bluuebunny/crossref_metadata_2025 huggingface dataset:
Reducing variability in along-tract analysis with diffusion profile realignment
Authors: St-Jean Samuel , Chamberland Maxime , Viergever Max A. , Leemans Alexander
Published: February 2019

Diffusion weighted magnetic resonance imaging (dMRI) provides a non invasive virtual reconstruction of the brain’s white matter structures through tractography. Analyzing dMRI measures along the trajectory of white matter bundles can provide a more specific investigation than considering a region of interest or tract-averaged measurements. However, performing group analyses with this along-tract strategy requires correspondence between points of tract pathways across subjects. This is usually achieved by creating a new common space where the representative streamlines from every subject are resampled to the same number of points. If the underlying anatomy of some subjects was altered due to, e.g., disease or developmental changes, such information might be lost by resampling to a fixed number of points. In this work, we propose to address the issue of possible misalignment, which might be present even after resampling, by realigning the representative streamline of each subject in this 1D space with a new method, coined diffusion profile realignment (DPR). Experiments on synthetic datasets show that DPR reduces the coefficient of variation for the mean diffusivity, fractional anisotropy and apparent fiber density when compared to the unaligned case. Using 100 in vivo datasets from the human connectome project, we simulated changes in mean diffusivity, fractional anisotropy and apparent fiber density. Pairwise Student’s t-tests between these altered subjects and the original subjects indicate that regional changes are identified after realignment with the DPR algorithm, while preserving differences previously detected in the unaligned case. This new correction strategy contributes to revealing effects of interest which might be hidden by misalignment and has the potential to improve the specificity in longitudinal population studies beyond the traditional region of interest based analysis and along-tract analysis workflows.
Spastin tethers lipid droplets to peroxisomes and directs fatty acid trafficking through ESCRT-III
Authors: Chang Chi-Lun , Weigel Aubrey V. , Ioannou Maria S. , Pasolli H. Amalia , Xu C. Shan , Peale David R. , Shtengel Gleb , Freeman Melanie , Hess Harald F. , Blackstone Craig , Lippincott-Schwartz Jennifer
Published: February 2019

Lipid droplets (LDs) are neutral lipid storage organelles that transfer lipids to various organelles including peroxisomes. Here, we show that the hereditary spastic paraplegia protein M1 Spastin, a membrane-bound AAA ATPase found on LDs, coordinates fatty acid (FA) trafficking from LDs to peroxisomes through two inter-related mechanisms. First, M1 Spastin forms a tethering complex with peroxisomal ABCD1 to promote LD-peroxisome contact formation. Second, M1 Spastin recruits the membrane-shaping ESCRT-III proteins IST1 and CHMP1B to LDs via its MIT domain to facilitate LD-to-peroxisome FA trafficking, possibly through IST1 and CHMP1B modifying LD membrane morphology. Furthermore, M1 Spastin, IST1 and CHMP1B are all required to relieve LDs of lipid peroxidation. M1 Spastin’s dual roles in tethering LDs to peroxisomes and in recruiting ESCRT-components to LD-peroxisome contact sites for FA trafficking may help explain the pathogenesis of diseases associated with defective FA metabolism in LDs and peroxisomes.
Ancient RNA from Late Pleistocene permafrost and historical canids shows tissue-specific transcriptome survival
Authors: Smith Oliver , Dunshea Glenn , Sinding Mikkel-Holger S. , Fedorov Sergey , Germonpre Mietje , Bocherens Hervé , Gilbert M.T.P.
Published: February 2019

While sequencing ancient DNA from archaeological material is now commonplace, very few attempts to sequence ancient transcriptomes have been made, even from typically stable deposition environments such as permafrost. This is presumably due to assumptions that RNA completely degrades relatively quickly, particularly when dealing with autolytic, nuclease-rich mammalian tissues. However, given the recent successes in sequencing ancient RNA (aRNA) from various sources including plants and animals, we suspect that these assumptions may be incorrect or exaggerated. To challenge the underlying dogma, we generated shotgun RNA data from sources that might normally be dismissed for such study. Here we present aRNA data generated from two historical wolf skins, and permafrost-preserved liver tissue of a 14,300-year-old Pleistocene canid. Not only is the latter the oldest RNA ever to be sequenced, but also shows evidence of biologically relevant tissue-specificity and close similarity to equivalent data derived from modern-day control tissue. Other hallmarks of RNA-seq data such as exon-exon junction presence and high endogenous ribosomal RNA content confirms our data’s authenticity. By performing independent technical replicates using two high-throughput sequencing platforms, we show not only that aRNA can survive for extended periods in mammalian tissues, but also that it has potential for tissue identification, and possibly further uses such as in vivo genome activity and adaptation, when sequenced using this technology.
Indirect pathway of caudate tail for choosing good objects in periphery
Authors: Amita Hidetoshi , Hikosaka Okihide
Published: February 2019

