bluuebunny/crossref_metadata_2025 huggingface dataset:
Murine bone properties and their relationship to gait during growth
Authors: Song Hyunggwi , Polk John D. , Kersh Mariana E.
Published: November 2018

Allometric relationships have been queried over orders of mammals to understand how bone accommodates the mechanical demands associated with increasing mass. However, less attention has been given to the scaling of bone within a single lifetime. We aimed to determine if bone morphology and apparent density is related to (1) bending and compressive strength, and (2) gait dynamics. Longitudinal in vivo computed tomography and gait data were collected from female rats (n=5, age 8 - 20 weeks). Cross sectional properties and apparent density were measured at the diaphysis, distal, and proximal regions of the tibia and scaling exponents were calculated. Finite-element models were used to simulate four-point bending and axial compression using time-specific ground reaction forces (GRF) to calculate the mean strain energy density (SED) at the midshaft. Second moment of area at the diaphysis followed strain similarity based allometry, while bone area was positively allometric. The average SED at the diaphysis decreased, especially after the age of 10 weeks (R2=0.99), while it increased in compression (R2=0.96). The apparent density in all regions initially increased and converged by 11 weeks of age and this was correlated with changes in joint angle. The scaling analyses implies that rodent tibia is (re)modeled in order to sustain bending at the midshaft during growth. The finite element results and relatively constant density after 10 weeks of age indicate that structural parameters may be the primary determinant of bone strength in the growing rodent tibia. The correlations between bone properties and joint angles imply that the changes in posture may affect bone growth in specific regions.
First Report of Recurrent Genomic Selection with Real Data in Popcorn and Genetic Gain Increases
Authors: Schwantes Ismael Albino , do Amaral Antônio Teixeira , de Almeida Filho Janeo Eustáquio , Vivas Marcelo , Cabral Pablo Diego Silva , Guimarães Amanda Gonçalves , de Lima e Silva Fernando Higino , Santos Pedro Henrique Araújo Diniz , Pereira Messias Gonzaga , Viana Alexandre Pio , Pena Guilherme Ferreira , Ferreira Fernando Rafael Alves
Published: November 2018

Recurrent Selection increases the frequencies of favorable alleles for economically important traits, which in the case of popcorn are popping expansion and grain yield. However, is time-consuming, since each selection cycle consists of three stages: progeny development and evaluation, and recombination of the best families. With the Recurrent Genomic Selection use, the time required for each selection cycle can be shortened, as it allows the evaluation and recombination phases to be performed simultaneously, reducing the time needed to complete one selection cycle to only one growing season. In this respect, the objective of this study was to determine the selection accuracy and genetic gains for different selection strategies: PhEN = estimates based exclusively on the phenotypic data of 98 plants; PhEN + GEN = estimates based exclusively on the phenotypic and genotypic data of 98 plants; and GEN = estimates based exclusively on SNP marker genotyping. The following traits were evaluated: 100-grain weight, ear height, grain yield, popping expansion, plant height, and popcorn volume. Field trials were carried out with 98 S1 progenies, at two locations, in an incomplete block design with three replications. The parents of these progenies were genotyped with a panel of ~ 21K SNPs. From the results based on the predictions by strategy GEN, at different selection intensities, the average annual genetic gain for the different traits was 29.1% and 25.2% higher than that by the strategies PhEN and GEN + PhEN for 98 selection candidates; 148.3% and 140.9% higher for 500; and 187.9% and 179.4% higher for 1,000 selection candidates, respectively. Therefore, recurrent genomic selection may result in a high genetic gain, provided that: i) phenotyping is accurate; ii) selection intensity is explored by genotyping several plants, increasing the number of selection candidates, and iii) genomic selection is used for early selection in recurrent selection.
Evidence of a noncoding transcript of theRIPK2gene overexpressed in head and neck tumor
Authors: Villagra Ulises M. M. , da Cunha Bianca R. , Polachini Giovana M. , Henrique Tiago , da Silva Carlos H. T. P. , Feitosa Olavo A. , Fukuyama Erica E. , López Rossana V. M. , Dias-Neto Emmanuel , Nunes Fabio D. , Severino Patricia , Tajara Eloiza H.
Published: November 2018

Receptor-interacting proteins are a family of serine/threonine kinases, which integrate extra and intracellular stress signals caused by different factors, including infections, inflammation and DNA damage. Receptor-interacting serine/threonine-protein kinase 2 (RIP-2) is a member of this family and an important component of the nuclear factor NF-kappa-B signaling pathway. The corresponding human geneRIPK2generates two transcripts by alternative splicing, the full-length and a short transcript. The short transcript has a truncated 5’ sequence, which results in a predicted isoform with a partial kinase domain but able to transduce signals through its caspase recruitment domain. In this study, the expression ofRIPK2was investigated in human tissue samples and, in order to determine if both transcripts are similarly regulated at the transcriptional level, cancer cell lines were submitted to temperature and acid stresses. We observed that both transcripts are expressed in all tissues analyzed, with higher expression of the short one in tumor samples, and they are differentially regulated following temperature stress. Despite transcription, no corresponding protein for the short transcript was detected in tissues and cell lines analyzed. We propose that the shorter transcript is a noncoding RNA and that its presence in the cell may play regulatory roles and affect inflammation and other biological processes related to the kinase activity of RIP-2.
Homeostatic Controllers Compensating for Growth and Perturbations
Authors: Ruoff Peter , Agafonov Oleg , Tveit Daniel M. , Thorsen Kristian , Drengstig Tormod
Published: November 2018

