bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebellar involvement in learning to balance a cart-pole system
Authors: Ludolph Nicolas , Ernst Thomas M. , Mueller Oliver M. , Goericke Sophia L. , Giese Martin A. , Timmann Dagmar , Ilg Winfried
Published: March 2019

The role of the cerebellum in error-based motor adaptation is well examined. In contrast, the involvement of the cerebellum in reward-based motor learning is less clear. In this study, we examined cerebellar involvement in a reward-based motor learning task, namely learning to control a virtual cart-pole system, over five consecutive days. Subjects with focal cerebellar lesions were compared to age-matched controls in terms of learning performance and underlying control mechanisms.

Based on the overall balancing performance we have identified two subgroups of patients: (1) patients with learning performance comparable to healthy controls and (2) patients with decelerated learning, unsaturated learning progress after five days and decreased inter-manual transfer. Furthermore, we found that online learning is impaired while offline learning is partly preserved in cerebellar subjects. Regarding control mechanisms, decreased control performance was associated with impairments in predictive action timing.

Voxel-wise lesion symptom mapping based on the two subgroups revealed strong associations between impairments in controlling the virtual cart-pole system and lesions in intermediate and lateral parts of lobules V and VI. These results together with previous reports suggest that the ability to predict the dynamics of the cart-pole system is an important factor for the reward-based skill acquisition process.
A molecular gradient along the longitudinal axis of the human hippocampus informs large-scale behavioral systems
Authors: Vogel Jacob W. , La Joie Renaud , Grothe Michel J. , Diaz-Papkovich Alex , Doyle Andrew , Vachon-Presseau Etienne , Lepage Claude , de Wael Reinder Vos , Iturria-Medina Yasser , Bernhardt Boris , Rabinovici Gil D. , Evans Alan C.
Published: March 2019

The functional organization of the hippocampus is distributed as a gradient along its longitudinal axis that explains its differential interaction with diverse brain systems. We show that the location of human tissue samples extracted along the longitudinal axis of the hippocampus can be predicted within 2mm using the expression pattern of less than 100 genes. When variation in this specific gene expression pattern was observed across the whole brain, a distinct anterioventral-posteriodorsal gradient was observed. Frontal, anterior temporal and brainstem regions involved in social and motivational behaviors, selectively vulnerable to frontotemporal dementia and more functionally connected to the anterior hippocampus could be clearly differentiated from posterior parieto-occipital and cerebellar regions involved in spatial cognition, selectively vulnerable to Alzheimers disease, and more functionally connected to the posterior hippocampus. These findings place the human hippocampus at the interface of two major brain systems defined by a single distinct molecular gradient. (148/150)
Co-developing climate services for public health: stakeholder needs and perceptions for the prevention and control ofAedes-transmitted diseases in the Caribbean
Authors: Stewart-Ibarra Anna M. , Romero Moory , Hinds Avery Q. J. , Lowe Rachel , Mahon Roché , Van Meerbeeck Cedric J. , Rollock Leslie , Gittens-St. Hilaire Marquita , St. Ville Sylvester , Ryan Sadie J. , Trotman Adrian R. , Borbor-Cordova Mercy J.
Published: March 2019

Background

Small island developing states (SIDS) in the Caribbean region are challenged with managing the health outcomes of a changing climate. Health and climate sectors have partnered to co-develop climate services to improve the management of these diseases, for example, through the development of climate-driven early warning systems. The objective of this study was to identify health and climate stakeholder perceptions and needs in the Caribbean, with respect to the development of climate services for arboviruses (e.g. dengue, chikungunya, and Zika).

Methods

Stakeholders included public decision makers and practitioners from the climate and health sectors at the regional (Caribbean) level and from the countries of Dominica and Barbados. From April to June 2017, we conducted interviews (n=41), surveys (n=32), and national workshops with stakeholders. Survey responses were tabulated and audio recordings were transcribed and analyzed using qualitative coding to identify responses by research topic, country/region, and sector.

Results

Health practitioners indicated that their jurisdiction is currently experiencing an increased risk of diseases transmitted byAe. aegyptidue to climate variability, and most anticipated that this risk will increase in the future. National health sectors reported financial limitations and a lack of technical expertise in geographic information systems (GIS), statistics, and modeling, which constrained their ability to implement climate services for arboviruses. National climate sectors were constrained by a lack of personnel. Stakeholders highlighted the need to strengthen partnerships with the private sector, academia, and civil society. They identified a gap in local research on climate-arbovirus linkages, which constrained the ability of the health sector to make informed decisions. Strategies to strengthen the climate-health partnership included a top-down approach by engaging senior leadership, multi-lateral collaboration agreements, national committees on climate and health, and shared spaces of dialogue. Mechanisms for mainstreaming climate services for health operations to control arboviruses included climate-health bulletins and an online GIS platform that would allow for regional data sharing and the generation of spatiotemporal epidemic forecasts.