Choosing good objects is essential for real life, which is controlled mainly by the basal ganglia. For that, a subject need to not only find good objects, but ‘reject’ bad objects. To reveal this ‘rejection’ mechanism, we created a sequential saccade choice task for monkeys and studied the indirect pathway of caudate tail mediated by cvGPe (caudal-ventral globus pallidus externus). The inhibitory responses of cvGPe neurons to bad objects were smaller when the monkey made saccades to them by mistake. Moreover, experimental reduction of the inhibitory response by local injection of bicuculline (GABAA antagonist) disabled the monkey to reject bad objects. In conclusion, rejecting bad objects is crucial for goal-directed behavior, which is controlled by the indirect pathway in the basal ganglia.
Memory quality modulates the effect of aging on memory consolidation during sleep: Reduced maintenance but intact gain
Authors: Muehlroth Beate E. , Sander Myriam C. , Fandakova Yana , Grandy Thomas H. , Rasch Björn , Shing Yee Lee , Werkle-Bergner Markus
Published: February 2019

Successful consolidation of associative memories relies on the coordinated interplay of slow oscillations and sleep spindles during non-rapid eye movement (NREM) sleep, enabling the transfer of labile information from the hippocampus to permanent memory stores in the neocortex. During senescence, the decline of the structural and functional integrity of the hippocampus and neocortical regions is paralleled by changes of the physiological events that stabilize and enhance associative memories during NREM sleep. However, the currently available evidence is inconclusive if and under which circumstances aging impacts memory consolidation. By tracing the encoding quality of single memories in individual participants, we demonstrate that previous learning determines the extent of age-related impairments in memory consolidation. Specifically, the detrimental effects of aging on memory maintenance were greatest for mnemonic contents of medium encoding quality, whereas memory gain of weakly encoded memories did not differ by age. Using multivariate techniques, we identified profiles of alterations in sleep physiology and brain structure characteristic for increasing age. Importantly, while both ‘aged’ sleep and ‘aged’ brain structure profiles were associated with reduced memory maintenance, inter-individual differences in neither sleep nor structural brain integrity qualified as the driving force behind age differences in sleep-dependent consolidation in the present study.
Unique and assay specific features of NOMe-, ATAC- and DNase I-seq data
Authors: Nordström Karl JV , Schmidt Florian , Gasparoni Nina , Salhab Abdulrahman , Gasparoni Gilles , Kattler Kathrin , Müller Fabian , Ebert Peter , Costa Ivan G. ,   DEEP consortium, Pfeifer Nico , Lengauer Thomas , Schulz Marcel H , Walter Jörn
Published: February 2019

Chromatin accessibility maps are important for the functional interpretation of the genome. Here, we systematically analysed assay specific differences between DNase I-Seq, ATAC-Seq and NOMe-Seq in a side by side experimental and bioinformatic setup. We observe that most prominent nucleosome depleted regions (NDRs, e.g. in promoters) are roboustly called by all three or at least two assays. However we also find a high proportion of assay specific NDRs that are often “called” by only one of the assays. We show evidence that these assay specific NDRs are indeed genuine open chromatin sites and contribute important information for accurate gene expression prediction. While technically ATAC-Seq and DNAse I-Seq provide a high NDR calling rate for relatively low sequencing costs in comparison to NOMe-Seq, NOMe-Seq singles out as it provides a multitude of information: it allows to not only detect NDRs but also endogenous DNA methylation, genome wide segmentation into heterochromatic A/B domains and local phasing of nucleosomes outside of NDRs. In summary our comparison strongly suggest to consider assay specific differences for the experimental desgin and for generalized and comparative functional interpretations.
Maize brace root mechanics vary by whorl, genotype, and reproductive stage
Authors: Hostetler Ashley N. , Erndwein Lindsay , Ganji Elahe , Reneau Jonathan W. , Killian Megan L. , Sparks Erin E.
Published: February 2019

Root lodging is responsible for significant crop losses world-wide. During root lodging, roots fail by breaking, buckling, or pulling out of the ground. In maize, above-ground roots, called brace roots, have been shown to reduce root lodging susceptibility. However, the underlying structural-functional properties of brace roots that prevent root lodging are poorly defined. In this study, we quantified structural mechanical properties, geometry, and bending moduli for brace roots from different whorls, genotypes, and reproductive stages. Using 3-point bend tests, we show that brace root mechanics are variable by whorl, genotype, and reproductive stage. Generally, we find that within each genotype and reproductive stage, the brace roots from the whorl closest to the ground had higher structural mechanical properties and a lower bending modulus than brace roots from the second whorl. There was additional variation between genotypes and reproductive stages. Specifically, genotypes with higher structural mechanical properties also had a higher bending modulus, and senesced brace roots had lower structural mechanical properties than hydrated brace roots. Collectively these results highlight the importance of considering whorl-of-origin, genotype, and reproductive stage for quantification of brace root mechanics, which is important for mitigating crop loss due to root mechanical failure.
The number of lateral hypothalamus orexin/hypocretin neurons contributes to individual differences in cocaine demand
Authors: Pantazis Caroline B. , James Morgan H. , Bentzley Brandon S. , Aston-Jones Gary
Published: February 2019

