bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular Risk Assessment in Pediatric Liver Transplant Patients
Authors: Dégi Arianna Amália , Bárczi Adrienn , Szabó Dolóresz , Kis Éva , Reusz György S. , Dezsőfi Antal
Published: January 2019

Objectives:

Cardiovascular (CV) diseases play a leading role in the mortality of adult liver transplant (LT) recipients. However, data regarding CV risk factors in children after LT remain sparse. The present study assessed the presence of CV risk factors and signs of CV impairment in LT children.

Methods:

A total of 42 LT recipients (21 men, age 9.93 ± 3.57 years) were studied. Body composition [body mass index standard deviation score, percentage of body fat (by bioimpedance analysis)], lipid profiles, glycemic control, blood pressure, and arterial stiffness [assessed by aortic pulse wave velocity (PWV)] were evaluated. The effect of different treatment modalities [tacrolimus (TAC) (n = 30) or cyclosporine (CyA) (n = 11)] was also analyzed.

Results:

Almost 18% of children were overweight or obese. Patients on TAC had a significantly higher body fat mass and percentage of body fat compared with the CyA group (P < 0.02). Borderline to high lipid values were present in 40% of patients. Children on CyA had higher serum cholesterol levels compared to TAC (P < 0.004). Nineteen percent of patients had hypertension. Half of the patients had glomerular filtration rate values <90 mL/min/1.73 m2, whereas PWV values were above the 95th percentile in 12%.

Conclusions:

Increased body fat, chronic kidney disease, high lipid content, hypertension, and increased arterial stiffness are already present and are in part related to the type of immunosuppression regimen in LT children >5 years following transplantation. Long‐term follow‐up is needed to evaluate their impact on CV health and survival.
Fecal Fat Concentration and Excretion in the First 2 Years of Life
Authors: Wieczorek‐Filipiak Mirosława , Drzymała‐Czyż Sławomira , Szczepanik Mariusz , Szydłowski Jarosław , Walkowiak Dariusz , Nowak Jan K. , Moczko Jerzy A. , Walkowiak Jarosław
Published: January 2019

Objectives:

Data on pancreatic exocrine secretion in the youngest children are scarce. The aim of the study was to determine the range of normal values for fecal fat concentration (FFC) and fecal fat excretion (FFE) in infants and toddlers up to 2 years of age.

Methods:

A total of 160 subjects aged 1 to 24 months (8 groups of 20: aged 1–3, 4–6 months, etc) were included in the study. In all children, FFC (%) and FFE (g/day) were assessed in 3‐day stool collection.

Results:

FFC correlated with age (r = −0.50, P < 0.0001). Of infants aged 1 to 3 months 65% had FFC higher than the <5% norm proposed for older children. The values of 90th/95th FFC percentile ranged from 9.7/13.0% at 1 month to 3.1/3.2% at 24 months. FFE did not differ between age groups. It was, however, higher than 4 and 3 g/day in 7.5% and 15.0% infants, respectively. The first detailed nomogram for the assessment of FFC and FFE in children aged 1 to 24 months was created.

Conclusions:

Healthy infants may have higher FFC and FFE than older children. We provide reference values, which should allow for both precise and facile FFC and FFE interpretation in clinical practice.
HomoplasyFinder: a simple tool to identify homoplasies on a phylogeny
Authors: Crispell Joseph , Balaz Daniel , Gordon Stephen Vincent
Published: January 2019

A homoplasy is a nucleotide identity resulting from a process other than inheritance from a common ancestor. Importantly, by distorting the ancestral relationships between nucleotide sequences, homoplasies can change the structure of the phylogeny. Homoplasies can emerge naturally, especially under high selection pressures and/or high mutation rates, or be created during the generation and processing of sequencing data. Identification of homoplasies is critical, both to understand their influence on the analyses of phylogenetic data and to allow an investigation into how they arose. Here we present HomoplasyFinder, a java application that can be used as a stand-a-lone tool or within the statistical programming environment R. Within R and Java, HomoplasyFinder is shown to be able to automatically, and quickly, identify any homoplasies present in simulated and real phylogenetic data. HomoplasyFinder can easily be incorporated into existing analysis pipelines, either within or outside of R, allowing the user to quickly identify homoplasies to inform downstream analyses and interpretation.
A sustained small increase in NOD1 expression promotes ligand-independent oncogenic activity
Authors: Rommereim Leah M. , Suresh Akhade Ajay , Dutta Bhaskar , Hutcheon Carolyn , Lounsbury Nicolas W. , Rostomily Clifford C. , Savan Ram , Fraser Iain D. C. , Germain Ronald N. , Subramanian Naeha
Published: January 2019

Small genetically-determined differences in transcription (eQTLs) are implicated in complex disease but the mechanisms by which small changes in gene expression impact complex disease are unknown. Here we show that a persistent small increase in expression of the innate sensor NOD1 precipitates large cancer-promoting changes in cell state. A ~1.2-1.4 fold increase in NOD1 protein concentration by loss of miR-15b/16 regulation sensitizes cells to ligand-induced inflammation, with an additional slight increase leading to ligand-independent NOD1 activation that is linked to poor prognosis in gastric cancer. Our data show that tight expression regulation of NOD1 prevents this sensor from exceeding a physiological switching checkpoint that promotes persistent inflammation and oncogene expression and reveal the impact of a single small quantitative change in cell state on cancer.