Cells and organisms have developed homeostatic mechanisms to maintain internal stabilities which protect them against a changing environment. How cellular growth and homeostasis interact is still not well understood, but of increasing interest to the synthetic and molecular biology community where molecular control circuits are sought and tried to maintain homeostasis that opposes the diluting effects of cell growth. In this paper we describe the performance of four negative feedback (inflow) controllers, which, for different observed growth laws (time-dependent increase in the cellular volume V) are able to compensate for various time-dependent removals of the controlled variable A. The four implementations of integral control are based on zero-order, first-order autocatalytic, second-order (antithetic), and derepressing inhibition kinetics. All controllers behave ideal in the sense that they for step-wise perturbations in V and A are able to drive the controlled variable precisely back to the controller’s theoretical set-point

The applied increase in cellular volume includes linear, exponential and saturating growth and reflect experimentally observed growth laws of single cell organisms and other cell types. During the increase in V, additional linear or exponential time-dependent perturbations which remove A are applied, and controllers are tested with respect to their ability to compensate for both the increase in volume V and the applied perturbations removing A. Our results show that the way how integral control is kinetically implemented and the structure of the negative feedback loop are essential determinants of a controller’s performance. The results provide a ranking between the four tested controller types. Considering exponential volume increases together with an exponentially increasing removal rate of A controllers based on derepression kinetics perform best, but break down when the control-inhibitor’s concentration gets too low. The first-order autocatalytic controller is able to defend time-dependent exponential growth and removals in A, but generally with a certain offset below its theoretical set-point

The controllers based on zero-order and second-order (antithetic) integral feedback can only manage linear increases in V and removals in A, in dependence of the controllers’ aggressiveness. Our results provide a theoretical basis what controller kinetics are needed in order to compensate for different growth laws.
Evaluating DNA methylation age on the Illumina’s methylationEPIC BeadChip
Authors: Radhika Dhingra , Kwee Lydia Coulter , Diaz-Sanchez David , Devlin Robert B. , Cascio Wayne , Haynes Carol , Hauser Elizabeth R. , Gregory Simon , Shah Svati , Kraus William , Olden Kenneth , Ward-Caviness Cavin K.
Published: November 2018

DNA methylation age (DNAm age) has become a widely utilized epigenetic biomarker for the aging process. The Horvath method for determining DNAm age is perhaps the most widely utilized and validated DNA methylation age assessment measure. Horvath DNAm age is calculated based on methylation measurements at 353 loci which were present on Illumina’s 450k and 27k DNA methylation microarrays. With the increasing use of the more recently developed Illumina MethylationEPIC (850k) microarray, it is worth revisiting this widely used aging measure to evaluate differences in DNA methylation age estimation based on array design. Of the requisite 353 loci, 17 are missing from the current 850k microarray. Using 17 datasets with 27k, 450k, and/or 850k methylation data, we calculated and compared each sample’s epigenetic age estimated from all 353 loci required from the Horvath DNAm age calculator (full), and using only the 336 loci present on the 27k, 450k, and 850k arrays (reduced). In 450k/27k data, missing loci caused underestimation of epigenetic age when compared with the full clock. Underestimation of full epigenetic age grew from ages 0 to ~20, remaining stable thereafter (mean= −3.46 y, SD=1.13) years for individuals ≥20 years. Underestimation of DNAm age by the reduced 450k/27k data was similar to the underestimation observed in the 850k data indicating that array differences in DNAm age estimation are primarily driven by missing probes. Correlations between age and DNAm age were not dependent on missing probes or on array designs and consequently associations between DNAm age and outcomes such as sex remained the same independent of missing probes and probe design. In conclusion, DNAm age estimations are array dependent driven by missing probes between arrays. Though correlations and associations with DNAm age may remain the same, researchers should exercise caution when interpreting results based on absolute differences in DNAm age or when mixing samples assayed on different arrays.

Disclaimer

This paper has been reviewed by the National Health and Environmental Effects Research Laboratory, U.S. EPA, and is approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the agency, nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The authors declare they have no competing financial interests.
Diversification in the microlepidopteran genusMompha(Lepidoptera: Gelechioidea: Momphidae) is explained more by tissue specificity than host plant family
Authors: Bruzzese Daniel J. , Wagner David L. , Harrison Terry , Jogesh Tania , Overson Rick P. , Wickett Norman J. , Raguso Robert A. , Skogen Krissa A.
Published: November 2018