Conclusions

These findings support the creation of interdisciplinary and intersectoral communities of practices and the co-design of climate services for the Caribbean public health sector. By fostering the effective use of climate information within health policy, research and practice, nations will have greater capacity to adapt to a changing climate.
Global Modulation in DNA Epigenetics during Pro-Inflammatory Macrophage Activation
Authors: Jain Nikhil , Shahal Tamar , Gabrieli Tslil , Gilat Noa , Torchinsky Dmitry , Michaeli Yael , Vogel Viola , Ebenstein Yuval
Published: March 2019

DNA methylation patterns create distinct gene expression profiles. These patterns are maintained after cell division, thus enabling the differentiation and maintenance of multiple cell types from the same genome sequence. The advantage of this mechanism for transcriptional control is that chemical-encoding allows to rapidly establish new epigenetic patterns “on-demand” through enzymatic methylation and de-methylation of DNA. Here we show that this feature is associated with the fast response of macrophages during their pro-inflammatory activation. By using a combination of mass spectroscopy and single-molecule imaging to quantify global epigenetic changes in the genomes of primary macrophages, we followed three distinct DNA marks (methylated, hydroxymethylated and unmethylated), involved in establishing new DNA methylation patterns during pro-inflammatory activation. The observed epigenetic modulation together with gene expression data generated for the involved enzymatic machinery, may suggest that de-methylation upon LPS-activation starts with oxidation of methylated CpGs, followed by excision-repair of these oxidized bases and their replacement with unmodified cytosine.
Co-localization of pain and reduced intra-epidermal nerve fiber density in individuals with HIV-associated sensory neuropathy
Authors: Patel Imraan G , Kamerman Peter R
Published: March 2019

Introduction

There is poor correlation between decreases in intra-epidermal nerve fiber density (IENFD) and the presence of pain in HIV-associated sensory neuropathy (HIV-SN) and other painful distal symmetrical polyneuropathies.

Objective

We investigated whether in individuals with HIV-SN, having pain at the ankle skin biopsy site was associated with lower IENFD compared to when there was no pain at the ankle biopsy site.

Methods

We recruited 15 individuals with symptomatic HIV-SN. Nine had pain at the site where the ankle biopsy was taken, while six did not. Skin punch biopsies for IENFD quantification were taken from the ankle and the thigh. Contrasts between the two groups were made using the overlap of confidence interval (CI) method.

Results

IENFD was substantially lower in the group that had pain at the site of the ankle biopsy compared to the other group [6.6 (CI: 5.3 to 7.2) vs. 3.3 (CI: 10.0 to 15.0) fibers/mm]. However, there was no group differences at the thigh biopsy site [15.6 (CI: 15.0 to 15.9) vs 16.2 (CI: 14.5 to 17.8) fibers/mm]. When taking the ratio of ankle IENFD:thigh IENFD, the point estimate for the pain at the ankle group [0.43 (CI: 0.36 to 0.48)] was about half that of the other group [0.81 (CI: 0.68 to 0.87)].

Conclusion

Thus, co-localization of pain to the ankle is associated with meaningful decreases in ankle IENFD.

Having pain at the ankle biopsy site is associated with lower intra-epidermal nerve fiber density compared to not having pain at the ankle biopsy site.
A tissue-like platform for studying engineered quiescent human T-cells’ interactions with dendritic cells
Authors: Abu-Shah Enas , Demetriou Philippos , Balint Stefan , Mayya Viveka , Kutuzov Mikhail A. , Dushek Omer , Dustin Michael L.
Published: March 2019

Research in the field of human immunology is restricted by the lack of a system that reconstitutes thein-situactivation dynamics of quiescent human antigen-specific T-cells interacting with dendritic cells. Here we report a tissue-like system that recapitulates the dynamics of engineered primary human immune cell. Our approach facilitates real-time single cell manipulations, tracking of interactions and functional responses complemented by population-based measurements of cytokines, activation status and proliferation. As a proof of concept, we recapitulate immunological phenomenon such as CD4 help to CD8 T-cells through enhanced maturation of DCs and effect of PD-1 checkpoint blockades. In addition, we characterise unique dynamics of T-cell/DC interactions as a function of antigen affinity.
Peaceful behaviour: a strategy employed by an obligate nest invader to avoid conflict with its host species
Authors: Hugo Helder , Cristaldo Paulo F. , DeSouza Og
Published: March 2019

In addition to its builders, termite nests are known to house a variety of secondary, opportunistic termite species, but little is known about the mechanisms governing the maintenance of such associations. In a single nest, host and intruder are likely to engage in intense conflict, due to their nestmate discrimination system. An intriguing question is how individuals cope with such a burden in the long term. Evasive behaviour has been previously suggested as a mechanism that reduces the frequency of encounters between non-nestmates. However, due to confinement imposed by the nests’ physical boundaries, it is likely that hosts and inquilines would eventually come across each other. Under these circumstances, it is plausible that inquilines would be required to behave accordingly to secure their housing. Here, we tested this hypothesis predicting that, once inevitably exposed to hosts, inquiline individuals would modulate their behaviour to circumvent conflict. While exploring the behavioural dynamics of the encounter between both cohabitants, we find evidence for an unusual lack of aggressiveness by inquilines towards hosts. Such a non-aggressive behaviour is characterised by evasive manoeuvres that include reversing direction, bypassing and a defensive mechanism using defecation to repel hosts. The behavioural adaptations we describe may play an intrinsic role in the stability of cohabitations between termite species: by reducing the costs of conflicts to both cohabitants, it may improve the chances for stable nest-sharing considerably.
A Divide-and-Conquer Method for Scalable Phylogenetic Network Inference from Multi-locus Data
Authors: Zhu Jiafan , Liu Xinhao , Ogilvie Huw A. , Nakhleh Luay K.
Published: March 2019

Reticulate evolutionary histories, such as those arising in the presence of hybridization, are best modeled as phylogenetic networks. Recently developed methods allow for statistical inference of phylogenetic networks while also accounting for other processes, such as incomplete lineage sorting (ILS). However, these methods can only handle a small number of loci from a handful of genomes.