One Sentence Summary

A small change in NOD1 expression has a large cancer-promoting impact on cell state.
Ends and middle: global force balance determines septum location in fission yeast
Authors: Goff Xavier Le , Comelles Jordi , Kervrann Charles , Riveline Daniel
Published: January 2019

The fission yeast cell is shaped as a very regular cylinder ending by hemi-spheres at both cell ends. Its conserved phenotypes are often used as read-outs for classifying interacting genes and protein networks. Using Pascal and Young-Laplace laws, we proposed a framework where scaling arguments predicted shapes. Here we probed quantitatively one of these relations which predicts that the division site would be located closer to the cell end with the larger radius of curvature. By combining genetics and quantitative imaging, we tested experimentally whether altered shapes of cell end correlate with a displaced division site, leading to asymmetric cell division. Our results show that the division site position depends on the radii of curvatures of both ends. This new geometrical mechanism for the proper division plane positioning could be essential to achieve even partitioning of cellular material at each cell division.
Registration for Image-Based Transcriptomics: Parametric Signal Features and Multivariate Information Measures
Authors: Chen Rebecca , Das Abhinav B. , Varshney Lav R.
Published: January 2019

Image-based transcriptomics involves determining spatial patterns in gene expression across cells and tissues. Image registration is a necessary component of data analysis pipelines that study gene expression levels across different cells and intracellular structures. We consider images from multiplexed single molecule fluorescentin situhybridization (smFISH) and multiplexedin situsequencing (ISS) datasets from the Human Cell Atlas project and demonstrate a novel approach to groupwise image registration using a parametric representation of images based on finite rate of innovation sampling, together with practical optimization of empirical multivariate information measures.
Positively twisted: The complex evolutionary history of Reverse Gyrase suggests a non-hyperthermophilic Last Universal Common Ancestor
Authors: Catchpole Ryan , Forterre Patrick
Published: January 2019

Reverse gyrase (RG) is the only protein found ubiquitously in hyperthermophilic organisms, but absent from mesophiles. As such, its simple presence or absence allows us to deduce information about the optimal growth temperature of long-extinct organisms, even as far as the last universal common ancestor of extant life (LUCA). The growth environment and gene content of the LUCA has long been a source of debate in which RG often features. In an attempt to settle this debate, we carried out an exhaustive search for RG proteins, generating the largest RG dataset to date. Comprising 376 sequences, our dataset allows for phylogenetic reconstructions of RG with unprecedented size and detail. These RG phylogenies are strikingly different from those of known LUCA-encoded proteins, even when using the same set of species. Unlike LUCA-encoded proteins, RG does not form monophyletic archaeal and bacterial clades, suggesting RG emergence after the formation of these domains, and/or significant horizontal gene transfer. Even more strikingly, the branch lengths separating archaeal and bacterial groups are very short, inconsistent with the tempo of evolution from the time of the LUCA. Despite this, phylogenies limited to archaeal RG resolve most archaeal phyla, suggesting predominantly vertical evolution since the time of the last archaeal ancestor. In contrast, bacterial RG indicates emergence after the last bacterial ancestor followed by significant horizontal transfer. Taken together, these results suggest a non-hyperthermophilic LUCA and bacterial ancestor, with hyperthermophily emerging early in the evolution of the archaeal and bacterial domains.
Validity and internal consistency of EQ-5D-3L quality of life tool among pre-dialysis patients with chronic kidney disease in Sri Lanka, a lower middle-income country
Authors: Senanayake Sameera , Mahesh PKB , Gunawardena Nalika , Graves Nicholas , Kularatna Sanjeewa
Published: January 2019

Objective

EQ-5D-3L is a generic QOL tool used mainly in economic evaluations. Burden of Chronic Kidney Disease (CKD) is rising in Sri Lanka. Assessing the validity of generic QOL tools creates new opportunities of their utilization among patients with CKD.

Methods

A cross-sectional study was conducted among 1036 CKD patients, selected using the simple random sampling technique. The validity was tested with six a-priori hypotheses. These included construct validity assessments, evaluating convergent validity and performing known group comparisons. EQ-5D-3L, Short Form-36 (SF-36), Center for Epidemiological Studies Depression Scale (CES-D-20) and General Health Questionnaire-12 (GHQ-12) were used to assess QOL, presence of depression and psychological distress respectively. Internal consistency of the whole tool and when each item is removed was assessed by Cronbach alpha.

Results

The response rate was 99.2%. Majority of participants were males (n=646,62.4%) in the age category of 41-60 (n=530; 51.2%). Most were in either stage 4 or 5 of CKD (n=646,75.1%). The summary measures of SF-36, positively and significantly correlated with the EQ-5D-3L index and VAS scores (p<0.001). EQ-5D-3L QOL scores were significantly different between the group with depression and without as measured by CES-D-20 (p<0.001). Assessed using GHQ-12, similar significance was detected between the group with psychological distress and without (p<0.001). The Cronbach alpha was 0.834 and when each item was removed, ranged from 0.782 to 0.832.

