my knowledge, this is the first study on Qatar that examines the performance of filter rules relative to a passive investor in the context of trading rules with individual share prices for a new stock market. Furthermore, this study adds to the literature through the empirical finding that technical analysts using filter strategies could generate excess returns relative to the buy-and-hold strategy on new emerging stock markets. This study also suggests the levels of transparency and accounting disclosure are limited, which may help Qatari policy makers understand the QSE context. Therefore, it might lead them to introduce regulatory changes to improve the QSE’s efficiency level.
Eosinophilic fasciitis associated with myositis: Report of four cases and review of the literature
Authors: Liu Yin , Zeng Yanping , Xie Yanchun , Gao Likun , Chu Hong , Xiao Zheman , Lu Zuneng
Published: December 2018

Eosinophilic fasciitis is a rare scleroderma‐like syndrome with an unknown aetiology. The characteristics of this disorder include lymphoplasmacytic inflammation involving the subcutaneous fat septa and fascia. Eosinophilic myositis is diagnosed when inflammation extends into the muscles. Here, we describe four patients who developed eosinophilic fasciitis, three of whom developed eosinophilic fasciitis with myositis. Fascial and muscle biopsies were used to confirm the diagnoses. All the patients presented with musculoskeletal symptoms; their electromyographic examinations showed myogenic lesions [short‐duration, low‐amplitude and polyphasic motor unit action potentials (MUPs), so‐called myopathic changes, frequently with abnormal spontaneous activity], in contrast with findings from other reports.
A novel, highly discriminatory risk model predicting acute severe right ventricular failure in patients undergoing continuous‐flow left ventricular assist device implant
Authors: Tchantchaleishvili Vakhtang , Maltais Simon , Sharma Shashank , Haglund Nicholas A. , Davis Mary E. , Cowger Jennifer , Shah Palak , Desai Shashank S. , Aaronson Keith D. , Pagani Francis D. , Dunlay Shannon M. , Stulak John M.
Published: December 2018

Various risk models with differing discriminatory power and predictive accuracy have been used to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. There remains an unmet need for a contemporary risk score for continuous flow (CF)‐LVADs. We sought to independently validate and compare existing risk models in a large cohort of patients and develop a simple, yet highly predictive risk score for acute, severe RVF. Data from the Mechanical Circulatory Support Research Network (MCSRN) registry, consisting of patients who underwent CF‐LVAD implantation, were randomly divided into equal‐sized derivation and validation samples. RVF scores were calculated for the entire sample, and the need for a right ventricular assist device (RVAD) was the primary endpoint. Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified. A risk score was developed based on the identified variables and their respective regression coefficients. Between May 2004 and September 2014, 734 patients underwent implantation of CF‐LVADs [HeartMate II LVAD, 76% (n = 560), HeartWare HVAD, 24% (n = 174)]. A RVAD was required in 4.5% (n = 33) of the patients [Derivation cohort, n = 15 (4.3%); Validation cohort, n = 18 (5.2%); P = 0.68)]. 19.5% of the patients (n = 143) were female, median age at implant was 59 years (IQR, 49.4–65.3), and median INTERMACS profile was 3 (IQR, 2–3). RVAD was required in 4.5% (n = 33) of the patients. Correlates of acute, severe RVF in the final model included heart rate, albumin, BUN, WBC, cardiac index, and TR severity. Areas under the curves (AUC) for most commonly used risk predictors ranged from 0.61 to 0.78. The AUC for the new model was 0.89 in the derivation and 0.92 in the validation cohort. Proposed risk model provides very high discriminatory power predicting acute severe right ventricular failure and can be reliably applied to patients undergoing placement of contemporary continuous flow left ventricular assist devices.
Introduction: Russia in the Asia‐Pacific
Authors: Lukin Alexander
Published: December 2018

In this special issue of Asian Politics & Policy, the authors argue that Russian‐Chinese rapprochement is a fundamental feature of the current changing system of international relations. The two countries are effectively enabling each other to conduct independent foreign policies often in direct opposition to the West. There is a degree of complimentarity between the two sides with Russia having comparative advantage in the military, intelligence and diplomatic fields and China being an economic superpower. The region of Central Asia has in reality become the cradle of the two countries’ cooperation which is now affecting a wide range of international issues. The Korean peninsula is another important area of coordination between Moscow and Beijing in the Asia‐Pacific. Russia and China have also been working on increasing interoperability of their military forces in the region since mid 2000s. Technically they have already done much in preparing the ground for a military alliance. However, politically they do not appear to be ready for that yet.