Insect herbivores and their hostplants constitute much of Earth’s described diversity, but how these often-specialized associations evolve and generate biodiversity is still not fully understood. We combined detailed hostplant data and comparative phylogenetic analyses of the lepidopteran family Momphidae to explore how shifts in the use of hostplant resources, not just hostplant taxonomy, contribute to the diversification of phytophagous insect lineages. We generated two phylogenies primarily from momphid species in the nominate genus,MomphaHübner. A six-gene phylogeny was constructed with exemplars from Onagraceae hosts in western and southwestern USA and a cytochromecoxidase subunit 1 (COI) phylogeny utilized both our collected sequences and publicly available accessions from the Barcode of Life Data System. Coalescent-based analyses combined with morphological data revealed ca. 56 undescribedMomphaspecies-level taxa, many of which are hostplant specialists on southwestern USA Onagraceae. Our phylogenetic reconstructions identified four major momphid clades: 1) an Onagraceae flower- and fruit-feeding clade, 2) a Melastomataceae galling clade, 3) an Onagraceae and Rubiaceae leafmining clade, and 4) a heterogeneous clade associated with multiple hostplant families, plant tissues, and larval feeding modes. Ancestral trait reconstructions on the COI tree identified leafmining on Onagraceae as the ancestral state for Momphidae. Cophylogenetic analyses detected loose phylogenetic tracking of hostplant taxa. Our study finds that shifts along three hostplant resource axes (hostplant taxon, plant tissue type, and larval feeding mode) contributed to the evolutionary success and diversification ofMompha. More transitions between exploited host tissue types than between hostplant families indicated that exploited host tissue (without a change in host) played an unexpectedly large role in the diversification of these moths.
Multimerization of Homo sapiens TRPA1 ion channel cytoplasmic domains
Authors: Martinez Gilbert Q. , Gordon Sharona E.
Published: November 2018

The transient receptor potential Ankyrin-1 (TRPA1) ion channel is modulated by myriad noxious stimuli that interact with multiple regions of the channel, including cysteine-reactive natural extracts from onion and garlic which modify residues in the cytoplasmic domains. The way in which TRPA1 cytoplasmic domain modification is coupled to opening of the ion-conducting pore has yet to be elucidated. The cryo-EM structure of TRPA1 revealed a tetrameric C-terminal coiled-coil surrounded by N-terminal ankyrin repeat domains (ARDs), an architecture shared with the canonical transient receptor potential (TRPC) ion channel family. Similarly, structures of the TRP melastatin (TRPM) ion channel family also showed a C-terminal coiled-coil surrounded by N-terminal cytoplasmic domains. This conserved architecture may indicate a common gating mechanism by which modification of cytoplasmic domains can transduce conformational changes to open the ion-conducting pore. We developed an in vitro system in which N-terminal ARDs and C-terminal coiled-coil domains can be expressed in bacteria and maintain the ability to interact. We tested three gating regulators: temperature; the polyphosphate compound IP6; and the covalent modifier allyl isothiocyanate to determine whether they alter N-and C-terminal interactions. We found that none of the modifiers tested abolished ARD-coiled-coil interactions, though there was a significant reduction at 37°C. We found that coiled-coils tetramerize in a concentration dependent manner, with monomers and trimers observed at lower concentrations. Our system provides a method for examining the mechanism of oligomerization of TRPA1 cytoplasmic domains as well as a system to study the transmission of conformational changes resulting from covalent modification.
BMN 250, a fusion of lysosomal alpha-N-acetylglucosaminidase with IGF2, exhibits different patterns of cellular uptake into critical cell types of Sanfilippo syndrome B disease pathogenesis
Authors: Yogalingam Gouri , Luu Amanda R , Prill Heather , Lo Melanie J. , Yip Bryan , Holtzinger John , Christianson Terri , Aoyagi-Scharber Mika , Lawrence Roger , Crawford Brett E. , LeBowitz Jonathan H.
Published: November 2018

Sanfilippo syndrome type B (Sanfilippo B; Mucopolysaccharidosis type IIIB) occurs due to genetic deficiency of lysosomal alpha-N-acetylglucosaminidase (NAGLU) and subsequent lysosomal accumulation of heparan sulfate (HS), which coincides with devastating neurodegenerative disease. Because NAGLU expressed in Chinese hamster ovary cells is not mannose-6-phosphorylated, we developed an insulin-like growth factor 2 (IGF2)-tagged NAGLU molecule (BMN 250; tralesinidase alfa) that binds avidly to the IGF2 / cation-independent mannose 6-phosphate receptor (CI-MPR) for glycosylation independent lysosomal targeting. BMN 250 is currently being developed as an investigational enzyme replacement therapy for Sanfilippo B. Here we distinguish two cellular uptake mechanisms by which BMN 250 is targeted to lysosomes. In normal rodent-derived neurons and astrocytes, the majority of BMN250 uptake over 24 hours reaches saturation, which can be competitively inhibited with IGF2, suggestive of CI-MPR-mediated uptake. Kuptake, defined as the concentration of enzyme at half-maximal uptake, is 5 nM and 3 nM in neurons and astrocytes, with a maximal uptake capacity (Vmax) corresponding to 764 nmol/hr/mg and 5380 nmol/hr/mg, respectively. Similar to neurons and astrocytes, BMN 250 uptake in Sanfilippo B patient fibroblasts is predominantly CI-MPR-mediated, resulting in augmentation of NAGLU activity with doses of enzyme that fall well below the Kuptake (5 nM), which are sufficient to prevent HS accumulation. In contrast, uptake of the untagged recombinant human NAGLU (rhNAGLU) enzyme in neurons, astrocytes and fibroblasts is negligible at the same doses tested. In microglia, receptor-independent uptake, defined as enzyme uptake resistant to competition with excess IGF2, results in appreciable lysosomal delivery of BMN 250 and rhNAGLU (Vmax=12,336 nmol/hr/mg and 5469 nmol/hr/mg, respectively). These results suggest that while receptor-independent mechanisms exist for lysosomal targeting of rhNAGLU in microglia, BMN 250, by its IGF2 tag moiety, confers increased CI-MPR-mediated lysosomal targeting to neurons and astrocytes, two additional critical cell types of Sanfilippo B disease pathogenesis.
Heterogeneity of Incipient Atrophy Patterns in Parkinson’s Disease
Authors: Maia Pedro D. , Pandya Sneha , Torok Justin , Gupta Ajay , Zeighami Yashar , Raj Ashish
Published: November 2018