In this paper, we introduce a novel two-step method for scalable inference of phylogenetic networks from the sequence alignments of multiple, unlinked loci. The method infers networks on subproblems and then merges them into a network on the full set of taxa. To reduce the number of trinets to infer, we formulate a Hitting Set version of the problem of finding a small number of subsets, and implement a simple heuristic to solve it. We studied their performance, in terms of both running time and accuracy, on simulated as well as on biological data sets. The two-step method accurately infers phylogenetic networks at a scale that is infeasible with existing methods. The results are a significant and promising step towards accurate, large-scale phylogenetic network inference.

We implemented the algorithms in the publicly available software package PhyloNet (https://bioinfocs.rice.edu/PhyloNet).

Contact

nakhleh@rice.edu
Membrane association of VAMP2 SNARE motif in cells and its regulation by different lipid phases of synaptic vesicle membrane
Authors: Wang Chuchu , Tu Jia , Zhang Shengnan , Cai Bin , Liu Zhenying , Hou Shouqiao , Liu Zhijun , Diao Jiajie , Zhu Zheng-Jiang , Liu Cong , Li Dan
Published: March 2019

Vesicle associated membrane protein 2 (VAMP2) contains a conserved SNARE motif that forms helix bundles with the homologous motifs of syntaxin-1 and SNAP25 to assemble into a SNARE complex for the exocytosis of synaptic vesicles (SV). Prior to SNARE assembly, the structure of VAMP2 is unclear. Here, using in-cell NMR spectroscopy, we described the dynamic membrane association of VAMP2 SNARE motif in mammalian cells at atomic resolution, and further tracked the intracellular structural changes of VAMP2 upon the lipid environmental changes. The underlying mechanistic basis was then investigated by solution NMR combined with mass-spectrometry-based lipidomic profiling. We analyzed the lipid compositions of lipid-raft and non-raft phases of SV membrane and revealed that VAMP2 configures distinctive conformations in different phases of SV membrane. The phase of cholesterol-rich lipid rafts could largely weaken the association of SNARE motif with SV membrane and thus, facilitate vesicle docking; While in the non-raft phase, the SNARE motif tends to hibernate on SV membrane with minor activity. Our work provides a spatial regulation of different lipid membrane phases to the structure of core SNARE proteins, which deepens our knowledge on the modulation of SNARE machinery.
Cyclophilin A protects HIV-1 from restriction by human TRIM5α
Authors: Kim Kyusik , Dauphin Ann , Komurlu Sevnur , Yurkovetskiy Leonid , Diehl William E. , McCauley Sean M. , Carbone Claudia , Strambio-De-Castillia Caterina , Campbell Edward M. , Luban Jeremy
Published: March 2019

The capsid (CA) protein lattice of HIV-1 and other retroviruses encases viral genomic RNA and regulates steps that are essential to retroviral invasion of target cells, including reverse transcription, nuclear trafficking, and integration of viral cDNA into host chromosomal DNA1. Cyclophilin A (CypA), the first cellular protein reported to bind HIV-1 CA2, has interacted with invading lentiviruses related to HIV-1 for millions of years3–7. Disruption of the CA-CypA interaction decreases HIV-1 infectivity in human cells8–12, but stimulates infectivity in non-human primate cells13–15. Genetic and biochemical data suggest that CypA interaction with CA protects HIV-1 from a restriction factor in human cells16–20. Discovery of the CA-specific restriction factor TRIM5α21, and of TRIM5-CypA fusion genes that were independently generated at least four times in phylogeny4,5,15,22–25, pointed to human TRIM5α as the CypA-sensitive restriction factor. However, significant HIV-1 restriction by human TRIM5α21, let alone inhibition of such activity by CypA26, has not been detected. Here, exploiting reverse genetic tools optimized for primary human CD4+T cells, macrophages, and dendritic cells, we demonstrate that disruption of the CA-CypA interaction renders HIV-1 susceptible to restriction by human TRIM5α, with the block occurring before reverse transcription. Identical findings were obtained with single-cycle vectors or with replication-competent HIV-1, including sexually-transmitted clones from sub-Saharan Africa. Endogenous TRIM5α was observed to associate with virion cores as they entered the macrophage cytoplasm, but only when the CA-CypA interaction was disrupted. These experiments resolve the long-standing mystery of the role of CypA in HIV-1 replication by demonstrating that this ubiquitous cellular protein shields HIV-1 from previously inapparent, but potent inhibition, imposed by human TRIM5α. Hopefully this reinvigorates development of CypA-inhibitors for treatment of HIV-1 and other CypA-dependent pathogens27–30.
Genomic acquisitions in emerging populations ofXanthomonas vasicolapv.vasculoruminfecting corn in the U.S. and Argentina
Authors: Perez-Quintero Alvaro L , Ortiz-Castro Mary , Wu Guangxi , Lang Jillian M. , Liu Sanzhen , Chapman Toni A , Chang Christine , Ziegle Janet , Peng Zhao , White Frank F. , Plazas Maria Cristina , Leach Jan E. , Broders Kirk
Published: March 2019