Conclusion

EQ-5D-3L is a valid generic QOL tool with satisfactory internal consistency to be used among CKD patients in the pre-dialysis stage.
Fast estimation of genetic correlation for Biobank-scale data
Authors: Wu Yue , Burch Kathryn S. , Ganna Andrea , Pajukanta Päivi , Pasaniuc Bogdan , Sankararaman Sriram
Published: January 2019

Genetic correlation is an important parameter in efforts to understand the relationships among complex traits. Current methods that analyze individual genotype data for estimating genetic correlation are challenging to scale to large datasets. Methods that analyze summary data, while being computationally efficient, tend to yield estimates of genetic correlation with reduced precision. We propose, SCORE, a randomized method of moments estimator of genetic correlation that is both scalable and accurate. SCORE obtains more precise estimates of genetic correlations relative to summary-statistic methods that can be applied at scale achieving a 50% reduction in standard error relative to LD-score regression (LDSC) and a 26% reduction relative to high-definition likelihood (HDL) (averaged over all simulations). The efficiency of SCORE enables computation of genetic correlations on the UK biobank dataset consisting of ≈ 300K individuals and ≈ 500K SNPs in a few hours (orders of magnitude faster than methods that analyze individual data such as GCTA). Across 780 pairs of traits in 291, 273 unrelated white British individuals in the UK Biobank, SCORE identifies significant genetic correlation between 200 additional pairs of traits over LDSC (beyond the 245 pairs identified by both).
Vocal Transmission of Breeding Status May Facilitate Dispersal in a Cooperative Breeding Primate
Authors: Robakis Efstathia , Erkenswick Gideon , Watsa Mrinalini
Published: January 2019

Social complexity may drive complexity in communicative systems due to an individual's need to navigate unpredictable interactions with multiple conspecifics. Cooperative breeding primates (marmosets and tamarins; family: Callitrichidae) live in groups with moderate to high reproductive skew, particularly in females, whereby sexually mature individuals are frequently prevented from breeding. Remarkably, dispersal from natal groups is not stereotyped upon reaching reproductive maturity. Individuals are often observed remaining in their natal groups until the same-sex breeder in their group or a neighboring group dies, experiencing hormonal reproductive suppression, aggression, and limited access to potential mates. Here we examined whether emperor tamarins (Saguinus imperator) might use vocal signals to reduce dispersal risks and maximize the likelihood of attaining a breeding position. Using six consecutive years of mark-recapture data, we showed that sexually mature non-breeders (herein "secondary breeders") are more likely to leave their groups from one year to the next than sexually mature breeders ("primary breeders"). This confirmed that, unlike primary breeders who do not need to disperse in order to reproduce, secondary breeders are choosing to accept the risks associated with dispersal and emigrating from their natal groups. We used neural networks to classify vocalizations according to individual breeding status, and conducted a series of playback experiments which demonstrated that tamarins discriminated between the calls of primary and secondary breeders. Our data support the hypotheses that secondary breeders disperse to increase mating opportunities and use vocalizations to signal their availability to potential mates. This species of cooperative breeder appears to use vocalization to navigate its social and reproductive systems, minimizing risks of dispersal and in turn increasing the likelihood of reproductive success. This research has important implications for our understanding of sexual signaling, partner choice, and reproductive success in cooperative breeders.
The large loop-8 insert in Saccharomyces cerevisiae kinesin-5 Cin8 is necessary and sufficient to promote noncanonical microtubule interactions
Authors: Bell Kayla M. , Cochran Jared C.
Published: January 2019

Saccharomyces cerevisiae kinesin-5 Cin8 displays unconventional biochemical behavior including bidirectional motility and ability to bind multiple motor domains per αβ tubulin dimer in the microtubule lattice. Previous research suggested that a large loop-8 insert near the microtubule binding interface of Cin8 was critical for its noncanonical microtubule binding behavior. Here we utilized mutagenesis, thermodynamic, and kinetic assays to further understand the mechanism for how this loop-8 insert promotes super-stoichiometric microtubule binding in Cin8. This loop-8 insert that interrupts the conserved β5a/b hairpin was swapped between Cin8, Eg5 (KIF11, a human kinesin-5) and Kip1 (another S. cerevisiae kinesin-5). Cin8 with the loop-8 insert from Eg5 (Cin8-EL8) binds one motor per tubulin dimer, whereas Eg5 with the loop-8 insert from Cin8 (Eg5-CL8) binds approximately 2-4 motors per tubulin dimer. Eg5-CL8 bound the canonical and noncanonical sites on the microtubule lattice with weakened oligomerization between motors, while Cin8-EL8 showed only canonical site binding. These results demonstrate that the large loop-8 insert in Cin8 is necessary and sufficient to promote noncanonical microtubule binding behavior.
Fast and robust method for drug response biomarker identification and sample stratification
Authors: Bhattacharya Simanti , Das Amit
Published: January 2019

With unprecedented progress of cancer research, the world is now prepared with versatile arsenal of drugs to combat cancer. However, individual’s response to any drug or combination treatment stands as a major challenge and hence there exists the sheer need for personalized medication. Identification of drug response biomarkers from a wholistic tumor microenvironment analysis would guide researchers to develop custom-tailored treatment regimen.

In this study, a fast and robust method has been developed to identify drug response biomarkers from entire transcriptomics data analysis in a data-driven manner. The biomarkers which were identified by the method, were able to stratify patients between responders vs non-responders population. Furthermore, bayesian network (BN) analysis, done on the data, brought forth a mechanistic insight into the role of identified biomarkers in regulating drug’s efficacy.

