bluuebunny/crossref_metadata_2025_split huggingface dataset:
TERC promotes cellular inflammatory response independent of telomerase
Authors: Liu Haiying , Yang Yiding , Ge Yuanlong , Liu Juanhong , Zhao Yong 
Published: July 2019

Abstract
TERC is an RNA component of telomerase. However, TERC is also ubiquitously expressed in most human terminally differentiated cells, which don’t have telomerase activity. The function of TERC in these cells is largely unknown. Here, we report that TERC enhances the expression and secretion of inflammatory cytokines by stimulating NK-κB pathway in a telomerase-independent manner. The ectopic expression of TERC in telomerase-negative cells alters the expression of 431 genes with high enrichment of those involved in cellular immunity. We perform genome-wide screening using a previously identified ‘binding motif’ of TERC and identify 14 genes that are transcriptionally regulated by TERC. Among them, four genes (LIN37, TPRG1L, TYROBP and USP16) are demonstrated to stimulate the activation of NK-κB pathway. Mechanistically, TERC associates with the promoter of these genes through forming RNA–DNA triplexes, thereby enhancing their transcription. In vivo, expression levels of TERC and TERC target genes (TYROBP, TPRG1L and USP16) are upregulated in patients with inflammation-related diseases such as type II diabetes and multiple sclerosis. Collectively, these results reveal an unknown function of TERC on stimulating inflammatory response and highlight a new mechanism by which TERC modulates gene transcription. TERC may be a new target for the development of anti-inflammation therapeutics.
The Pol IV largest subunit CTD quantitatively affects siRNA levels guiding RNA-directed DNA methylation
Authors: Wendte Jered M , Haag Jeremy R , Pontes Olga M , Singh Jasleen , Metcalf Sara , Pikaard Craig S 
Published: July 2019

Abstract
In plants, nuclear multisubunit RNA polymerases IV and V are RNA Polymerase II-related enzymes that synthesize non-coding RNAs for RNA-directed DNA methylation (RdDM) and transcriptional gene silencing. Here, we tested the importance of the C-terminal domain (CTD) of Pol IV’s largest subunit given that the Pol II CTD mediates multiple aspects of Pol II transcription. We show that the CTD is dispensable for Pol IV catalytic activity and Pol IV termination-dependent activation of RNA-DEPENDENT RNA POLYMERASE 2, which partners with Pol IV to generate dsRNA precursors of the 24 nt siRNAs that guide RdDM. However, 24 nt siRNA levels decrease ∼80% when the CTD is deleted. RNA-dependent cytosine methylation is also reduced, but only ∼20%, suggesting that siRNA levels typically exceed the levels needed for methylation of most loci. Pol IV-dependent loci affected by loss of the CTD are primarily located in chromosome arms, similar to loci dependent CLSY1/2 or SHH1, which are proteins implicated in Pol IV recruitment. However, deletion of the CTD does not phenocopy clsy or shh1 mutants, consistent with the CTD affecting post-recruitment aspects of Pol IV activity at target loci.
Copepod carcasses in the subtropical convergence zone of the Sargasso Sea: implications for microbial community composition, system respiration and carbon flux
Authors: Tang Kam W , Backhaus Liv , Riemann Lasse , Koski Marja , Grossart Hans-Peter , Munk Peter , Nielsen Torkel Gissel 
Published: July 2019

Abstract
The oligotrophic subtropical gyre covers a vast area of the Atlantic Ocean. Decades of time-series monitoring have generated detailed temporal information about zooplankton species and abundances at fixed locations within the gyre, but their live/dead status is often omitted, especially in the dynamic subtropical convergence zone (STCZ) where the water column stratification pattern can change considerably across the front as warm and cold water masses converge. We conducted a detailed survey in the North Atlantic STCZ and showed that over 85% of the copepods were typically concentrated in the upper 200 m. Copepod carcasses were present in all samples and their proportional numerical abundances increased with depth, reaching up to 91% at 300–400 m. Overall, 14–19% of the copepods within the upper 200 m were carcasses. Shipboard experiments showed that during carcass decomposition, microbial respiration increased, and the bacterial community associated with the carcasses diverged from that in the ambient water. Combining field and experimental data, we estimated that decomposing copepod carcasses constitute a negligible oxygen sink in the STCZ, but sinking carcasses may represent an overlooked portion of the passive carbon sinking flux and should be incorporated in future studies of carbon flux in this area.
Predictors of successful discontinuation of biologic and targeted synthetic DMARDs in patients with rheumatoid arthritis in remission or low disease activity: a systematic literature review
Authors: Schlager Lukas , Loiskandl Michaela , Aletaha Daniel , Radner Helga 
Published: July 2019

Abstract

Objective
To systematically review possible predictors of successful discontinuation of biologic or targeted synthetic DMARDs (b/tsDMARDs) in RA patients in remission or low disease activity.