Lateral hypothalamus (LH) orexin neuron signaling has been implicated in the motivation to seek and take drugs of abuse. The number of LH orexin neurons has been shown to vary with behavioral state and can be upregulated with exposure to drugs of abuse. We sought to determine if the number of LH orexin neurons related to individual differences in motivation (demand) for cocaine in our behavioral economics (BE) paradigm, and whether knockdown of these cells predicted changes in economic demand. We quantified LH orexin cell numbers in animals immediately following our BE paradigm, as well as BE-experienced animals after a two-week period of abstinence to relate the number of LH orexin cells to economic demand for cocaine. We also unilaterally knocked down LH orexin expression prior to BE with an orexin morpholino antisense to determine how reduced orexin numbers impacted cocaine demand. Animals with greater motivation for cocaine (lower demand elasticity) had more LH orexin neurons. Following a two-week abstinence from BE, the number of LH orexin neurons predicted economic demand for cocaine prior to abstinence. Reducing LH orexin cell numbers with antisense decreased motivation for cocaine (increased demand elasticity) without affecting baseline consumption. In addition, the number of spared LH orexin neurons after antisense treatment correlated with individual demand for cocaine. These studies point to a role for the endogenous number of LH orexin neurons in individual differences in motivation for cocaine.
Convergent seed color adaptation during repeated domestication of an ancient new world grain
Authors: Stetter Markus G , Vidal-Villarejo Mireia , Schmid Karl J
Published: February 2019

Out of the almost 2,000 plants that have been selected as crops, only few are fully domesticated, and many intermediates between wild plants and domesticates exist. Genetic constraints might be the reason why incompletely domesticated plants have few characteristic crop traits, and retained numerous wild plant features. Here, we investigate the incomplete domestication of an ancient grain from the Americas, amaranth. We sequenced 121 genomes of the crop and its wild ancestors to show that grain amaranth has been selected three times independently from a single wild ancestor, but has not been fully domesticated. Our analysis identified a MYB-like transcription factor gene as key regulator for seed color variation and shows that the trait was independently converted in Central and South America. We suggest a low effective population size at the time of domestication as potential cause for the lack of adaptation of complex domestication traits. Our results show how genetic constraints influenced domestication and might have set the fate of hundreds of crops.
Reduced competition between tool action neighbors in left hemisphere stroke
Authors: Garcea Frank E. , Stoll Harrison , Buxbaum Laurel J.
Published: February 2019

When pantomiming the use of tools, patients with limb apraxia after left hemisphere stroke (LCVA) produce more spatiotemporal hand action errors with tools associated with conflicting actions for use versus grasp-to-pick-up (e.g., corkscrew) than tools having a single action for both use and grasp (e.g., hammer). There are two possible accounts for this pattern of results. Reduced performance with ‘conflict’ tools may simply reflect weakened automaticity of use action activation, which is evident only when the use and grasp actions are not redundant. Alternatively, poor use performance may reflect reduced ability of appropriate tool use actions to compete with task-inappropriate action representations. To address this issue, we developed a Stroop-like experiment in which 21 LCVA and 8 neurotypical participants performed pantomime actions in blocks containing two tools that were similar (“neighbors”) in terms of hand action or function, or unrelated on either dimension. In a congruent condition, they pantomimed the use action associated with the visually presented tool, whereas in an incongruent condition, they pantomimed the use action for the other tool in the block. Relative to controls and other task conditions, LCVA participants showed reductions in hand action errors in incongruent relative to congruent action trials; furthermore, the degree of reduction in this incongruence effect was related to the participants’ susceptibility to grasp-on-use conflict in a separate test of pantomime to the sight of tools. Support vector regression lesion-symptom mapping analyses identified the left inferior frontal gyrus, supramarginal gyrus, and superior longitudinal fasciculus as core neuroanatomical sites associated with abnormal performance on both tasks. Collectively, the results indicate that weakened activation of tool use actions in limb apraxia gives rise to reduced ability of these actions to compete for task-appropriate selection when competition arises within single tools (grasp-on-use conflict) as well as between two tools (reduced neighborhood effects).
Investigation of the effect of estradiol and subculturing on the receptor expression within hormone-dependent breast cancer cells
Authors: Mallick Avijit , Ahmed Sabbir
Published: February 2019

It is now known that a very crucial role in breast cancer development, prognosis and occurrence is played by the estrogen receptor (ER). The steroid hormone estradiol (E2) acts via two nuclear receptors, estrogen receptor-α (ERα) and estrogen receptor-β (ERβ). E2 was shown previously to increase breast cancer cell proliferation in a dose-dependent manner and also induce apoptosis in long term estrogen deprived breast cancer cells. Studies have also shown that the degree of subculturing affects cell line property including gene expression. The aim of this study was to investigate the effect of E2 concentration on cell proliferation, morphology and ER expression and to investigate the effect of subculturing on the expression of ER. Our results have shown that an increase in E2 concentration was found to increase MCF-7 cell proliferation, but extreme concentrations caused significantly low cell proliferation and induced apoptosis. Moreover, ERα expression was significantly upregulated with an increase in E2 concentration, whereas ERβ2 expression was found to be unchanged at low E2 concentration and significantly upregulated at higher E2 concentration. ERα expression at passage 3 ([E2]=1nM) was significantly downregulated compared to the cells at passage 0, in addition to the significant downregulation of the same at E2 concentrations of 1nM and 10µM compared to the untreated control sample. Overall, our data suggests that high concentration of E2 can reduce proliferation and induce apoptosis in the breast cancer cells. Increased E2 exposure and subculturing also appear to change the ERα expression significantly in the breast cancer cell line.
Work Flows for Cellular Epidemiology, From Conception to Translation
Authors: Nathanson Anton D. , Ngo Lucy , Garbowski Tomasz , Srikantha Abhilash , Wojek Christian , Zeidler Dirk , Knothe Tate Melissa L.
Published: February 2019