Xanthomonas vasicolapv.vasculorum (Xvv)is an emerging bacterial plant pathogen that causes bacterial leaf streak on corn. First described in South Africa in 1949, reports of this bacteria have greatly increased in the past years in South America and in the U.S., where it is now present in most of the corn producing states. Phenotypic characterization showed that the emerging U.S. and South American Xvvpopulations may have increased virulence in corn compared to older strains. To understand the genetic mechanisms behind the increased virulence in this group, we used comparative genomics to identify gene acquisitions inXvvgenomes from the U.S. and Argentina. We sequenced 41 genomes ofXvvand the related sorghum-infectingX. vasicolapv.holcicola(Xvh).A comparison of all availableX. vasicolagenomes showed the phylogenetic relationships in the group and identified clusters of genes associated with the emergingXvvpopulations. The newly acquired gene clusters showed evidence of horizontal transfer toXvvand included candidate virulence factors. One cluster, in particular, corresponded to a prophage transferred fromXvhto allXvvfrom Argentina and the U.S. The prophage contains putative secreted proteins, which represent candidates for virulence determinants in these populations and await further molecular characterization.
NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains
Authors: Lhoumaud Priscillia , Badri Sana , Hernaez Javier Rodriguez , Sakellaropoulos Theodore , Sethia Gunjan , Kloetgen Andreas , Cornwell MacIntosh , Bhattacharyya Sourya , Ay Ferhat , Bonneau Richard , Tsirigos Aristotelis , Skok Jane A.
Published: March 2019

CTCF and cohesin play a key role in organizing chromatin into TAD structures. Disruption of a single CTCF binding site is sufficient to change chromosomal interactions leading to alterations in chromatin modifications and gene regulation. However, the extent to which alterations in chromatin modifications can disrupt 3D chromosome organization leading to transcriptional changes is unknown. In multiple myeloma a 4;14 translocation induces overexpression of the histone methyltransferase, NSD2 resulting in expansion of H3K36me2 and shrinkage of antagonistic H3K27me3 domains. Using isogenic cell lines producing high and low levels of NSD2, we find oncogene activation is linked to alterations in H3K27ac and CTCF within H3K36me2 enriched chromatin. A linear regression model reveals that changes in both CTCF and/or H3K27ac significantly increase the probability that a gene sharing the same insulated domain will be differentially expressed. These results identify a bidirectional relationship between 2D chromatin and 3D genome organization in gene regulation.
Lower Extremity Long-Latency Reflexes Differentiate Walking Function After Stroke
Authors: Banks Caitlin L. , Little Virginia L. , Walker Eric R. , Patten Carolynn
Published: March 2019

The neural mechanisms of walking impairment after stroke are not well characterized. There is a need for a neurophysiologic marker that can unambiguously differentiate functional status and potential for walking recovery. The long-latency reflex (LLR) is a supraspinally-mediated response that integrates sensorimotor information during movement. It is hypothesized that lower extremity LLRs contribute to regulation of motor output during walking in healthy individuals. The goal of the present study was to assess the relationship between lower extremity LLRs, measures of supraspinal drive, and walking function. Thirteen individuals with chronic post-stroke hemiparesis and thirteen healthy controls performed both isometric and dynamic plantarflexion. Transcranial magnetic stimulation (TMS) assessed supraspinal drive to the tibialis anterior. LLR activity was assessed during dynamic voluntary plantarflexion and individuals post-stroke were classified as either LLR present (LLR+) or absent (LLR-). All healthy controls and nine individuals post-stroke exhibited LLRs, while four did not. LLR+ individuals revealed higher clinical scores, walking speeds, and greater ankle plantarflexor power during walking compared to LLR- individuals. LLR- individuals exhibited exaggerated responses to TMS during dynamic plantarflexion relative to healthy controls. This LLR- subset revealed dysfunctional modulation of stretch responses and antagonist supraspinal drive relative to healthy controls and the higher functioning LLR+ individuals post-stroke. These abnormal responses allow for unambiguous differentiation between individuals post-stroke and are associated with multiple measures of motor function. These findings provide an opportunity to distinguish among the heterogeneity of lower extremity motor impairments present following stroke by associating them with responses at the nervous system level.
Seascape genomics as a new tool to empower coral reef conservation strategies: an example on north-western PacificAcropora digitifera
Authors: Selmoni Oliver , Rochat Estelle , Lecellier Gael , Berteaux-Lecellier Veronique , Joost Stéphane
Published: March 2019

Coral reefs are suffering a major decline due to the environmental constraints imposed by climate change. Over the last 20 years, three major coral bleaching events occurred in concomitance of anomalous heat waves, provoking a severe loss of coral cover worldwide. The conservation strategies for preserving reefs, as they are implemented now, cannot cope with global climatic shifts. Consequently, researchers are advocating the set-up of preservation frameworks to reinforce coral adaptive potential. However, the main obstacle to this implementation is that studies on coral adaption are usually hard to generalize at the scale of a reef system.