Methods
MEDLINE database and Cochrane Library were scanned for studies that discontinued b/tsDMARDs in remission/low disease activity and searched for predictors of successful discontinuation. Additionally, EULAR and ACR meeting abstracts were hand searched.

Results
Thirty-four studies with a total of 5724 patients were included. Predictors of successful b/tsDMARD discontinuation were (number of studies): low disease activity (n = 13), better physical function (n = 6), low or absence of rheumatoid factor (n = 5) or ACPA (n = 3), low levels of CRP (n = 3) or ESR (n = 3), shorter disease duration (n = 3), low signals of disease activity by ultrasound (n = 3). Only one study with high risk of bias was identified on tsDMARD discontinuation.

Conclusion
Several predictors of successful bDMARD discontinuation were identified. Although studies are heterogeneous, these predictors may inform clinical decision making in patients who are considered for a potential bDMARD discontinuation.
Methodological considerations when analysing and interpreting real-world data
Authors: Stürmer Til , Wang Tiansheng , Golightly Yvonne M , Keil Alex , Lund Jennifer L , Jonsson Funk Michele 
Published: July 2019

Abstract
In the absence of relevant data from randomized trials, nonexperimental studies are needed to estimate treatment effects on clinically meaningful outcomes. State-of-the-art study design is imperative for minimizing the potential for bias when using large healthcare databases (e.g. claims data, electronic health records, and product/disease registries). Critical design elements include new-users (begin follow-up at treatment initiation) reflecting hypothetical interventions and clear timelines, active-comparators (comparing treatment alternatives for the same indication), and consideration of induction and latent periods. Propensity scores can be used to balance measured covariates between treatment regimens and thus control for measured confounding. Immortal-time bias can be avoided by defining initiation of therapy and follow-up consistently between treatment groups. The aim of this manuscript is to provide a non-technical overview of study design issues and solutions and to highlight the importance of study design to minimize bias in nonexperimental studies using real-world data.
Prevalence and Pattern of Congenital Anomalies in a Tertiary Hospital in Central Vietnam
Authors: Giang Hoang Thi Nam , Bechtold-Dalla Pozza Susanne , Ulrich Sarah , Linh Le Khac , Tran Hoang Thi 
Published: July 2019

Abstract

Background
Burden and pattern of congenital anomalies are insufficiently reported in Vietnam. This study aims to determine the prevalence and pattern of congenital anomalies in neonates in a tertiary hospital in central Vietnam.

Methods
A prospective cross-sectional study recruited all newborns with congenital anomalies in Da Nang Hospital for Women and Children—where nearly 60% neonates in the city are delivered.

Results
Over a 1-year period, 551 out of 14 335 registered live births were found to have congenital anomalies, equivalent to an overall prevalence of 384.4 per 10 000 live births. Congenital heart defects were the most common type (52.3%) with the prevalence of 200.9 per 10 000 live births, followed by anomalies of musculoskeletal system, digestive system.

Conclusions
This study revealed a high prevalence of congenital anomalies with the most common type being congenital heart defects in central Vietnam compared to both higher income countries and resource-limited settings.
Clinical and epidemiologic profile of venomous snakebites in Chongqing Wuling mountainous area, western China
Authors: Chen Xi , He Hongmei , Cai Hongke 
Published: July 2019

Abstract

Background
In China, venomous snakebites are an important medical emergency and cause of hospital admission, but few studies have looked at the clinical and epidemiologic profile of human snakebite victims.

Methods
We conducted a retrospective study of 440 snakebite cases encountered at a single hospital in the Chongqing Wuling mountainous area of western China from July 2004 to August 2018. Data were collected from the electronic medical record system.