The authors have withdrawn their manuscript after issues with the cell viability validation (Fig. 8) were found. In the interest of furthering science and ensuring that clinical decisions are based on best practices and evidence, the issue is described in more detail in the peer-reviewed, published paper: https://www.frontiersin.org/articles/10.3389/fphys.2021.647603/full

Knothe Tate ML, Srikantha A, Wojek C, Zeidler D (2021) Connectomics of Bone to Brain— Probing Physical Renderings of Cellular Experience, Frontiers in Physiology 12: 1018, doi: 10.3389/fphys.2021.647603

As noted in that published work: “Osteocyte coordinates can be extracted from the YOLO classified image set, enabling high throughput analyses of massive datasets, which in the future could include other cellular inhabitants of tissues including blood cells, immune cells, chondrocytes, etc. While the method shows great promise for automated detection of cells, the greatest limitation of the method is the definition of appropriate and unbiased classifiers. The definition of osteocytes as pyknotic and viable based on the number of cell processes was shown to be flawed in a parallel study testing the assumption using biochemical based viability measures (Anastopolous and Knothe Tate, 2021).”

Therefore, the authors do not wish this work to be cited as reference for the project.

If you have any questions, please contact the corresponding author.
Phylogeographic parallelism: concordance of patterns in closely related species illuminates underlying mechanisms in the historically glaciated Tasmanian landscape
Authors: Kreger K. , Shaban B. , Wapstra E. , Burridge C.P.
Published: February 2019

Phylogeography provides a means to understand mechanisms that shaped the distribution and abundance of species, including the role of past climate change. While concordant phylogeographic relationships across diverse taxa suggest shared underlying mechanisms (“phylogeographic parallelism”), it is also possible that similar patterns are the product of different mechanisms (“phylogeographic convergence”), reflecting variation among taxa in factors such as environmental tolerances, life histories, and vagility. Hence, phylogeographic concordance among closely related and ecologically similar species can yield a more confident understanding of the past mechanisms which shaped their distribution and abundance. This study documented mitochondrial and nuclear phylogeographic patterns in the ectotherm skink,Niveoscincus metallicus, which occupies historically glaciated regions of Tasmania, and contrasted these with the closely related and broadly sympatricN. ocellatus. Major phylogeographic breaks were similar in location between the two species, and indicative of isolation caused by retreat from high elevation areas during glaciations, but with long-term persistence at multiple low elevation sites. Hence, Pleistocene glacial refugia were altitudinal rather than latitudinal, a pattern mirrored in other temperate Southern Hemisphere taxa. This study also examined phylogeographic patterns across the intermittently inundated Bassian Isthmus between mainland Australia and the island of Tasmania, and revealed that structuring is similarly maintained when populations were physically isolated during interglacial rather than glacial stages.
Dynamic membrane topology in an unassembled membrane protein
Authors: Seurig Maximilian , Ek Moira , von Heijne Gunnar , Fluman Nir
Published: February 2019

Helical membrane proteins constitute roughly a quarter of all proteomes and perform diverse biological functions. To avoid aggregation, they undergo cotranslational membrane insertion and are typically assumed to attain stable transmembrane topologies immediately upon insertion. To what extent post-translational changes in topology are possible in-vivo and how they may affect biogenesis is incompletely understood. Here, we show that monomeric forms of Small Multidrug Resistance (SMR) proteins display topological dynamics, where the N-terminal transmembrane helix equilibrates between membrane-inserted and non-inserted states. We characterize the kinetics of the process and show how the composition of the helix regulates the topological dynamics. We further show that topological dynamics is a property of the unassembled monomeric protein, as the N-terminal helix becomes fixed in a transmembrane disposition upon dimerization. Membrane protein topology can thus remain dynamic long after cotranslational membrane insertion, and can be regulated by later assembly processes.
Bridging the gap between single-cell migration and collective dynamics
Authors: Thüroff Florian , Goychuk Andriy , Reiter Matthias , Frey Erwin
Published: February 2019

A wealth of experimental data relating to the emergence of collective cell migration as one proceeds from the behavioral dynamics of small cohorts of cells to the coordinated migratory response of cells in extended tissues is now available. Integrating these findings into a mechanistic picture of cell migration that is applicable across such a broad range of system sizes constitutes a crucial step towards a better understanding of the basic factors that determine the emergence of collective cell motion. Here we present a cellular-automaton-based modeling framework, which focuses on the integration of high-level cell functions and their concerted effect on cellular migration patterns. In particular, we adopt a top-down approach to incorporate a coarse-grained description of cell polarity and its response to mechanical cues, and address the impact of cell adhesion on collective migration in cell groups. We demonstrate that the model faithfully reproduces typical cell shapes and movements down to the level of single cells, yet is computationally efficient enough to allow for the simulation of (currently) up to 𝒪(104) cells. To develop a mechanistic picture that illuminates the relationship between cell functions and collective migration, we present a detailed study of small groups of cells in confined circular geometries, and discuss the emerging patterns of collective motion in terms of specific cellular properties. Finally, we apply our computational model at the level of extended tissues, and investigate stress and velocity distributions, as well as front morphologies, in expanding cellular sheets.
Data Driven Modelling of a Chemically Defined Growth Medium for Cupriavidus necator H16
Authors: Azubuike Christopher C , Edwards Martin G , Gatehouse Angharad M. R , Howard Thomas Paul
Published: February 2019