Here, we study the relationships between frequencies of genetic markers with that of environmental characteristics of the sea (seascape genomics), in combination with connectivity analysis, to investigate the adaptive potential of a flagship coral species of the Ryukyu Archipelago (Japan). By associating genotype frequencies with descriptors of historical environmental conditions, we discovered six genomic regions hosting polymorphisms that might promote resistance against thermal stress. Remarkably, annotations of genes in these regions were consistent with molecular roles associated with heat responses. Furthermore, we combined information on genetic and spatial distances between reefs to predict connectivity at a regional scale.

The combination between the results of these analyses portrayed the adaptive potential of this population: we were able to identify reefs carrying potential adaptive genotypes and to understand how they disperse to neighbouring reefs. This information was summarized by objective, quantifiable, and mappable indices covering the whole region, which can be extremely useful for future prioritization of reefs in conservation planning. This framework is transferable to any coral species on any reef system, and therefore represents a valuable tool for empowering preservation efforts dedicated to the protection of coral reef in warming oceans.
Proteomics analysis of extracellular matrix remodeling during zebrafish heart regeneration
Authors: Garcia-Puig Anna , Mosquera Jose Luis , Jiménez-Delgado Senda , García-Pastor Cristina , Jorba Ignasi , Navajas Daniel , Canals Francesc , Raya Angel
Published: March 2019

Adult zebrafish, in contrast to mammals, are able to regenerate their hearts in response to injury or experimental amputation. Our understanding of the cellular and molecular bases that underlie this process, although fragmentary, has increased significantly over the last years. However, the role of the extracellular matrix (ECM) during zebrafish heart regeneration has been comparatively rarely explored. Here, we set out to characterize the ECM protein composition in adult zebrafish hearts, and whether it changed during the regenerative response. For this purpose, we first established a decellularization protocol of adult zebrafish ventricles that significantly enriched the yield of ECM proteins. We then performed proteomic analyses of decellularized control hearts and at different times of regeneration. Our results show a dynamic change in ECM protein composition, most evident at the earliest (7 days post-amputation) time-point analyzed. Regeneration associated with sharp increases in specific ECM proteins, and with an overall decrease in collagens and cytoskeletal proteins. We finally tested by atomic force microscopy that the changes in ECM composition translated to decreased ECM stiffness. Our cumulative results identify changes in the protein composition and mechanical properties of the zebrafish heart ECM during regeneration.
On the move: Redox –dependent protein relocation
Authors: Foyer Christine H. , Baker Alison , Wright Megan , Sparkes Imogen A. , Mhamdi Amna , Schippers Jos H.M. , Van Breusegem Frank
Published: March 2019

Compartmentation of proteins and processes is a defining feature of eukaryotic cells. The growth and development of organisms is critically dependent on the accurate sorting of proteins within cells. The mechanisms by which cytosol-synthesized proteins are delivered to the membranes and membrane compartments have been extensively characterised. However, the protein complement of any given compartment is not precisely fixed and some proteins can move between compartments in response to metabolic or environmental triggers. The mechanisms and processes that mediate such relocation events are largely uncharacterized. Many proteins can in addition perform multiple functions, catalyzing alternative reactions or performing structural, non-enzymatic functions. These alternative functions can be equally important functions in each cellular compartment. Such proteins are generally not dual targeted proteins in the classic sense of having targeting sequences that directde novosynthesised proteins to specific cellular locations. Accumulating evidence suggests that redox post-translational modifications (PTMs) can control the compartmentation of many such proteins, including antioxidant and/or redox associated enzymes.
Childhood intelligence attenuates the association between biological ageing and health outcomes in later
Authors: Stevenson Anna J. , McCartney Daniel L. , Hillary Robert F. , Redmond Paul , Taylor Adele M. , Zhang Qian , McRae Allan F. , Spires-Jones Tara L. , McIntosh Andrew M. , Deary Ian J. , Marioni Riccardo E.
Published: March 2019

The identification of biomarkers that discriminate individual ageing trajectories is a principal target in ageing research. Some of the most promising predictors of biological ageing have been developed using DNA methylation. One recent candidate, which tracks age-related phenotypes in addition to chronological age, is ‘DNAm PhenoAge’. Here, we performed a phenome-wide association analysis of this biomarker in a cohort of older adults to assess its relationship with a comprehensive set of both historical and contemporaneously-measured phenotypes. Higher than expected DNAm PhenoAge compared to chronological age, known as epigenetic age acceleration, was found to associate with a number of blood, cognitive, physical fitness and lifestyle variables, and with mortality. Notably, DNAm PhenoAge, assessed at age 70, was associated with cognitive ability at age 11, and with educational attainment. Adjusting for age 11 cognitive ability attenuated the majority of the cross-sectional later-life associations between DNAm PhenoAge and health outcomes. These results highlight the importance of early-life factors on healthy ageing.
Serum Flt3 ligand is biomarker of progenitor cell mass and prognosis in acute myeloid leukemia
Authors: Milne Paul , Wilhelm-Benartzi Charlotte , Grunwald Michael R. , Bigley Venetia , Publicover Amy , Pagan Sarah , Marr Helen , Jones Gail , Dickinson Anne , Grech Angela , Burnett Alan , Russell Nigel , Levis Mark , Knapper Steven , Collin Matthew
Published: March 2019