Results
The majority of bite victims were male (58.4%), 41–60 y of age (37.9%) and the bites occurred during the daytime (51.1%) in July–September (62.5%). The lower limbs were the most vulnerable sites to snakebites (73.9%). The most common local toxicity consisted of pain (86.1%), oedema (78.4%) and bleeding (35.9%). Of the systemic toxicities, haematuria (14.3%) and ophthalmoplegia (9.5%) were common. The majority (86.4%) of individuals presented to the hospital within 6 h.

Conclusions
This study describes the clinical and epidemiologic profile of venomous snakebites in the Chongqing Wuling mountainous area of western China. Multicentre prospective studies were needed in the entire country of China.
Imaging live bacteria at the nanoscale: comparison of immobilisation strategies
Authors: Benn Georgina , Pyne Alice L. B. , Ryadnov Maxim G. , Hoogenboom Bart W 
Published: July 2019

AbstractAtomic force microscopy (AFM) provides an effective, label-free technique enabling the imaging of live bacteria under physiological conditions with nanometre precision. However, AFM is a surface scanning technique, and the accuracy of its performance requires the effective and reliable immobilisation of bacterial cells onto substrates. Here, we compare the effectiveness of various chemical approaches to facilitate the immobilisation of Escherichia coli onto glass cover slips in terms of bacterial adsorption, viability and compatibility with correlative imaging by fluorescence microscopy. We assess surface functionalisation using gelatin, poly-L-lysine, Cell-Tak™, and Vectabond®. We describe how bacterial immobilisation, viability and suitability for AFM experiments depend on bacterial strain, buffer conditions and surface functionalisation. We demonstrate the use of such immobilisation by AFM images that resolve the porin lattice on the bacterial surface; local degradation of the bacterial cell envelope by an antimicrobial peptide (Cecropin B); and the formation of membrane attack complexes on the bacterial membrane.
Functional maturation of human neural stem cells in a 3D bioengineered brain model enriched with fetal brain-derived matrix
Authors: Sood Disha , Cairns Dana M. , Dabbi Jayanth M. , Ramakrishnan Charu , Deisseroth Karl , Black Lauren D. , Santaniello Sabato , Kaplan David L. 
Published: July 2019

AbstractBrain extracellular matrix (ECM) is often overlooked in vitro brain tissue models, despite its instructive roles during development. Using developmental stage-sourced brain ECM in reproducible 3D bioengineered culture systems, we demonstrate enhanced functional differentiation of human induced neural stem cells (hiNSCs) into healthy neurons and astrocytes. Particularly, fetal brain tissue-derived ECM supported long-term maintenance of differentiated neurons, demonstrated by morphology, gene expression and secretome profiling. Astrocytes were evident within the second month of differentiation, and reactive astrogliosis was inhibited in brain ECM-enriched cultures when compared to unsupplemented cultures. Functional maturation of the differentiated hiNSCs within fetal ECM-enriched cultures was confirmed by calcium signaling and unsupervised cluster analysis. Additionally, the study identified native biochemical cues in decellularized ECM with notable comparisons between fetal and adult brain-derived ECMs. The development of novel brain-specific biomaterials for generating mature in vitro brain models provides an important path forward for interrogation of neuron-glia interactions.
Meta-gene markers predict meningioma recurrence with high accuracy
Authors: Zador Zsolt , Landry Alexander , Haibe-Kains Benjamin , Cusimano Michael D. 
Published: July 2019

AbstractBackgroundMeningiomas, the most common adult brain tumors, recur in up to half of cases[1–3]. This requires timely intervention and therefore accurate risk assessment of recurrence is essential. Our current practice relies heavily on histological grade and extent of surgical excision to predict meningioma recurrence. However, prediction accuracy can be as poor as 50% for low or intermediate grade tumors, which constitute more than 90% of all cases. Moreover, attempts to find molecular markers, particularly for predicting recurrence of intermediate tumors have been impeded by low[4] or heterogenous[5–8] genetic signal. We therefore sought to apply systems-biology approaches to transcriptomic data to better predict meningioma recurrence.MethodsWe apply gene co-expression networks to a cohort of 252 adult patients from the publicly-available genetic repository Gene Expression Omnibus. Resultant gene clusters (“modules”) were represented by the first principle component of their expression levels, and their ability to predict recurrence assessed with a logistic regression model. External validation was done using an independent merged cohort of 108 patients using the same modules. We used the bioinformatics database DAVID[9] to examine the gene ontology associations of each module.ResultsUsing gene co-expression analysis, we were able predict tumor recurrence with high accuracy using a single module which mapped to cell cycle-related functions (AUC of 0.81 ± 0.09 in external validation). Further, the module maintained its accuracy with removal of up to 20 of it’s most individually predictive genes, suggesting robustness against noise at the single gene level.ConclusionsWith the easy accessibility of gene panels in healthcare diagnostics, our results offer a basis for routine molecular testing in meningioma management.
MethylNet: An Automated and Modular Deep Learning Approach for DNA Methylation Analysis
Authors: Levy Joshua J. , Titus Alexander J. , Petersen Curtis L. , Chen Youdinghuan , Salas Lucas A. , Christensen Brock C. 
Published: July 2019