Cupriavidus necator is a Gram-negative soil bacterium of major biotechnological interest. It is a producer of the bioplastic 3-polyhydroxybutyrate, has been exploited in bioremediation processes, and it's lithoautotrophic capabilities suggest it may function as a microbial cell factory upgrading renewable resources to fuels and chemicals. It remains necessary however to develop appropriate experimental resources to permit controlled bioengineering and system optimisation of this microbial chassis. A key resource for physiological, biochemical and metabolic studies of any microorganism is a chemically defined growth medium. Here we use 1 mL micro-well cell cultures, automated liquid handling and a statistical engineering approach to develop a model that describes the effect of key media components and their interactions on C. necator culture cell density. The model is predictive and was experimentally validated against novel media compositions. Moreover, the model was further validated against larger culture volumes at 100 mL and 1 L volumes and found to correlate well. This approach provides valuable and quantifiable insights into the impact of media components on cell growth as well as providing predictions to guide culture scale-up.
HEXOKINASE 1 Control of Post-Germinative Seedling Growth
Authors: Lincoln Matthew J. , Ganpudi Ashwin , Romanowski Andrés , Halliday Karen J.
Published: February 2019

In darkness, PHYTOCHROME INTERACTING FACTOR (PIF)-induced skotomorphogenic seedling growth, is exemplified by increased hypocotyl elongation. HEXOKINASE1 (HXK1), which is also implicated in seedling establishment, can operate as a glycolytic enzyme or as a glucose-activated sensor signalling molecule. Under light and nutrient limiting conditions, the HXK1 sensor-signalling has been shown to control hypocotyl elongation. Little is known of whether HXK1 glycolytic function, or HXK1 and PIF cross-talk, is required to control hypocotyl growth.

We demonstrate HXK1 glycolytic activity is critical for cell expansion, and hypocotyl growth, post-germination. Notably, application of glucose-6-phosphate, the HXK1 enzymatic product, can restore shortgin2-1/hxk1-1mutant hypocotyls to wild-type length. Further, HXK1 sensor-signalling complex components, VHA-B1 and RPT5B, do not contribute to this response, for unlikegin2-1/hxk1-1, thevha-B1andrpt5balleles only disrupt hypocotyl growth following exogenous glucose application.

mRNA-seq analysis illustrates that HXK1 and PIF signalling converge at genes with known roles in light signalling. HXK1 imposes strong regulation on chloroplast and mitochondrial encoded genes, also branched chain amino acid catabolism pathway genes, which can provide a source of respiratory substrates in starvation conditions.

Our study establishes the importance of HXK1 enzymatic function in supporting cell expansion and hypocotyl growth. We demonstrate a degree of cross-talk between HXK1 and PIFs through common target gene set.
mRNA structure regulates protein expression through changes in functional half-life
Authors: Mauger David M. , Cabral B. Joseph , Presnyak Vladimir , Su Stephen V. , Reid David W. , Goodman Brooke , Link Kristian , Khatwani Nikhil , Reynders John , Moore Melissa J. , McFadyen Iain J.
Published: February 2019

Messenger RNAs (mRNAs) encode information in both their primary sequence and their higher order structure. The independent contributions of factors like codon usage and secondary structure to regulating protein expression are difficult to establish as they are often highly correlated in endogenous sequences. Here, we used two approaches, global inclusion of modified nucleotides and rational sequence design of exogenously delivered constructs to understand the role of mRNA secondary structure independent from codon usage. Unexpectedly, highly-expressed mRNAs contained a highly-structured coding sequence (CDS). Modified nucleotides that stabilize mRNA secondary structure enabled high expression across a wide-variety of primary sequences. Using a set of eGFP mRNAs that independently altered codon usage and CDS structure, we find that the structure of the CDS regulates protein expression through changes in functional mRNA half-life (i.e. mRNA being actively translated). This work highlights an underappreciated role of mRNA secondary structure in the regulation of mRNA stability. [150 words]

Highlights

Protein expression from modified mRNAs tends to follow the pattern m1 Ψ > U >mo5U

Protein expression correlates with mRNA thermodynamic stability: Ψ≈ m1Ψ > U > mo5U

A highly structured CDS correlates with high expression

Increased structured mRNAs extend functional half-life
Variable Retention of Differentiation-specific DNA Replication Timing in Human Pediatric Leukemia
Authors: Rivera-Mulia Juan Carlos , Sasaki Takayo , Trevilla-Garcia Claudia , Nakamichi Naoto , Knapp David , Hammond Colin , Chang Bill , Tyner Jeffrey W. , Devidas Meenakshi , Zimmerman Jared , Klein Kyle N. , Somasundaram Vivek , Druker Brian , Gruber Tanja A. , Koren Amnon , Eaves Connie , Gilbert David M.
Published: February 2019