Parkinson’s Disease (PD) is a the second most common neurodegenerative disorder after Alzheimer’s disease and is characterized by cell death in the amygdala and in substructures of the basal ganglia such as the substantia nigra. Since neuronal loss in PD leads to measurable atrophy patterns in the brain, there is clinical value in understanding where exactly the pathology emerges in each patient and how incipient atrophy relates to the future spread of disease. A recent seed-inference algorithm combining an established network-diffusion model with an L1-penalized optimization routine led to new insights regarding the non-stereotypical origins of Alzheimer’s pathologies across individual subjects. Here, we leverage the same technique to PD patients, demonstrating that the high variability in their atrophy patterns also translates into heterogeneous seed locations. Our individualized seeds are significantly more predictive of future atrophy than a single seed placed at the substantia nigra or the amygdala. We also found a clear distinction in seeding patterns between two PD subgroups – one characterized by predominant involvement of brainstem and ventral nuclei, and the other by more widespread frontal and striatal cortices. This might be indicative of two distinct etiological mechanisms operative in PD. Ultimately, our methods demonstrate that the early stages of the disease may exhibit incipient atrophy patterns that are more complex and variable than generally appreciated.
Maximizing the quality of NMR automatic metabolite profiling by a machine learning based prediction of signal parameters
Authors: Cañueto Daniel , Navarro Miriam , Bulló Mónica , Correig Xavier , Cañellas Nicolau
Published: November 2018

The quality of automatic metabolite profiling in NMR datasets in complex matrices can be compromised by the multiple sources of variability in the samples. These sources cause uncertainty in the metabolite signal parameters and the presence of multiple low-intensity signals. Lineshape fitting approaches might produce suboptimal resolutions or distort the fitted signals to adapt them to the complex spectrum lineshape. As a result, tools tend to restrict their use to specific matrices and strict protocols to reduce this uncertainty. However, the analysis and modelling of the signal parameters collected during a first profiling iteration can further reduce the uncertainty by the generation of narrow and accurate predictions of the expected signal parameters. In this study, we show that, thanks to the predictions generated, better profiling quality indicators can be outputted and the performance of automatic profiling can be maximized. Thanks to the ability of our workflow to learn and model the sample properties, restrictions in the matrix or protocol and limitations of lineshape fitting approaches can be overcome.
A structure-based approach towards identification of inhibitory fragments for eleven-nineteen-leukemia protein (ENL) YEATS domain
Authors: Heidenreich David , Moustakim Moses , Schmidt Jurema , Merk Daniel , Brennan Paul E. , Fedorov Oleg , Chaikuad Apirat , Knapp Stefan
Published: November 2018

Lysine acetylation is an epigenetic mark that is principally recognized by bromodomains and recently structurally diverse YEATS domains also emerged as readers of lysine acetyl/acylations. Here we present a crystallography-based strategy and the discovery of fragments binding to the ENL YEATS domain, a potential drug target. Crystal structures combined with synthetic efforts led to the identification of a sub-micromolar binder, providing first starting points for the development of chemical probes for this reader domain family.
Genomic architecture and introgression shape a butterfly radiation
Authors: Edelman Nathaniel B. , Frandsen Paul B. , Miyagi Michael , Clavijo Bernardo , Davey John , Dikow Rebecca , García-Accinelli Gonzalo , van Belleghem Steven , Patterson Nick , Neafsey Daniel E. , Challis Richard , Kumar Sujai , Moreira Gilson , Salazar Camilo , Chouteau Mathieu , Counterman Brian , Papa Riccardo , Blaxter Mark , Reed Robert D. , Dasmahapatra Kanchon , Kronforst Marcus , Joron Mathieu , Jiggins Chris D. , McMillan W. Owen , Di Palma Federica , Blumberg Andrew J. , Wakeley John , Jaffe David , Mallet James
Published: November 2018