AbstractBackgroundDNA methylation (DNAm) is an epigenetic regulator of gene expression programs that can be altered by environmental exposures, aging, and in pathogenesis. Traditional analyses that associate DNAm alterations with phenotypes suffer from multiple hypothesis testing and multi-collinearity due to the high-dimensional, continuous, interacting and non-linear nature of the data. Deep learning analyses have shown much promise to study disease heterogeneity. DNAm deep learning approaches have not yet been formalized into user-friendly frameworks for execution, training, and interpreting models. Here, we describe MethylNet, a DNAm deep learning method that can construct embeddings, make predictions, generate new data, and uncover unknown heterogeneity with minimal user supervision.ResultsThe results of our experiments indicate that MethylNet can study cellular differences, grasp higher order information of cancer sub-types, estimate age and capture factors associated with smoking in concordance with known differences.ConclusionThe ability of MethylNet to capture nonlinear interactions presents an opportunity for further study of unknown disease, cellular heterogeneity and aging processes.
SynToxProfiler: an approach for top drug combination selection based on integrated profiling of synergy, toxicity and efficacy
Authors: Ianevski Aleksandr , Kononov Alexander , Timonen Sanna , Aittokallio Tero , Giri Anil K 
Published: July 2019

AbstractDrug combinations are becoming a standard treatment of many complex diseases due to their capability to overcome resistance to monotherapy. Currently, in the preclinical drug combination screening, the top hits for further study are often selected based on synergy alone, without considering the combination efficacy and toxicity effects, even though these are critical determinants for the clinical success of a therapy. To promote the prioritization of drug combinations based on integrated analysis of synergy, efficacy and toxicity profiles, we implemented a web-based open-source tool, SynToxProfiler (Synergy-Toxicity-Profiler). When applied to 20 anti-cancer drug combinations tested both in healthy control and T-cell prolymphocytic leukemia (T-PLL) patient cells, as well as to 77 anti-viral drug pairs tested on Huh7 liver cell line with and without Ebola virus infection, SynToxProfiler was shown to prioritize synergistic drug pairs with higher selective efficacy (difference between efficacy and toxicity level) as top hits, which offers improved likelihood for clinical success.
Domain-centric dissection and classification of prokaryotic poly(3-hydroxyalkanoate) synthases
Authors: Liu Zhanzhong , Zhu Zuobin , Yang Jianye , Wu Sheng , Liu Qinghua , Wang Mengmeng , Cheng Huiling , Yan Jiawei , Wang Liang 
Published: July 2019

AbstractAlthough many enzymes and multiple pathways involve in Polyhydroxyalkanoates (PHAs) synthesis, PHA synthases play a determinant role in the process, which include three subunits of PhaC, PhaE, and PhaR. Currently, PHA synthases are categorized into four classes according to its primary sequences, substrate specificity, and subunit composition. However, theoretical analysis of PHA synthases from the domain perspective has not been performed. In this study, we dissected PHA synthases thoroughly through analysis of domain organization. Both referenced bacterial and archaeal proteomes were then screened for the presence and absence of different PHA synthases along NCBI taxonomy ID-based phylogenetic tree. In addition, sequences annotated as bacterial and archaeal PhaCs in UniProt database were also analyzed for domain organizations and interactions. In sum, the in-silico study provided a better understanding of the domain features of PHA synthases in prokaryotes, which also assisted in the production of PHA polymers with optimized chemical properties.
Evaluating the Potential of Younger Cases and Older Controls Cohorts to Improve Discovery Power in Genome-wide Association Studies of Late-onset Diseases
Authors: Oliynyk Roman Teo 
Published: July 2019