Human B-lineage precursor acute lymphoid leukemias (BCP-ALLs) comprise a group of genetically and clinically distinct disease entities with features of differentiation arrest at known stages of normal B-lineage differentiation. We previously showed BCP-ALL cells display unique and clonally heritable DNA-replication timing (RT) programs; i.e., programs describing the variable order of replication of megabase-scale chromosomal units of DNA in different cell types. To determine the extent to which BCP-ALL RT programs mirror or deviate from specific stages of normal human B-cell differentiation, we transplanted immunodeficient mice with quiescent normal human CD34+ cord blood cells and obtained RT signatures of the regenerating B-lineage populations. We then compared these with RT signatures for leukemic cells from a large cohort of BCP-ALL patients. The results identify BCP-ALL subtype-specific features that resemble specific stages of B-cell differentiation and features that appear associated with relapse. These results suggest the genesis of BCP-ALL involves alterations in RT that reflect clinically relevant leukemia-specific genetic and/or epigenetic changes.

Genome-wide DNA replication timing profiles of >100 pediatric leukemic samples and normally differentiating human B-lineage cells isolated from xenografted immunodeficient mice were generated. Comparison of these identified potentially clinically relevant features that both match and deviate from the normal profiles.
Detection of Base Analogs Incorporated During DNA Replication by Nanopore Sequencing
Authors: Georgieva Daniela , Liu Qian , Wang Kai , Egli Dieter
Published: February 2019

DNA synthesis is a fundamental requirement for cell proliferation and DNA repair, but no tools exist to identify the location, direction and speed of replication forks with base pair resolution. Mammalian cells have the ability to incorporate thymidine analogs along with the natural A, T, G and C bases during DNA synthesis, which allows for labelling of replicating or repaired DNA. Most sequencing platforms rely on base-pairing to identify the four canonical nucleotides, and are thus unable to distinguish them from these analogs. In contrast, the Oxford Nanopore Technologies (ONT) MinION infers nucleotide identity from changes in the ionic current as DNA strands are pulled through nanopores and can in principle differentiate noncanonical nucleotides from natural ones. Here, we demonstrate the use of the ONT MinION to detect 11 different thymidine analogs including CldU, BrdU, IdU, as well as, EdU alone or coupled to Biotin and other bulky adducts in synthetic DNA templates. We also show detection of IdU in the genome of mouse pluripotent stem cells. We find that different modifications generate variable shifts in ionic signals, providing a method of using analog combinations to identify the location and direction of DNA synthesis and repair at high resolution. We conclude that this novel method has the potential for single-base, genome-wide examination of DNA replication in stem cell differentiation or cell transformation.
Dynamics of living cells in a cytomorphological state space
Authors: Chang Amy Y. , Marshall Wallace F.
Published: February 2019

Cells are non-equilibrium systems that rely on a continuous exchange of matter and energy with the environment to sustain their metabolic needs. The non-equilibrium nature of this system presents considerable challenges to developing a general theory describing its behavior; however, studies have demonstrated that when studied at appropriate spatiotemporal scales, the behavior of ensembles of non-equilibrium systems can resemble that of system at equilibrium. Here we apply this principle to a population of cells within a cytomorphological state space and demonstrate that cellular transition dynamics within this space can be suitably described using equilibrium dynamics formalisms. We use this framework to map the effective energy landscape underlying the cytomorphological state space of a population of mouse embryonic fibroblasts (MEFs) and identify topographical non-uniformity in this space, indicating non-uniform occupation of cytomorphological states within an isogenic population. The introduction of exogenous apoptotic agents altered this energy landscape, inducing formation of additional energy minima that correlated directly with changes in sensitivity to apoptotic induction. The measured application of equilibrium dynamics formalism allows us to accurately capture and these findings suggest that though cells are complex non-equilibrium systems, the application of formalisms derived from equilibrium thermodynamics can provide insight into the basis of non-genetic heterogeneities as well as the relationship between morphological and functional heterogeneity.
Assessing the potential impact of Medicaid work requirements on African-Americans via a welfare reform analysis: a systematic review
Authors: Hall Garrett , Burrowes Sahai
Published: February 2019

The Centers for Medicare and Medicaid Services are currently approving Medicaid demonstration projects involving work and community engagement requirements. The fear among public health professionals and policymakers is that these work requirements will disproportionately limit access to health insurance for African-Americans. To investigate these new work requirements for Medicaid, we conducted a systematic review of the Temporary Assistance for Needy Families program, the last major welfare program to have such work requirements. We used the ProQuest database and selected scholarly journal studies in English and published between January 1991-August 2018. Our selection strategy yielded 14 eligible studies, eight of which focused on caseload movements and six focused on sanctions. We found that African-Americans entered TANF at a higher rate than Whites, remained on TANF longer, and were subject to sanctions more frequently and stringently than Whites were. These results suggest that African-Americans may disproportionately experience reduced access to care through sanctioning such as lockout periods. Recommended policy changes include prohibiting work activities as a condition of Medicaid coverage, strengthening Medicaid in other ways, combating discriminatory hiring practices, and easing burdensome reporting requirements.
De novo assembly and annotation of Asiatic lion (Panthera leo persica) genome
Authors: Mitra Siuli , Sreenivas Ara , Sowpati Divya Tej , Kumar Amitha Sampat , Awasthi Gowri , Kumar M. Milner , Tabusum Wajeeda , Gaur Ajay
Published: February 2019