We here pioneer a low-cost assembly strategy for 20 Heliconiini genomes to characterize the evolutionary history of the rapidly radiating genusHeliconius. A bifurcating tree provides a poor fit to the data, and we therefore explore a reticulate phylogeny forHeliconius. We probe the genomic architecture of gene flow, and develop a new method to distinguish incomplete lineage sorting from introgression. We find that most loci with non-canonical histories arose through introgression, and are strongly underrepresented in regions of low recombination and high gene density. This is expected if introgressed alleles are more likely to be purged in such regions due to tighter linkage with incompatibility loci. Finally, we identify a hitherto unrecognized inversion, and show it is a convergent structural rearrangement that captures a known color pattern switch locus within the genus. Our multi-genome assembly approach enables an improved understanding of adaptive radiation.
Consensus sequence design as a general strategy to create hyperstable, biologically active proteins
Authors: Sternke Matt , Tripp Katherine W. , Barrick Doug
Published: November 2018

Consensus sequence design offers a promising strategy for designing proteins of high stability while retaining biological activity since it draws upon an evolutionary history in which residues important for both stability and function are likely to be conserved. Although there have been several reports of successful consensus design of individual targets, it is unclear from these anecdotal studies how often this approach succeeds, and how often it fails. Here, we attempt to assess generality by designing consensus sequences for a set of six protein families with a range of chain-lengths, structures, and activities. We characterize the resulting consensus proteins for stability, structure, and biological activities in an unbiased way. We find that all six consensus proteins adopt cooperatively folded structures in solution. Strikingly, four out of six of these consensus proteins show increased thermodynamic stability over naturally-occurring homologues. Each consensus protein tested for function maintained at least partial biological activity. Though peptide binding affinity by a consensus-designed SH3 is rather low, Kmvalues for consensus enzymes are similar to values from extant homologues. Though consensus enzymes are slower than extant homologues at low temperature, they are faster than some thermophilic enzymes at high temperature. An analysis of sequence properties shows consensus proteins to be enriched in charged residues, and rarified in uncharged polar residues. Sequence differences between consensus and extant homologues are predominantly located at weakly conserved surface residues, highlighting the importance of these residues in the success of the consensus strategy.

Significance Statement

A major goal of protein design is to create proteins that have high stability and biological activity. Drawing on evolutionary information encoded within extant protein sequences, consensus sequence design has produced several successes in achieving this goal. Here we explore the generality with which consensus design can be used to enhance protein stability and maintain biological activity. By designing and characterizing consensus sequences for six unrelated protein families, we find that consensus design shows high success rates in creating well-folded, hyperstable proteins that retain biological activities. Remarkably, many of these consensus proteins show higher stabilities than naturally-occurring sequences of their respective protein families. Our study highlights the utility of consensus sequence design and informs the mechanisms by which it works.
Systems-level properties of EGFR/Ras/ERK signalling amplify local signals to generate gene expression plasticity
Authors: Davies Alexander E. , Gillies Taryn E. , Siebert Stefan , Pargett Michael , Tobin Savannah J. , Ram Abhineet R. , Juliano Celina , Quon Gerald , Bissell Mina J. , Albeck John G.
Published: November 2018

The EGFR/Ras/ERK signalling pathway is a driver of cancer cell proliferation and metastasis in tumours that exhibit high cell-to-cell heterogeneity. While the signalling activity of this pathway is frequently amplified in tumours, it is not understood how the kinetic aspects of its activation in tumours differ from normal cellular signalling. Using live-cell reporters of ERK signalling in the breast cancer progression series HMT-3522, we found that ERK activity in invasive cells is similar in amplitude to isogenic non-malignant cells but is highly dynamic and more disordered, leading to more heterogeneous expression of ERK target genes. Our analysis reveals that this diversification arises from systems-level functions of the pathway, including intracellular amplification of amphiregulin-mediated paracrine signalling and differential kinetic filtering by genes including Fra-1, c-Myc, and Egr1. Our findings establish a mechanism for the generation of non-genetic tumour cell plasticity arising from the specific quantitative properties of a signal transduction pathway.
Prefrontal cortex creates novel navigation sequences from hippocampal place-cell replay with spatial reward propagation
Authors: Cazin Nicolas , Alonso Martin Llofriu , Chiodi Pablo Scleidorovich , Pelc Tatiana , Harland Bruce , Weitzenfeld Alfredo , Fellous Jean-Marc , Dominey Peter Ford
Published: November 2018

As rats learn to search for multiple sources of food or water in a complex environment, they generate increasingly efficient trajectories between reward sites, across multiple trials. This optimization capacity has been characterized in the Traveling Salesrat Problem (TSP) (de Jong et al (2011). Such spatial navigation capacity involves the replay of hippocampal place-cells during awake states, generating small sequences of spatially related place-cell activity that we call “snippets”. These snippets occur primarily during sharp-wave-ripple (SWR) events. Here we focus on the role of replay during the awake state, as the animal is learning across multiple trials. We hypothesize that snippet replay generates synthetic data that can substantially expand and restructure the experience available to make PFC learning more optimal. We developed a model of snippet generation that is modulated by reward, propagated in the forward and reverse directions. This implements a form of spatial credit assignment for reinforcement learning. We use a biologically motivated computational framework known as ‘reservoir computing’ to model PFC in sequence learning, in which large pools of prewired neural elements process information dynamically through reverberations. This PFC model is ideal to consolidate snippets into larger spatial sequences that may be later recalled by subsets of the original sequences. Our simulation experiments provide neurophysiological explanations for two pertinent observations related to navigation. Reward modulation allows the system to reject non-optimal segments of experienced trajectories, and reverse replay allows the system to “learn” trajectories that is has not physically experienced, both of which significantly contribute to the TSP behavior.