AbstractFor more than a decade, genome-wide association studies have been making steady progress in discovering the causal gene variants that contribute to late-onset human diseases. Polygenic late-onset diseases in an aging population display the risk allele frequency decrease at older ages, caused by individuals with higher polygenic risk scores becoming ill proportionately earlier and bringing about a change in the distribution of risk alleles between new cases and the as-yet-unaffected population. This phenomenon is most prominent for diseases characterized by high cumulative incidence and high heritability, examples of which include Alzheimer’s disease, coronary artery disease, cerebral stroke, and type 2 diabetes, while for late-onset diseases with relatively lower prevalence and heritability, exemplified by cancers, the effect is significantly lower. Computer simulations have determined that genome-wide association studies of the late-onset polygenic diseases showing high cumulative incidence together with high initial heritability will benefit from using the youngest possible age-matched cohorts. Moreover, rather than using age-matched cohorts, study cohorts combining the youngest possible cases with the oldest possible controls may significantly improve the discovery power of genome-wide association studies.
Autocatalytic chemical networks preceded proteins and RNA in evolution
Authors: Xavier Joana C. , Hordijk Wim , Kauffman Stuart , Steel Mike , Martin William F. 
Published: July 2019

AbstractModern cells embody metabolic networks containing thousands of elements and form autocatalytic molecule sets that produce copies of themselves. How the first self-sustaining metabolic networks arose at life’ s origin is a major open question. Autocatalytic molecule sets smaller than metabolic networks were proposed as transitory intermediates at the origin of life, but evidence for their role in prebiotic evolution is lacking. Here we identify reflexively autocatalytic food-generated networks (RAFs)—self-sustaining networks that collectively catalyze all their reactions—embedded within microbial metabolism. RAFs in the metabolism of ancient anaerobic autotrophs that live from H2 and CO2 generate amino acids and bases, the monomeric components of protein and RNA, and acetyl-CoA, but amino acids and bases do not generate metabolic RAFs, indicating that small-molecule catalysis preceded polymers in biochemical evolution. RAFs uncover intermediate stages in the origin of metabolic networks, narrowing the gaps between early-Earth chemistry and life.
Isolation of secreted proteins fromDrosophilaovaries and embryos throughin vivoBirA-mediated biotinylation
Authors: Stevens Leslie M. , Zhang Yuan , Volnov Yuri , Chen Geng , Stein David S. 
Published: July 2019

AbstractThe extraordinarily strong non-covalent interaction between biotin and avidin (kD = 10-14-10-16) has permitted this interaction to be used in a wide variety of experimental contexts. The Biotin Acceptor Peptide (BAP), a 15 amino acid motif that can be biotinylated by theE. coliBirA protein, has been fused to proteins of interest, making them substrates forin vivobiotinylation. Here we report on the construction and characterization of a modified BirA bearing signals for secretion and endoplasmic reticulum (ER) retention, for use in experimental contexts requiring biotinylation of secreted proteins. When expressed in theDrosophilafemale germline or ovarian follicle cells under Gal4-mediated transcriptional control, the modified BirA protein could be detected and shown to be enzymatically active in ovaries and progeny embryos. Surprisingly, however, it was not efficiently retained in the ER, and instead appeared to be secreted. To determine whether this secreted protein, now designated secBirA, could biotinylate secreted proteins, we generated BAP-tagged versions of two secretedDrosophilaproteins, Torsolike (Tsl) and Gastrulation Defective (GD), which are normally expressed maternally and participate in embryonic pattern formation. Both Tsl-BAP and GD-BAP were shown to exhibit normal patterning activity. Co-expression of Tsl-BAP together with secBirA in ovarian follicle cells resulted in its biotinylation, which permitted its isolation from both ovaries and progeny embryos using Avidin-coupled affinity matrix. In contrast, co-expression with secBirA in the female germline did not result in detectable biotinylation of GD-BAP, possibly because the C-terminal location of the BAP tag made it inaccessible to BirAin vivo. Our results indicate that secBirA directs biotinylation of proteins bound for secretionin vivo, providing access to powerful experimental approaches for secreted proteins of interest. However, efficient biotinylation of target proteins may vary depending upon the location of the BAP tag or other structural features of the protein.