Fms-like tyrosine kinase 3 (Flt3) is a hematopoietic growth factor receptor expressed on lymphomyeloid progenitors and frequently, by AML blasts. Its ligand, Flt3L, has non-hematopoietic and lymphoid origins, is detectable during homeostasis and increases to high levels in states of hypoplasia due to genetic defects or treatment with cytoreductive agents. Measurement of Flt3L by ELISA reveals that Flt3+AML, is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering CR, but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the BM. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 135 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney p < 0.0001). Day 26 Flt3L was also associated with survival: Flt3L ≤ 291pg/ml was associated with inferior event-free survival; and, Flt3L >1185pg/ml was associated with higher overall survival (p = 0.0119). Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML further illustrated the potential value of declining Flt3L to identify relapse. Together these observations suggest that measurement of Flt3L provides a non-invasive estimate of progenitor cell mass in most patients with AML, with the potential to inform clinical decisions.

Graphical abstract
tailfindr: Alignment-free poly(A) length measurement for Oxford Nanopore RNA and DNA sequencing
Authors: Krause Maximilian , Niazi Adnan M. , Labun Kornel , Torres Cleuren Yamila N. , Müller Florian S. , Valen Eivind
Published: March 2019

Polyadenylation at the 3’-end is a major regulator of messenger RNA and its length is known to affect nuclear export, stability and translation, among others. Only recently, strategies have emerged that allow for genome-wide poly(A) length assessment. These methods identify genes connected to poly(A) tail measurements indirectly by short-read alignment to genetic 3’-ends. Concurrently Oxford Nanopore Technologies (ONT) established full-length isoform RNA sequencing containing the entire poly(A) tail. However, assessing poly(A) length through basecalling has so far not been possible due the inability to resolve long homopolymeric stretches in ONT sequencing.

Here we presenttailfindr, an R package to estimate poly(A) tail length on ONT long-read sequencing data.tailfindroperates on unaligned, basecalled data. It measures poly(A) tail length from both native RNA and DNA sequencing, which makes poly(A) tail studies by full-length cDNA approaches possible for the first time. We assesstailfindr’sperformance across different poly(A) lengths, demonstrating thattailfindris a versatile tool providing poly(A) tail estimates across a wide range of sequencing conditions.
Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes
Authors: McGlinchey Aidan , Sinioja Tim , Lamichhane Santosh , Sen Partho , Bodin Johanna , Siljander Heli , Dickens Alex M. , Geng Dawei , Carlsson Cecilia , Duberg Daniel , Ilonen Jorma , Virtanen Suvi M. , Dirven Hubert , Berntsen Hanne Friis , Zimmer Karin , Nygaard Unni C. , Orešič Matej , Knip Mikael , Hyötyläinen Tuulia
Published: March 2019

In the last decade, increasing incidence of type 1 diabetes (T1D) stabilized in Finland, a phenomenon that coincides with tighter regulation of perfluoroalkyl substances (PFAS). Here, we quantified PFAS to examine their effects, during pregnancy, on lipid and immune-related markers of T1D risk in children. In a mother-infant cohort (264 dyads), high PFAS exposure during pregnancy associated with decreased cord serum phospholipids and progression to T1D-associated islet autoantibodies in the offspring. This PFAS-lipid association appears exacerbated by increased human leukocyte antigen-conferred risk of T1D in infants. Exposure to a single PFAS compound or a mixture of organic pollutants in non-obese diabetic mice resulted in a lipid profile characterized by a similar decrease in phospholipids, a marked increase of lithocholic acid, and accelerated insulitis. Our findings suggest that PFAS exposure during pregnancy contributes to risk and pathogenesis of T1D in offspring.
Ontogeny and expression profiles of steroid hormone receptors in a mouse model of endometriosis
Authors: Mishra Anuradha , Galvankar Mosami , Singh Neha , Vaidya Shantashri , Chaudhari Uddhav , Modi Deepak
Published: March 2019

Endometriosis is a chronic incurable disorder of unknown etiology affecting a large proportion of women in reproductive age. In order to understand the pathogenesis and preclinical testing of drugs,animal models that recapitulate the key features of the disorder are highly desirous. Herein, we describe the ontogeny of the ectopic endometrial lesion in a mouse model where uterine tissue was ligated to the intestinal mesentery and the animals were followed up from day 5 to day 60 post-surgery. Out of 60 animals that underwent surgery, 58 developed endometriosis using this strategy. Most lesions were pale, fluid filled while red lesions were seen in ~10% of animals. Histologically, in most animals there was one large cystic gland with well differentiated epithelium, in 13% of animals there was mixed phenotype (well and poorly differentiated). There was extensive stromal compaction and increased number of macrophages in ectopic lesions. During the course of endometriosis, there was an increase in number of PCNA positive epithelial and stromal cells. The epithelial cells at all the time point were cytokeratin positive and the stroma was vimentin positive. However, at day 30 and 60, the stromal cells were also cytokeratin positive. The mRNA levels of estrogen receptorsEsr1andGper1were reduced while those ofEsr2were elevated as compared to normal endometrium, the levels of progesterone receptor (Pgr) were found to be downregulated in ectopic lesions as compared to control. However, these differences were not statistically significant due to high biological variability. Low abundance ofCyp19a1transcripts (aromatase gene) were only detected in the ectopic endometrium. Immunohistochemically, the expression of ERα and ERβ was significantly reduced only in stromal cells; the epithelial cell staining was maintained. GPER1 and PR immunoreactivity was significantly low in both epithelial and stromal cells. The immunostaining of all the steroid receptors was highly heterogeneous in the ectopic tissues with some areas of sections had stained intensely while others had negligible staining. We propose that temporal and spatial difference in the expression of steroid hormone receptors during the course of endometriosis development coupled with micro-heterogeneity may alter the effectiveness of steroid hormone analogues resulting in variable outcomes and often failure of therapy.
AluMine: alignment-free method for the discovery of polymorphic Alu element insertions
Authors: Puurand Tarmo , Kukuškina Viktoria , Pajuste Fanny-Dhelia , Remm Maido
Published: March 2019