The importance of this work lies with the protocol that is time saving and requires less computation power, yet analyzes a whole system data and helps the researchers to take a step forward towards the development of personalized care in effective cancer treatment.

Highlights

Supervised machine learning approach to analyze gene expression data.

Drug response biomarker identification.

Categorization of samples for their drug response with the help of identified biomarkers.

Functional enrichment to understand the biomarkers association with biological processes.

Bayesian network analysis to develop causal structure among identified biomarkers and drug targets.

Time and cost-effective pipeline for fast and robust prediction of drug response biomarkers.
Role of Era in Assembly and Homeostasis of the Ribosomal Small Subunit
Authors: Razi Aida , Davis Joseph H. , Hao Yumeng , Jahagirdar Dushyant , Thurlow Brett , Basu Kaustuv , Jain Nikhil , Gomez-Blanco Josue , Britton Robert A. , Vargas Javier , Guarné Alba , Woodson Sarah A. , Williamson James R. , Ortega Joaquin
Published: January 2019

To reveal the role of the essential protein Era in the assembly of the 30S ribosomal subunit, we analyzed assembly intermediates that accumulated in Era-depletedEscherichia colicells using quantitative mass spectrometry, cryo-electron microscopy and in-cell footprinting. Our combined approach allowed for visualization of the small subunit as it assembled and revealed that with the exception of key helices in the platform domain, all other 16S rRNA domains were able to fold even in the absence of Era. Notably, the maturing particles did not stall while waiting for the platform domain to mature and instead re-routed their folding pathway to enable concerted maturation of other structural motifs spanning multiple rRNA domains. We also found that binding of Era to the mature 30S subunit destabilized helix 44 and the decoding center preventing binding of YjeQ, another assembly factor. This work establishes Era’s role in ribosome assembly and suggests new roles in maintaining ribosome homeostasis.
Multimodal cell type correspondence by intersectional mFISH in intact tissues
Authors: Nicovich Philip R. , Taormina Michael J. , Baker Christopher A. , Nguyen Thuc Nghi , Thomsen Elliot R. , Garren Emma , Long Brian , Gorham Melissa , Miller Jeremy A. , Hage Travis , Bosma-Moody Alice , Murphy Gabe J. , Levi Boaz P. , Close Jennie L. , Tasic Bosiljka , Lein Ed S. , Zeng Hongkui
Published: January 2019

Defining a complete set of cell types within the cortex requires reconciling disparate results achieved through diverging methodologies. To address this correspondence problem, multiple methodologies must be applied to the same cells across multiple single-cell experiments. Here we present a new approach applying spatial transcriptomics using multiplexed fluorescencein situhybridization, (mFISH) to brain tissue previously interrogated through two photon optogenetic mapping of synaptic connectivity. This approach can resolve the anatomical, transcriptomic, connectomic, electrophysiological, and morphological characteristics of single cells within the mouse cortex.
Human DNA polymerase delta is a pentameric holoenzyme with dimeric p12 subunit: Implications in enzyme architecture and PCNA interaction
Authors: Khandagale Prashant , Peroumal Doureradjou , Manohar Kodavati , Acharya Narottam
Published: January 2019

Human DNA polymerase delta (Polδ), a holoenzyme consisting of p125, p50, p68 and p12 subunits, plays an essential role in all the three DNA transaction processes. Herein, using multiple physicochemical and cellular approaches we found that the p12 protein forms a dimer in solution.In vitroreconstitution and pull-down of cellular Polδ by tagged p12 authenticates pentameric nature of this critical holoenzyme. Further, a consensus PIP motif at the extreme carboxyl terminal tail and a homodimerization domain at the amino-terminus of the p12 subunit were identified. Our mutational analyses of p12 subunit suggest that3RKR5motif is critical for dimerization that facilitates p12 binding to IDCL of PCNA via its PIP motif98QCSLWHLY105. Additionally, we observed that oligomerization of the smallest subunit of Polδs is evolutionarily conserved as Cdm1 ofS. pombealso dimerzes. Thus, we suggest that human Polδ is a pentameric complex with a dimeric p12 subunit; and discuss implications of p12 dimerization in regulating enzyme architecture and PCNA interaction during DNA replication.
AGO1 in association with NEAT1 lncRNA contributes to nuclear and 3D chromatin architecture in human cells
Authors: Shuaib Muhammad , Parsi Krishna Mohan , Kawaji Hideya , Thimma Manjula , Adroub Sabir Abdu , Fort Alexandre , Ghosheh Yanal , Yamazaki Tomohiro , Mannen Taro , Seridi Loqmane , Fallatah Bodor , Albawardi Waad , Ravasi Timothy , Carninci Piero , Hirose Tetsuro , Orlando Valerio
Published: January 2019