Author Summary

As rats search for multiple sources of food in a complex environment, they generate increasingly efficient trajectories between reward sites, across multiple trials, characterized in the Traveling Salesrat Problem (TSP). This likely involves the coordinated replay of place-cell “snippets” between successive trials. We hypothesize that “snippets” can be used by the prefrontal cortex (PFC) to implement a form of reward-modulated reinforcement learning. Our simulation experiments provide neurophysiological explanations for two pertinent observations related to navigation. Reward modulation allows the system to reject non-optimal segments of experienced trajectories, and reverse replay allows the system to “learn” trajectories that it has not physically experienced, both of which significantly contribute to the TSP behavior.
The distinct biochemical property enables thymidylate kinase as a drug target and participates in pyrimidine drug sensitivity inCandida albicans
Authors: Huang Chang-Yu , Chen Yee-Chun , Wu-Hsieh Betty A. , Fang Jim-Min , Chang Zee-Fen
Published: November 2018

The ability to overcome drug resistance in outbreaks ofCandida albicansinfection is an unmet need in health management. Here, we investigatedCDC8, which encodes thymidylate kinase (TMPK), as a potential drug target for the treatment ofC. albicansinfection. In this study, we found that the specific region spanning amino acids 106-123, namely, the Ca-loop ofC. albicansTMPK (CaTMPK) contributes to the hyperactivity of this enzyme compared to the human enzyme (hTMPK) and to the utilization of deoxyuridine monophosphate (dUMP)/ deoxy-5-Fluorouridine monophosphate (5-FdUMP) as a substrate. Notably, CaTMPK but not hTMPK enables dUTP/5-FdUTP-mediated DNA toxicity in yeast. CRISPR-mediated deletion of this Ca-loop inC. albicansdemonstrated the critical role of this Ca-loop in fungal growth and susceptibility to 5-Fluorouridine (5-FUrd). Moreover, pathogenic and drug-resistantC. albicansclones were similarly sensitive to 5-FUrd. Thus, this study not only identified a target site for the development of CaTMPK-selective drugs but also revealed 5-FUrd to be a potential drug for the treatment ofC. albicansinfection.

Author summary

The emergence of drug-resistantC. albicansstrains is a serious medical concern that may be addressed by targeting an essential fungal enzyme.CDC8encodes thymidylate kinase (TMPK), which is the key enzyme required for dTTP synthesis and is an essential gene for yeast growth. Therefore, the differences of TMPK between human andC. albicanscan be a potential drug targeting site. This study defines a specific Ca-loop unique to CaTMPK fromC. albicans, contributing to hyper-activity over human enzyme (hTMPK). CRSPR-edited deletion of this loop also suppressed the growth ofC. albicans. Moreover, we present evidence that this loop enables dUMP utilization by CaTMPK, but not hTMPK. CaTMPK is also capable of using 5-FdUMP as a substrate, which contributes to 5-FUrd-mediated toxicity. Importantly, we found that many drug resistant pathogenicC. albicansisolates from patients are sensitive to 5-FUrd, which has not been used as a drug against fungal infection.
Mitotic phosphorylation by Nek6 and Nek7 reduces microtubule affinity of EML4 to alter spindle dynamics and promote chromosome congression
Authors: Adib Rozita , Montgomery Jessica M. , Atherton Joseph , O’Regan Laura , Richards Mark W. , Straatman Kees R. , Roth Daniel , Straube Anne , Bayliss Richard , Moores Carolyn A. , Fry Andrew M.
Published: November 2018

EML4 is a microtubule-associated protein that promotes microtubule stability. We show here that EML4 is distributed as punctate foci along the microtubule lattice in interphase but exhibits reduced association with spindle microtubules in mitosis. Microtubule sedimentation and cryo-electron microscopy and 3D reconstruction reveal that EML4 binds via its basic N-terminal domain to the acidic C-terminal tails of α- and β-tubulin on the microtubule surface. The mitotic kinases Nek6 and Nek7 can phosphorylate EML4 N-terminal domain at S144 and S146 in vitro, and depletion of these kinases leads to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only binds inappropriately to mitotic microtubules but also interferes with chromosome congression. Meanwhile, constitutive activation of Nek6 or Nek7 reduces EML4 association with interphase microtubules. Together, these data support a model in which Nek6 and Nek7-dependent phosphorylation promotes dissociation of EML4 from microtubules in mitosis thereby altering microtubule dynamics to enable chromosome congression.
Field induced cell proliferation and death in a thick epithelium
Authors: Sarkar Niladri , Prost Jacques , Jülicher Frank
Published: November 2018