We report the first draft of the whole genome assembly of a male Asiatic lion, Atul and whole transcriptomes of five Asiatic lion individuals. Evaluation of genetic diversity placed the Asiatic lion in the lowest bracket of genomic diversity index highlighting the gravity of its conservation status. Comparative analysis with other felids and mammalian genomes unraveled the evolutionary history of Asiatic lion and its position among other felids. The genome is estimated to be 2.3 Gb (Gigabase) long with 62X sequence coverage and is found to have 20,543 protein-coding genes. About 2.66% of the genome is covered by simple sequence repeats (SSRs) and 0.4% is estimated to have segmental duplications. Comparison with seven well annotated genomes indicates the presence of 6,295 single copy orthologs, 4 co-orthologs, 21 paralogs uniquely present in Asiatic lion and 8,024 other orthologs. Assessment of male and female transcriptomes gave a list of genes specifically expressed in the male.

Our genomic analyses provide candidates for phenotypes characteristic to felids and lion, inviting further confirmation of their contribution through population genetic studies. An Asiatic lion-specific expansion is detected in the Cysteine Dioxygenase-I (CDO-I) family that is responsible for taurine biosynthesis in cats. Wilm’s tumor-associated protein (WT1) family, a non-Y chromosome genetic factor underlying male-sex determination and differentiation is found to have undergone expansion, interestingly like that of the human genome. Another protein family, translation machinery-associated protein 7 (TMA7) that has undergone expansion in humans, also expanded in Asiatic lion and can be further investigated as a candidate responsible for mane in lions because of its role in hair follicle morphogenesis.
Mixed-polarity random-dot stereograms alter GABA and Glx concentration in the early visual cortex
Authors: Rideaux Reuben , Goncalves Nuno , Welchman Andrew E
Published: February 2019

The offset between images projected onto the left and right retinae (binocular disparity) provides a powerful cue to the three-dimensional structure of the environment. It was previously shown that depth judgements are better when images comprise both light and dark features, rather than only dark or only light elements. Since Harris and Parker (1995) discovered the “mixed-polarity benefit”, there has been limited evidence supporting their hypothesis that the benefit is due to separate bright and dark channels. Goncalves and Welchman (2017) observed that single- and mixed-polarity stereograms evoke different levels of positive and negative activity in a deep neural network trained on natural images to make depth judgements, which also showed the mixed-polarity benefit. Motivated by this discovery, here we seek to test the potential for changes in the balance of excitation and inhibition that are produced by viewing these stimuli. In particular, we use magnetic resonance spectroscopy to measure Glx and GABA concentration in the early visual cortex of adult humans while viewing single- and mixed-polarity random-dot stereograms (RDS). We find that observers’ Glx concentration is significantly higher while GABA concentration is significantly lower when viewing mixed-polarity RDS than when viewing single-polarity RDS. These results indicate that excitation and inhibition facilitate processing of single- and mixed-polarity stereograms in the early visual cortex to different extents, consistent with recent theoretical work (Goncalves & Welchman, 2017).
Ribosomal DNA harbors an evolutionarily conserved clock of biological aging
Authors: Wang Meng , Lemos Bernardo
Published: February 2019

The ribosomal DNA (rDNA) is the most evolutionarily conserved segment of the genome and gives origin to the nucleolus, an energy intensive nuclear organelle and major hub influencing myriad molecular processes from cellular metabolism to epigenetic states of the genome. The rDNA/nucleolus has been directly and mechanistically implicated in aging and longevity in organisms as diverse as yeasts, Drosophila, and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity. Here, we introduce an age clock built exclusively with CpG methylation within the rDNA. The ribosomal clock is sufficient to accurately estimate individual age within species, is responsive to genetic and environmental interventions that modulate life-span, and operates across species as distant as humans, mice, and dogs. Further analyses revealed a significant excess of age-associated hypermethylation in the rDNA relative to other segments of the genome, and which forms the basis of the rDNA clock. Our observations identified an evolutionarily conserved marker of aging that is easily ascertained, grounded on nucleolar biology, and could serve as a universal marker to gauge individual age and response to interventions in humans as well as laboratory and wild organisms across a wide diversity of species.
Grazing-incidence X-ray scattering of lamellar thin films
Authors: Smilgies Detlef-M.
Published: February 2019

Recently, surface and thin-film studies using area detectors have become prevalent. An important class of such systems are lamellar thin films formed by small molecules, liquid crystals or semicrystalline polymers. Frequently, the lamellae align more or less parallel to the substrate. Such structures can be easily discerned by their characteristic X-ray scattering close to the incident plane. This paper describes how such patterns can be simulated, in order to extract morphological information about the thin film.
Hydrogen bonding in two benzene-1,2-diaminium pyridine-2-carboxylate salts and a cocrystal of benzene-1,2-diamine and benzoic acid
Authors: Powers Kyle A. , Geiger David K.
Published: February 2019