Aside from their roles in the cytoplasm, RNA-interference components have been reported to localize also in the nucleus of human cells. In particular, AGO1 associates with active chromatin and appears to influence global gene expression. However, the mechanistic aspects remain elusive. Here, we identify AGO1 as a paraspeckle component that in combination with the NEAT1 lncRNA maintains 3D genome architecture. We demonstrate that AGO1 interacts with NEAT1 lncRNA and its depletion affects NEAT1 expression and the formation of paraspeckles. By Hi-C analysis in AGO1 knockdown cells, we observed global changes in chromatin organization, including TADs configuration, and A/B compartment mixing. Consistently, distinct groups of genes located within the differential interacting loci showed altered expression upon AGO1 depletion. NEAT1 knockout cells displayed similar changes in TADs and higher-order A/B compartmentalization. We propose that AGO1 in association with NEAT1 lncRNA can act as a scaffold that bridges chromatin and nuclear bodies to regulate genome organization and gene expression in human cells.
Tandem Directional CTCF Sites Balance Protocadherin Promoter Usage
Authors: Wu Qiang , Guo Ya , Lu Yujia , Li Jingwei , Wu Yonghu , Jia Zhilian
Published: January 2019

CTCF is a key insulator-binding protein and mammalian genomes contain numerous CTCF-binding sites (CBSs), many of which are organized in tandem arrays. Here we provide direct evidence that CBSs, if located between enhancers and promoters in the Pcdhα and β-globin clusters, function as an enhancer-blocking insulator by forming distinct directional chromatin loops, regardless whether enhancers contain CBS or not. Moreover, computational simulation and experimental capture revealed balanced promoter usage in cell populations and stochastic monoallelic expression in single cells by large arrays of tandem variable CBSs. Finally, gene expression levels are negatively correlated with CBS insulators located between enhancers and promoters on a genome-wide scale. Thus, single CBS insulators ensure proper enhancer insulation and promoter activation while tandem-arrayed CBS insulators determine balanced promoter usage. This finding has interesting implications on the role of topological insulators in 3D genome folding and developmental gene regulation.
A High-Throughput Physiological Functional Phenotyping System for Time- and Cost-Effective Screening of Potential Biostimulants
Authors: Dalal Ahan , Bourstein Ronny , Haish Nadav , Shenhar Itamar , Wallach Rony , Moshelion Menachem
Published: January 2019

The improvement of crop productivity under abiotic stress is one of the biggest challenges faced by the agricultural scientific community. Despite extensive research, the research-to-commercial transfer rate of abiotic stress-resistant crops remains very low. This is mainly due to the complexity of genotype◻×◻environment interactions and in particular, the ability to quantify the dynamic plant physiological response profile to a dynamic environment.

Most existing phenotyping facilities collect information using robotics and automated image acquisition and analysis. However, their ability to directly measure the physiological properties of the whole plant is limited. We demonstrate a high-throughput functional phenotyping system (HFPS) that enables comparing plants’ dynamic responses to different ambient conditions in dynamic environments due to its direct and simultaneous measurement of yield-related physiological traits of plants under several treatments. The system is designed as one-to-one (1:1) plant–[sensors+controller] units, i.e., each individual plant has its own personalized sensor, controller and irrigation valves that enable (i) monitoring water-relation kinetics of each plant–environment response throughout the plant’s life cycle with high spatiotemporal resolution, (ii) a truly randomized experimental design due to multiple independent treatment scenarios for every plant, and (iii) reduction of artificial ambient perturbations due to the immobility of the plants or other objects. In addition, we propose two new resilience-quantifying-related traits that can also be phenotyped using the HFPS: transpiration recovery rate and night water reabsorption.

We use the HFPS to screen the effects of two commercial biostimulants (a seaweed extract—ICL-SW, and a metabolite formula—ICL-NewFo1) on Capsicum annuum under different irrigation regimes. Biostimulants are considered an alternative approach to improving crop productivity. However, their complex mode of action necessitates cost-effective pre-field phenotyping. The combination of two types of treatment (biostimulants and drought) enabled us to evaluate the precision and resolution of the system in investigating the effect of biostimulants on drought tolerance. We analyze and discuss plant behavior at different stages, and assess the penalty and trade-off between productivity and survivability. In this test case, we suggest a protocol for the screening of biostimulants’ physiological mechanisms of action.
Neuroinflammation and protein aggregation co-localize across the frontotemporal dementia spectrum
Authors: Bevan-Jones W Richard , Cope Thomas E , Jones P Simon , Passamonti Luca , Hong Young T , Fryer Tim D , Arnold Robert , Coles Jonathan P , Aigbirhio Franklin I , Larner Andrew J , Patterson Karalyn , O’Brien John T , Rowe James B
Published: January 2019

The clinical syndromes of frontotemporal dementia are clinically and neuropathologically heterogeneous, but processes such as neuroinflammation may be common across the disease spectrum. We investigated how neuroinflammation relates to the aggregation of Tau and TDP-43 in frontotemporal dementia, and to the heterogeneity of clinical disease. We used positron emission tomographyin vivowith (a) [11C]PK-11195, a marker of activated microglia and a proxy index of neuroinflammation, and (b) [18F]AV-1451, a radioligand with increased binding to pathologically affected regions in tauopathies and diseases associated with TDP-43 protein aggregation, and which is used as a surrogate marker of non-β-amyloid protein aggregation. We assessed 31 patients with frontotemporal dementia (10 with behavioural variant frontotemporal dementia, 11 with the semantic variant of primary progressive aphasia and 10 with the non-fluent variant of primary progressive aphasia), 28 of whom underwent both [18F]AV-1451 and [11C]PK-11195 PET, and matched controls (14 for [18F]AV-1451 and 15 for [11C]PK-11195). We used univariate region-of-interest analyses, and multivariate analysis of the distribution of binding that explicitly control for individual differences in ligand affinity for TDP-43 and different Tau isoforms. We found differences between patients and controls in frontotemporal regions for both neuroinflammation and protein aggregation, and a strong positive correlation between these two processes in all disease groups. Despite this regional co-localisation, the multivariate distribution of [11C]PK-11195 binding related better to clinical heterogeneity than did the distribution of [18F]AV-1451: distinct spatial modes of neuroinflammation were associated with different frontotemporal dementia syndromes and supported accurate group classification of participants. Thesein vivofindings indicate a close association between neuroinflammation and protein aggregation in frontotemporal dementia. The inflammatory component may be important in shaping the clinical and neuropathological patterns of the diverse clinical syndromes of frontotemporal dementia.
A dynamic control of human telomerase holoenzyme
Authors: Sayed Mohammed E. , Cheng Ao , Yadav Gaya , Ludlow Andrew T. , Shay Jerry W. , Wright Woodring E. , Jiang Qiu-Xing
Published: January 2019