Background

Recently, alignment-free sequence analysis methods have gained popularity in the field of personal genomics. These methods are based on counting frequencies of short k-mer sequences, thus allowing faster and more robust analysis compared to traditional alignment-based methods.

Results

We have created a fast alignment-free method, AluMine, to analyze polymorphic insertions of Alu elements in the human genome. We tested the method on 2,241 individuals from the Estonian Genome Project and identified 28,962 potential polymorphic Alu element insertions. Each tested individual had on average 1,574 Alu element insertions that were different from those in the reference genome. In addition, we propose an alignment-free genotyping method that uses the frequency of insertion/deletion-specific 32-mer pairs to call the genotype directly from raw sequencing reads. Using this method, the concordance between the predicted and experimentally observed genotypes was 98.7%. The running time of the discovery pipeline is approximately 2 hours per individual. The genotyping of potential polymorphic insertions takes between 0.4 and 4 hours per individual, depending on the hardware configuration.

Conclusions

AluMine provides tools that allow discovery of novel Alu element insertions and/or genotyping of known Alu element insertions from personal genomes within few hours.
Structural and mutational analysis of the ribosome-arresting human XBP1u
Authors: Shanmuganathan Vivekanandan , Schiller Nina , Magoulopoulou Anastasia , Cheng Jingdong , Braunger Katharina , Cymer Florian , Berninghausen Otto , Beatrix Birgitta , Kohno Kenji , von Heijne Gunnar , Beckmann Roland
Published: March 2019

XBP1u, a central component of the unfolded protein response (UPR), is a mammalian protein containing a functionally critical translational arrest peptide (AP). Here, we present a 3 Å cryo-EM structure of the stalled human XBP1u AP. It forms a unique turn in the upper part of the ribosomal exit tunnel and causes a subtle distortion of the peptidyl transferase center, explaining the temporary translational arrest induced by XBP1u. During ribosomal pausing the hydrophobic region 2 (HR2) of XBP1u is recognized by SRP, but fails to efficiently gate the Sec61 translocon. An exhaustive mutagenesis scan of the XBP1u AP revealed that only 10 out of 21 mutagenized positions in the XBP1u AP are optimal with respect to translational arrest activity. Thus, XBP1u has evolved to induce an intermediate level of translational arrest, allowing efficient targeting by SRP without activating the Sec61 channel and thereby serving its central function in the UPR.
Study on the Health Communication Behavior of Chinese Doctors on Network Media——Based on the Empirical Investigation of 119 Chinese Doctors
Authors: Fangyuan Hu , Pu Wang
Published: March 2019

Introduction

In order to reduce the perceived risk of medical decision-making, Chinese patients tend to spend time and energy to understand relevant medical knowledge. After comparing online reviews and news reports of Chinese doctors, they carefully choose doctors. It is precisely because of the patient’s treatment habits that many doctors have spread health information through their own microblogs, WeChat public numbers, websites, videos and other means. Therefore, doctors’ speeches in cyberspace often play a dominant role in the development of health communication and guide the risk communication. This paper studies the influencing factors of Chinese doctors’ healthy communication behavior in online media. This has positive reference value for improving the health literacy of the whole people and the crisis management and guidance of public events.

Methods

In order to maximize the representativeness of the sample, the universality of the problems reflected in the survey data, and the adaptability of the purpose and method of the research questions, this paper adopts a multi-stage sampling method. In each region, a medical institution is selected according to a simple random sampling method in three types of hospitals: public hospitals, social hospitals, and primary medical institutions. A total of 10-11 medical institutions were selected in each region, and a total of 32 hospitals were selected from the three regions. According to the PPS sampling method, a corresponding number of working doctors are drawn in each hospital. Statistical analysis of the data was performed using SPSS 21.0 statistical software.