The isostructural salts benzene-1,2-diaminium bis(pyridine-2-carboxylate), 0.5C6H10N2
2+·C6H4NO2
−, (1), and 4,5-dimethylbenzene-1,2-diaminium bis(pyridine-2-carboxylate), 0.5C8H14N2
2+·C6H4NO2
−, (2), and the 1:2 benzene-1,2-diamine–benzoic acid cocrystal, 0.5C6H8N2·C7H6O2, (3), are reported. All of the compounds exhibit extensive N—H...O hydrogen bonding that results in interconnected rings. O—H...N hydrogen bonding is observed in (3). Additional π–π and C—H...π interactions are found in each compound. Hirshfeld and fingerprint plot analyses reveal the primary intermolecular interactions and density functional theory was used to calculate their strengths. Salt formation by (1) and (2), and cocrystallization by (3) are rationalized by examining pK
a differences. The R
2
2(9) hydrogen-bonding motif is common to each of these structures.
FM perceptions on occupant impact and the shaping of occupant engagement practice
Authors: Valle Cristian Roberto , Verhulst Elli , Pettersen Ida Nilstad , Junghans Antje , Berker Thomas
Published: February 2019

Purpose

This paper aims to apply frame analysis to explore the mental models by which building managers interpret the impact of building occupants on energy use and rationalize their approach to occupant engagement.

Design/methodology/approach

Findings from four energy-efficient buildings (two schools and two office buildings) in Norway are presented. The methodology includes individual semi-structured interviews with both operational and strategic facilities managers

Findings

Concepts and theoretical perspectives with the potential to shape the building managers’ perceptions include technical knowledge and expertise, management responsibilities, familiarity with occupant routines and understanding of energy-efficient technologies. No significant impact was attributed to the actions of occupants in the areas of comfort, core function and behavior. Significant impact was attributed to their movement and presence. Perceptions of impact were found to influence, yet not determine, the building managers’ choices of practice.

Practical implications

Factors with the potential to affect the adoption of occupant engagement initiatives were highlighted. This study pointed to the role that automation and centralization can play in influencing facilities managers to rescind from their management responsibilities.

Originality/value

To the knowledge of the authors, this is the first study to use framings in thoughts to investigate the process by which facilities managers rationalize occupant engagement, in relation to their perception of occupant impact on energy use.
Using informatics to improve healthcare quality
Authors: Otokiti Ahmed
Published: February 2019

Purpose

The purpose of this paper is to provide insights into contemporary challenges associated with applying informatics and big data to healthcare quality improvement.

Design/methodology/approach

This paper is a narrative literature review.

Findings

Informatics serve as a bridge between big data and its applications, which include artificial intelligence, predictive analytics and point-of-care clinical decision making. Healthcare investment returns, measured by overall population health, healthcare operation efficiency and quality, are currently considered to be suboptimal. The challenges posed by informatics/big data span a wide spectrum from individual patients to government/regulatory agencies and healthcare providers.

Practical implications

The paper utilizes informatics and big data to improve population health and healthcare quality improvement.

Originality/value

Informatics and big data utilization have the potential to improve population health and service quality. This paper discusses the challenges posed by these methods as the author strives to achieve the aims.
Iranian hospital efficiency: a systematic review and meta-analysis
Authors: Rezaei Satar , Hajizadeh Mohammad , Nouri Bijan , Ahmadi Sina , Rezaeian Shahab , Salimi Yahya , Karyani Ali Kazemi
Published: February 2019

Purpose

The purpose of this paper (systematic review and meta-analysis) is to synthesize and analyze studies that assessed Iranian hospital efficiency.

Design/methodology/approach

A systematic literature search was conducted using both international (the Institute for Scientific Information, Scopus and PubMed) and Iranian scientific (Magiran, IranMedex and Scientific Information Database) databases. The review included original studies that used the Pabon Lasso Model to examine Iranian hospital performance, published in Persian or English. A self-administered checklist was used to collect data. In total, 12 questions were used for quality assessment.

Findings

In total, 34 studies met our inclusion criteria. The fixed-effects meta-analysis indicated that 19.2 percent (95% confidence interval (CI): 15.6–23.2 percent) of hospitals were in Zone 1 (poor performance: low bed turnover rate (BTR) and bed occupancy rate (BOR) and high average hospital stay (ALoS)), 23.7 percent (95% CI: 20.1–27.8 percent) were in Zone 2, 31.7 percent (95% CI: 27.7–36 percent) in Zone 3 (good performance: high BTR and BOR and low ALoS) and 25.4 percent (95% CI: 21.7–29.5 percent) in Zone 4.

Practical implications

Results help Iranian health policymakers to understand hospital performance, which, in turn, may lead to promoting greater awareness and policy attention to improve Iranian hospital efficiency.

Originality/value

This study indicated that most Iranian hospitals had sub-optimal performance. Further studies are required to understand factors that explain the country’s hospital inefficiency.