Human telomerase functions in maintaining genome stability by adding telomeric repeats to the termini of linear chromosomes. Past studies have revealed profound insights into telomerase functions. However, low abundance of functional telomerase and difficulty in quantifying its activity leave partially characterized its thermodynamic and kinetic properties. Using a newly developed method to count individual extension products, we demonstrate that human telomerase holoenzymes contain fast- and slow-acting catalytic sites. Surprisingly, both active sites become inactive after two consecutive rounds of catalysis. The fast active sites turn off ~40-fold quicker than the slow ones and exhibit higher affinity to substrates. In dimeric enzymes, the two sites work in tandem with the faster site functioning before the slower one. In monomeric enzymes, the active sites also perform single-run catalysis. Interestingly, the inactive enzymes can be reactivated by intracellular telomerase-activating factors (iTAFs) available in multiple cell types. Together, the single-run catalysis and the iTAF-triggered reactivation serve as a novel control circuit to ensure that the telomerase holoenzymes are dynamically controlled to match their number of active sites with the number of telomeres they extend. Such exquisite kinetic control of telomerase activity is expected to play important roles in cell division and ageing.
Local inhibition of PRC2 activity by H3.3K27M drives DNA replication defects through misregulation of the JNK pathway
Authors: Delaney Kamila , Strobino Maude , Wenda Joanna M. , Pankowski Andrzej , Steiner Florian A.
Published: January 2019

Substitution of lysine 27 with methionine in histone H3.3 is a recently discovered driver mutation of pediatric high-grade gliomas. Mutant tumor cells show decreased levels and altered distribution of H3K27me3. How these chromatin changes are established genome-wide and lead to tumorigenesis only in specific tissues remains unclear. Here we show that H3.3K27M-mediated alterations in H3K27me3 distribution result in ectopic DNA replication and cell cycle progression of germ cells inCaenorhabditis elegans. By genetically inducing changes in the H3.3 distribution, we demonstrate that both H3.3K27M oncohistone incorporation and pre-existing H3K27me3 act locally and antagonistically on Polycomb Repressive Complex 2 (PRC2) in a concentration-dependent manner, explaining the observed H3K27me3 distribution in mutant cells. The altered heterochromatin patterns lead to extensive misregulation of gene expression. Through unbiased genetic screening, we found that inhibiting JNK pathway components, which are overexpressed in H3.3K27M cells, suppresses the ectopic DNA replication and cell cycle progression without rescuing the altered H3K27me3 distribution. Moreover, we show that JNK inhibition suppresses the replicative fate in human tumor-derived H3.3K27M cells, thus establishingC. elegansas a powerful model for the identification of potential drug targets for treatment of H3.3K27M tumors.
Regionally Diffuse Muscle Pain-Hypersensitivity in Humans During Acute Muscle Pain
Authors: Dunn J. S. , Nagi S. S. , Mahns D. A.
Published: January 2019

Background

We have previously shown that an intramuscular infusion of 5% hypertonic saline (HS) produces a painful response to normally innocuous stimuli applied to overlying and adjacent skin regions. In the current study, we explored whether a similar interaction could be observed between adjacent, contralateral and remote muscles. Indeed, widespread muscle pain-hypersensitivity is a hallmark of chronic pain conditions such as fibromyalgia.

Methods

5% HS was infused into the flexor carpi ulnaris (FCU) muscle to develop a stable baseline pain (n=30). In separate experiments, each of the three test locations (n=10 per site), the adjacent abductor digiti minimi (ADM), contralateral FCU and contralateral tibialis anterior (TA) (part 1-3, respectively), 50μL of 0.9% normal saline (NS) was infused (in triplicate) prior to, during and following HS-induced muscle pain.

Results

Under control conditions (no background pain), the infusion of NS was imperceptible by all subjects. In the presence of HS-induced background pain (FCU), in part 1 the NS co-infusion into ADM increased overall pain by 17%. This was replicated in the contralateral FCU (part 2) with a 12% pain increase, and in the TA (part 3) with a 15% pain increase in response to the NS co-infusions. Notably, over 80% of subjects perceived the NS-induced increase in pain at the HS-infusion location (FCU) rather than the NS-infusion location (adjacent, contralateral and remote).

Conclusions

Intramuscular infusion of HS results in pain-hypersensitivity to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.