We study the dynamics of a thick polar epithelium subjected to the action of both an electric and a flow field in a planar geometry. We develop a generalized continuum hydrodynamic description and describe the tissue as a two component fluid system. The cells and the interstitial fluid are the two components and we keep all terms allowed by symmetry. In particular we keep track of the cell pumping activity for both solvent flow and electric current and discuss the corresponding orders of magnitude. We study the growth dynamics of tissue slabs, their steady states and obtain the dependence of the cell velocity, net cell division rate, and cell stress on the flow strength and the applied electric field. We find that finite thickness tissue slabs exist only in a restricted region of phase space and that relatively modest electric fields or imposed external flows can induce either proliferation or death.
Defining TP53 pioneering capabilities with competitive nucleosome binding assays
Authors: Yu Xinyang , Buck Michael J.
Published: November 2018

Accurate gene expression requires the targeting of transcription factors (TFs) to regulatory sequences often occluded within nucleosomes. The ability to target a TF binding site (TFBS) within a nucleosome has been the defining characteristic for a special class of TFs known as pioneer factors. Recent studies suggest TP53 functions as a pioneer factor that can target its TFBS within nucleosomes, but it remains unclear how TP53 binds to nucleosomal DNA. To comprehensively examine TP53 nucleosome binding, we competitively bound TP53 to multiple in vitro–formed nucleosomes containing a high- or low-affinity TP53 TFBS located at differing translational and rotational positions within the nucleosome. Stable TP53–nucleosome complexes were isolated and quantified using next-generation sequencing. Our results demonstrate TP53 binding is limited to nucleosome edges with significant binding inhibition occurring within 50 bp of the nucleosome dyad. Binding site affinity only affects TP53 binding for TFBSs located at the same nucleosomal positions; otherwise, nucleosome position takes precedence. Furthermore, TP53 has strong nonspecific nucleosome binding facilitating its interaction with chromatin. Our in vitro findings were confirmed by examining TP53-induced binding in a cell line model, showing induced binding at nucleosome edges flanked by a nucleosome-free region. Overall, our results suggest that the pioneering capabilities of TP53 are driven by nonspecific nucleosome binding with specific binding at nucleosome edges.
DIG-seq: a genome-wide CRISPR off-target profiling method using chromatin DNA
Authors: Kim Daesik , Kim Jin-Soo
Published: November 2018

To investigate whether and how CRISPR-Cas9 on-target and off-target activities are affected by chromatin in eukaryotic cells, we first identified a series of identical endogenous DNA sequences present in both open and closed chromatin regions and then measured mutation frequencies at these sites in human cells using Cas9 complexed with matched or mismatched sgRNAs. Unlike matched sgRNAs, mismatched sgRNAs were highly sensitive to chromatin states, suggesting that off-target but not on-target DNA cleavage is hindered by chromatin. We next performed Digenome-seq using cell-free chromatin DNA (now termed DIG-seq) and histone-free genomic DNA in parallel and found that only a subset of sites, cleaved in histone-free DNA, were cut in chromatin DNA, suggesting that chromatin can inhibit Cas9 off-target effects in favor of its genome-wide specificity in cells.
Upgraded SSRF BL19U2 beamline for small-angle X-ray scattering of biological macromolecules in solution
Authors: Liu Guangfeng , Li Yiwen , Wu Hongjin , Wu Xibo , Xu Xianhui , Wang Weihua , Zhang Rongguang , Li Na
Published: November 2018

The biological small-angle X-ray scattering (BioSAXS) beamline (BL19U2) at the Shanghai Synchrotron Radiation Facility, China, is dedicated exclusively to small-angle scattering experiments for biological macromolecules in solution. With recent advances in data-analysis algorithms and X-ray detectors, SAXS becomes an ideal complementary technique to other structural and biophysical methods, but it can also be applied alone to obtain important structural information. Owing to the increasing interest in solution scattering studies from the biological community, the workload on BL19U2 has steadily risen. A major upgrade of BL19U2 was performed to improve the beamline data quality, to enrich the possible sample environments and to provide a user-friendly interface. These upgrades involved the major components of BL19U2, including the optical system (slits, beamstop), the electronics, the control and acquisition software, and the sample environments, which resulted in improvements to the collected angular range in BL19U2. These upgrades have significantly broadened the scope of macromolecule size (from kilodaltons to gigadaltons) analysed at the beamline. The dedicated BL19U2 BioSAXS beamline now offers fully automated data-collection and remote-control possibilities. These developments have paved the way for high-throughput studies that generate significant quantities of structure information over a short period of time.
Size-exclusion chromatography small-angle X-ray scattering of water soluble proteins on a laboratory instrument
Authors: Bucciarelli Saskia , Midtgaard Søren Roi , Nors Pedersen Martin , Skou Søren , Arleth Lise , Vestergaard Bente
Published: November 2018