Analysis

The study found that doctors’ transmission of health-related content on online media is still at a lower level of involvement, and the frequency of transmission is significantly lower than the general level. There are also significant differences in the health transmission of doctors from different backgrounds on the Internet. In the context of control hospital background, continue to examine the impact of Media usage and occupational psychology on doctors’ dissemination of health-related content. The results show that the influence of Media usage on the health communication behavior of doctors on the Internet media, to a certain extent, verifies that the rise of online media plays a significant role in putting doctors into health science. This also shows that the media has fostered the doctor’s communication behavior. In addition, the higher the self-efficacy of doctors in the workplace, the more cautious they are about their words and deeds, the more they care about the impact of their speech on interpersonal communication.
Extensive adaptive immune response of AAVs and Cas proteins in non-human primates
Authors: Xiao Puhao , Bai Raoxian , Zhang Ting , Zhou Yin , Zhou Zhigang , Zhuo Yan , Gong Nannan , Liu Jie , Ren Shuaiwei , Wu Ruo , Shen Bin , Li Shangang , Niu Yuyu , Ji Weizhi , Chen Yongchang
Published: March 2019

The CRISPR-mediated Cas system is the most widely used tool in gene editing and gene therapy for its convenience and efficiency. Delivery of the CRISPR system by adeno-associated viruses (AAVs) is currently the most promising approach to gene therapy. However, pre-existing adaptive immune responses against CRISPR nuclease (PAIR-C) and AAVs has been found in human serum, indicating that immune response is a problem that cannot be ignored, especially for in vivo gene correction. Non-human primates (NHPs) share many genetic and physiological traits with human, and are considered as the bridge for translational medicine. However, whether NHPs have same PAIR-C status with human is still unknown. Here, macaques (rhesus and cynomolgus), including normal housed and CRISPR-SpCas9 or TALENs edited individuals, were used to detect PAIR-C which covered SaCas9, SpCas9, AsCas12a and LbCas12a. Dogs and mice were also detected to expand the range of species. In addition, pre-existing adaptive antibodies to AAV8 and AAV9 were performed against macaques of different ages. The results showed that adaptive immunity was pre-existing in the macaques regardless of Cas proteins and AAVs. These findings indicate that the pre-existing adaptive immune of AAV-delivered CRISPR construction and correction system should be concerned for in vivo experiments.
MgO nanoparticles coated with Polyethylene Glycol as carrier for 2-Methoxyestradiol anticancer drug
Authors: Alfaro Aline , León Andrea , Guajardo Eduardo , Reuquen Patricia , Torres Francisco , Mery Mario , Segura Rodrigo , Zapata Paula A. , Orihuela Pedro A.
Published: March 2019

Novel Magnesium Oxide (MgO) nanoparticles (NPs) modified with the polymer poliethylene glycol (PEG) were synthesized as carrier for the anticancer drug 2-Methoxyestradiol (2ME) to improve its clinical application. The functionalized NPs were characterized by Infrared spectroscopy with Fourier transform to elucidate the vibration modes of this conjugate, indicating the formation of the MgO-PEG-2ME nanocomposite. The studies of absorption and liberation determined that MgO-PEG-2ME NPs incorporated 98.51 % of 2ME while liberation of 2ME was constant during 7 days at pH 2, 5 and 7.35. Finally, the MgO-PEG-2ME NPs decreased the viability of the prostate cancer cell line LNCap suggesting that this nanocomposite is suitable as a drug delivery system for anticancer prostate therapy.
Emotional intelligence, emotional labor strategies and satisfaction of secondary teachers in Pakistan
Authors: Pervaiz Sonia , Ali Amjad , Asif Muhammad
Published: March 2019

Purpose

Emotional intelligence (EI) is crucial to determine the emotional labor (EL) strategies and satisfaction of teachers. The purpose of this paper is to investigate the relationships of EI with EL strategies, emotional exhaustion and teaching satisfaction (TS) of secondary teachers in private schools.

Design/methodology/approach

A self-administered questionnaire was used to collect data conveniently from 322 secondary teachers working in 22 private schools.

Findings

Results indicate that teachers’ EI positively affect surface acting, expression of naturally felt emotions (ENFE) and TS. Surface acting and ENFE are positively related with TS. Deep acting and ENFE exhibit positive relations with emotional exhaustion of teachers. The study also confirms direct as well as indirect effects of EI on TS through surface acting and ENFE.

Practical implications

This study recommends teachers to make a higher use of surface acting and ENFE because they produce the most TS and the least emotional exhaustion.

Originality/value

This is the first study that examines the mediating role of EL strategies for EI and TS.
Thinking about service encounters boosts talking about them
Authors: Söderlund Magnus , Mattsson Jan
Published: March 2019

Purpose

This paper aims to examine the impact of thinking about an event as an antecedent to subsequent talk about this event with others (i.e. word-of-mouth). Thinking has been a neglected variable in word-of-mouth research, despite the fact that several conceptual arguments indicate that thinking is likely to enhance talking. Here, the thinking–talking association is examined in the context of service encounters.

Design/methodology/approach

Data were collected with a critical incident method, and the main variables were measured with questionnaire items.

Findings

Thinking about a service encounter – after it has been completed – had a positive influence on subsequent talk to others about the encounter. The association was mediated by the memorability of the service encounter and the extent to which what had happened had been subject to rehearsal with the purpose of telling others about it. In addition, with respect to antecedents of consumer thinking, the results indicate that service encounter incongruity had a special role in why the consumer thinks about encounters after they have been completed.

Originality/value

The findings should be seen in relation to the dominant position of customer satisfaction as an antecedent to word-of-mouth in the existing literature. The present results, however, indicate that satisfaction’s contribution to the variation in talking about the encounter was modest.