Significance

This work provides evidence for a regionally diffuse type of pain hypersensitivity, manifesting as a painful response to normally sub-perceptual stimulation in the context of acute experimentally induced muscle pain. This phenomenon may provide parallels to clinically relevant painful conditions and neuropathies.
Enabling MHC-mismatched hematopoietic stem cell transplants and organ graft tolerance without chemotherapy or radiation
Authors: George Benson M. , Kao Kevin S. , Chen Angela , Le Alan C. , Chhabra Akanksha , Burnett Cassandra , Loh Kyle M. , Shizuru Judith A. , Weissman Irving L.
Published: January 2019

Hematopoietic stem cell (HSC) transplantation can replace diseased blood systems with a healthy one, thereby treating or curing genetic blood and immune disorders including autoimmune diseases and immunodeficiencies. However, toxic chemotherapy or radiation is necessary to ablate an animal’s existing blood system prior to HSC transplantation, leading to significant morbidity. To accomplish safer blood-system replacement we developed a combination of six monoclonal antibodies to safely and specifically deplete the HSCs, T cells and NK cells of immune-competent mice. Remarkably, immunologically-foreign (allogeneic) HSCs mismatched at half or all the MHC genes could engraft these antibody-treated mice, generating donor blood systems that stably co-existed with host blood cells. These chimeric immune systems were immunologically tolerant to heart tissue from the HSC donor, providing a safe platform for HSC transplantation as a means to solid organ transplantation. The ability to transplant MHC-mismatched HSCs without chemotherapy or radiation has significant ramifications for regenerative medicine.
Accelerated loss of hypoxia response in zebrafish with familial Alzheimer’s disease-like mutation of Presenilin 1
Authors: Newman Morgan , Nik Hani Moussavi , Sutherland Greg T. , Hin Nhi , Kim Woojin S. , Halliday Glenda M. , Jayadev Suman , Smith Carole , Laird Angela , Lucas Caitlin , Kittipassorn Thaksaon , Peet Dan J. , Lardelli Michael
Published: January 2019

Ageing is the major risk factor for Alzheimer’s disease (AD), a condition involving brain hypoxia. The majority of early onset familial AD (EOfAD) cases involve dominant mutations in the gene PSEN1. PSEN1 null mutations do not cause EOfAD. We exploited putative hypomorphic and EOfAD-like mutations in the zebrafish psen1 gene to explore the effects of age and genotype on brain responses to acute hypoxia. Both mutations accelerate age-dependent changes in hypoxia-sensitive gene expression supporting that ageing is necessary, but insufficient, for AD occurrence. Curiously, the responses to acute hypoxia become inverted in extremely aged fish. This is associated with an apparent inability to upregulate glycolysis. Wild type PSEN1 allele expression is reduced in post-mortem brains of human EOfAD mutation carriers (and extremely aged fish), possibly contributing to EOfAD pathogenesis. We also observed that age-dependent loss of HIF1 stabilisation under hypoxia is a phenomenon conserved across vertebrate classes.
Caveolae and scaffold detection from single molecule localization microscopy data using deep learning
Authors: Khater Ismail M. , Aroca-Ouellette Stephane T. , Meng Fanrui , Nabi Ivan Robert , Hamarneh Ghassan
Published: January 2019

Caveolae are plasma membrane invaginations whose formation requires caveolin-1 (Cav1), the adaptor protein polymerase I, and the transcript release factor (PTRF or CAVIN1). Caveolae have an important role in cell functioning, signaling, and disease. In the absence of CAVIN1/PTRF, Cav1 forms non-caveolar membrane domains called scaffolds. In this work, we train machine learning models to automatically distinguish between caveolae and scaffolds from single molecule localization microscopy (SMLM) data. We apply machine learning algorithms to discriminate biological structures from SMLM data. Our work is the first that is leveraging machine learning approaches (including deep learning models) to automatically identifying biological structures from SMLM data. In particular, we develop and compare three binary classification methods to identify whether or not a given 3D cluster of Cav1 proteins is a caveolae. The first uses a random forest classifier applied to 28 hand-crafted/designed features, the second uses a convolutional neural net (CNN) applied to a projection of the point clouds onto three planes, and the third uses a PointNet model, a recent development that can directly take point clouds as its input. We validate our methods on a dataset of super-resolution microscopy images of PC3 prostate cancer cells labeled for Cav1. Specifically, we have images from two cell populations: 10 PC3 and 10 CAVIN1/PTRF-transfected PC3 cells (PC3-PTRF cells) that form caveolae. We obtained a balanced set of 1714 different cellular structures. Our results show that both the random forest on hand-designed features and the deep learning approach achieve high accuracy in distinguishing the intrinsic features of the caveolae and non-caveolae biological structures. More specifically, both random forest and deep CNN classifiers achieve classification accuracy reaching 94% on our test set, while the PointNet model only reached 83% accuracy. We also discuss the pros and cons of the different approaches.
The response of genes and pathways of immunological system induced by irradiation
Authors: Ribeiro F. M. , Silveira D. A. , Simão E. M. , Mattos V. L. D. , Góes E. G.
Published: January 2019