Coupling of size-exclusion chromatography with biological solution small-angle X-ray scattering (SEC-SAXS) on dedicated synchrotron beamlines enables structural analysis of challenging samples such as labile proteins and low-affinity complexes. For this reason, the approach has gained increased popularity during the past decade. Transportation of perishable samples to synchrotrons might, however, compromise the experiments, and the limited availability of synchrotron beamtime renders iterative sample optimization tedious and lengthy. Here, the successful setup of laboratory-based SEC-SAXS is described in a proof-of-concept study. It is demonstrated that sufficient quality data can be obtained on a laboratory instrument with small sample consumption, comparable to typical synchrotron SEC-SAXS demands. UV/vis measurements directly on the SAXS exposure cell ensure accurate concentration determination, crucial for direct molecular weight determination from the scattering data. The absence of radiation damage implies that the sample can be fractionated and subjected to complementary analysis available at the home institution after SEC-SAXS. Laboratory-based SEC-SAXS opens the field for analysis of biological samples at the home institution, thus increasing productivity of biostructural research. It may further ensure that synchrotron beamtime is used primarily for the most suitable and optimized samples.
Microscopic behavior and metallic iron morphology from reduction of iron oxide by CO/H2in a fluidized bed
Authors: Lu Feng , Wen Liangying , Zhong Hong , Xu Jian , Zhang Shengfu , Duan Huamei , Yang Zhongqing
Published: November 2018

Fe2O3particles reduced by CO or H2exhibit different metallic iron morphology. To determine the mechanism of metallic iron formation during the reduction of iron oxide particles by CO/H2in a fluidized bed, an innovative multiscale method was used. This method was validated by experimental results. Density functional theory calculations demonstrate that the CO molecule has a strong stretching effect on the iron ion of wustite in the vertical direction, but the H2molecule has no directional force on the structure of wustite. The energy released from CO reduction is used to overcome the energy barrier of iron ion diffusion. However, H2addition will hinder iron ion diffusion by consuming energy. By analysis of the thermogravimetric curves of Fe2O3reduction, it was found that the adsorption ability of H2on the surface of FeO is weaker than that of CO. However, the reduction rate is higher under H2atmosphere, according to Langmuir adsorption isotherm theory. The morphology of metallic iron during the reduction of iron oxide particles by CO/H2was observed with a scanning electron microscope equipped with an energy dispersive X-ray spectroscopy detector
trans-Bis(2,2′-bipyridine-4,4′-dicarboxylic acid-κ2
N,N′)dichloridoruthenium(III) perchlorate
Authors: Soares Lívia Gonçalves Leida , Padilha Diego Silva , Amado Roberto Salgado , Scarpellini Marciela
Published: November 2018

In the crystal structure of the ruthenium(III) complex, trans-[RuIII(dcbpy)2Cl2]ClO4 (dcbpy = 2,2′-bipyridine-4,4′-dicarboxylic acid, C12H8N2O4), the RuIII atom lies on an inversion centre, showing a small distortion in its octahedral environment. The Ru—Cl bond lengths are shorter than those present in the analogous trans-ruthenium(II) compound containing the bipyridine ligand. The C—O distances in the two symmetry-independent carboxylic acid moieties of the ligand are similar in one group, but different in the other. This is probably due to the different intermolecular interactions they experience with neighbouring cationic complexes. The hydrogen-bonding interactions in which they are involved form a three-dimensional structure, similar to those found in coordination polymers.
Technology efficiency or allocation efficiency
Authors: Cai Hailong , Yan Tianyao
Published: November 2018

Purpose

The emergence of mega-farms in middle-income countries like Brazil and Ukraine and the efforts to consolidate small farms into larger ones in China and elsewhere have suggested that new institutional arrangements and technology progress may increase the significant farm economies of size, and therefore challenging the classical inverse relationship (IR) between productivity and farm size. The purpose of this paper is to conduct a research to examine the existence of IR in China’s cereal production and further explore the possible mechanism.

Design/methodology/approach

Based on the panel data concerning farms from 31 provinces in China in 2009–2014, technology efficiency and allocation efficiency in cereal production were measured based on the Translog production function.

Findings

In China, an IR exists between wheat, rice and maize production after controlling the related variables. Further, the presence of this IR is due to allocation efficiency rather than technology efficiency. Results of technology efficiency show that there is no significant difference between different size groups; in other words, even the larger size groups enjoy a higher technology efficiency in rice production. Results of allocation efficiency demonstrate that, compared with the larger farms, smaller holders tend to invest more in factors which are beneficial in growing productivity. Hence, yields of small-size farms exceed those of large-size farms, which consequently leads to the IR.

Practical implications

The scale consolidation of cropland is harmless to the efficiency of factor utilization and, conversely, may contribute in improving the technology efficiency of specific crops (like rice). Based on the results of allocation efficiency estimation, the extent of misallocation in large scales is relatively less due to their less input of fertilizer and pesticide; thus, the size-improving policy of farmland may contribute to the ease of the non-point pollution in agriculture.

Originality/value

The existing discussions of the IR in the context of recent China mainly focus on the accurate verification of IRs. This paper steps forward from the perspective of technology efficiency and allocation efficiency and explores the exact resources of IR with up-to-date and representative data and hopes to find some new conclusions.