Current studies have shown that ionizing radiation (IR) could increase the efficiency of radiation therapy by the stimulation of the immune system. This occurs in low-dose radiation as well as doses within hypofractionated range usually used in radiotherapy. However, the elucidation of the mechanisms of immunogenic modulation reported at these doses remain an issue. In this study, we analyzed transcriptome data available in Gene Expression Omnibus (GEO) database related to B cells isolated from whole blood of 95 donors and then irradiated with 10 Gy. The aim of this study is to investigate the regulation of genes and pathways of the immune system considering the B7-CD28/CTLA4 superfamily, CD40-CD40LG molecules, and cytokines expressed by B cells irradiated. The connection between genes and pathways is established by the Reactome database. Relative activity and diversity of pathways were calculated to determine the modulation of the immune system response to irradiation. Analysis of variance (ANOVA) with repeated measures and Bonferroni’s method were used to determine differentially expressed genes. It was observed that IR up-modulates the response of pathways and genes considered in this study, which indicates that 10 Gy can enhance antitumor immune responses.
Triangular mesh generation on free-form surfaces based on bubble dynamics simulation
Authors: Wang Qisheng , Gao Boqing , Wu Hui
Published: January 2019

Purpose

Modern CAD systems facilitate the creation of any surface geometry imaginable, and complex surfaces for free-form grid shells are often represented by a set of Non-Uniform Rational B-Splines surface patches. But it remains an intractable issue how to generate high-quality grids on complex surfaces efficiently. To solve this issue, an automatic triangular mesh generation method is presented, based on bubble dynamics simulation and a modified Delaunay method.

Design/methodology/approach

A moderate amount of points are first distributed on a given surface. Next, by regarding the points as elastic bubbles with the same size and introducing the forces acting on bubbles, the motion control equations of bubbles are established. The equilibrium state of the bubble system is found by Verlet algorithm. Then, the Voronoi diagram on the surface is obtained by calculating the intersection between the surface and the three-dimensional (3D) Voronoi diagram of the centers of bubbles. Finally, a triangular mesh, Delaunay triangulation on the surface, is determined based on the dual change of the Voronoi diagram.

Findings

This method generates meshes on the surface directly, unlike mapping-based methods, avoiding the mapping distortion. Examples are given to demonstrate the successful execution of this method. The result also illustrates that this method is applicable to various surfaces in high automation level and resultant meshes are highly uniform and well-shaped.

Originality/value

Thus, this method provides the convenience for the geometry design of complex free-form grid structure.
For diversity scholars who have considered activism when scholarship isn’t enough!
Authors: Holmes IV Oscar
Published: January 2019

Purpose

The paper is the abridged text of the author’s opening keynote address given on June 28, 2017 at the 10th Annual Equality Diversity Inclusion Conference hosted at Brunel University (London, UK). The conference theme was Borders. The paper aims to discuss this issue.

Design/methodology/approach

The address was given orally accompanied with slides that included pictures and quotes of referenced authors and works, websites, memes and various civil rights events. The address interwove personal experiences, published research, social movement strategies and current events and social issues. A brief question and answer period followed the address.

Findings

The address made the case that while scholarship is important, diversity scholars need to do more than publish scholarship but also engage in activism. In fact, the author argued that history has informed us that scholarship has never been enough to produce significant civil rights advancements.

Originality/value

Toward this end, the author provides three action steps that diversity scholars can take to engage in activism that produces results: translate research for the general public; partner with activist groups, and call out respectability politics and false equivalencies.
Diverse perspectives on inclusion
Authors: Singletary Walker Sarah , Ruggs Enrica N. , Botsford Morgan Whitney , W. DeGrassi Sandra
Published: January 2019

Purpose

The purpose of this paper is to examine the extent to which racioethnicity influences perceptions of inclusion (i.e. information sharing, collective efficacy, satisfaction and relationship conflict) when working in racially heterogeneous groups.

Design/methodology/approach

Individuals were placed in groups in order to participate in ethical-decision making tasks.

Findings

Results reveal that individuals representing varied racioethnic groups are in general satisfied working in racially heterogeneous groups. However, reports of relationship conflict and information sharing varied as a function of racioethnicity.

Originality/value

The authors discuss possible rationales for differences in how racioethnic groups perceive and experience group processes over time as well as practical implications for social psychology and diversity in teams.
Changes in higher education teachers’ perceptions of curriculum
Authors: Nguyen Thi Van Su , Laws Kevin
Published: January 2019

Purpose

The purpose of this paper is to examine the degree to which a compulsory induction program for Vietnamese higher education teachers influences participants’ perceptions of curriculum and course design.

Design/methodology/approach

This case study uses a qualitative, interpretive approach to data collection. Semi-structured interviews were conducted with 15 program participants before they started the program and immediately after they completed the program. Five program presenters also were interviewed and documents related to the program were analyzed.

Findings

The findings reflect the influence of Biggs’ (2003) constructive alignment approach on participants’ curriculum perceptions, although this approach was not explicitly stated in the program guidelines. Upon the completion of the program, participants realized the importance of their voices in curriculum construction and course design, which was absent from the pre-program findings. However, students’ agency in co-constructing the curriculum and the “being” of curriculum were not perceived.

Research limitations/implications

The paper adds to the growing literature on induction programs and their relation to curriculum perceptions.

Practical implications

The paper provides examples of the changes in participants’ perceptions of curriculum and accentuates, what is neglected in the construction of curriculum.

Originality/value

The paper invites reflection on the design and implementation of curriculum from academic developers, education practitioners and researchers in similar contexts.