bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mesoscale, Cantilever-Based Indentation Device for Mechanical Characterization of Soft Matter and Biological Tissue
Authors: Rubiano Andres , Simmons Chelsey S. 
Published: September 2019

AbstractTissue engineering has been driving a growing interest in mesoscale tissue mechanics (10−4 – 10−2 m), requiring tools to compare modulus between irregularly shaped primary tissue explants and synthetic scaffolds. We have designed and built a simple cantilever-based mesoscale indentation device to record force-displacement data during spring-loading, stress-relaxation, and creep experiments. Its simple design enables quantification of a wide range of soft matter moduli, from ~500 Pa collagen hydrogels to ~2 MPa silicones, by its compatibility with cantilevers of different stiffnesses and indentation probes of different sizes. A piezo-electric stage is used to drive a cylindrical or spherical indentation tip into the sample, while custom programming in LabVIEW through a data acquisition card enables stage control and acquisition of cantilever deflection using a capacitive sensor. Cantilever stiffness, deflection, and piezoelectric stage positions, acquired at a rate of 10Hz, are used to calculate force and indentation depth throughout indentation cycles. Using xyz manual coarse stages, tissue properties can be mapped across the sample surface. We have also built in commands to tune initial tip location using the piezo-stage to more easily find the sample surface, which is critical for accurate application of contact models. Here, we provide detailed information on how to design, build, and code a system for mesoscale indentation.
Shift in worker physiology and gene expression pattern from reproductive to diapause-like with colony age in the bumble beeBombus impatiens
Authors: Treanore Erin D. , Kiner Jacklyn M. , Kerner Mackenzie E. , Amsalem Etya 
Published: September 2019

AbstractInsects maximize their fitness by exhibiting predictable and adaptive seasonal patterns in response to changing environmental conditions. These seasonal patterns are often expressed even when insects are kept in captivity, suggesting they are functionally and evolutionary important.In this study we examined whether workers of the eusocial bumble beeBombus impatiensmaintained a seasonal signature when kept in captivity. We used an integrative approach and compared worker egg-laying, ovarian activation, body size and mass, lipid content in the fat body, cold tolerance and expression of genes related to cold tolerance, metabolism, and stress throughout colony development.We found that bumble bee worker physiology and gene expression patterns shift from reproductive-like to diapause-like as the colony ages. Workers eclosing early in the colony cycle had increased egg-laying and ovarian activation, and reduced cold tolerance, body size, mass, and lipid content in the fat body, in line with a reproductive-like profile, while late-eclosing workers exhibited the opposite characteristics. Furthermore, expression patterns of genes associated with reproduction and diapause differed between early- and late-eclosing workers, partially following the physiological patterns.We suggest that a seasonal signature, innate to individual workers, the queen or the colony is used by workers as a social cue determining the phenology of the colony and discuss possible implications for understanding reproductive division of labor in bumble bee colonies and the evolutionary divergence of female castes in the genusBombus.
Example Based Hebbian Learning may be sufficient to support Human Intelligence
Authors: Wong Eric C. 
Published: September 2019

AbstractIn this hypothesis paper we argue that when driven by example behavior, a simple Hebbian learning mechanism can form the core of a computational theory of learning that can support both low level learning and the development of human level intelligence. We show that when driven by example behavior Hebbian learning rules can support semantic, episodic and procedural memory. For humans, we hypothesize that the abilities to manipulate an off-line world model and to abstract using language allow for the generation and communication of rich example behavior, and thereby support human learning and a gradual increase of collective human intelligence across generations. We also compare the properties of Example Based Hebbian (EBH) learning with those of backpropagation-based learning and argue that the EBH mechanism is more consistent with observed characteristics of human learning.
Lineage-specific control of convergent differentiation by a Forkhead repressor
Authors: Mizeracka Karolina , Rogers Julia M. , Rumley Jonathan D. , Shaham Shai , Bulyk Martha L. , Murray John I. , Heiman Maxwell G. 
Published: September 2019

ABSTRACTDuring convergent differentiation, multiple developmental lineages produce a highly similar or identical cell type. However, few molecular players that drive convergent differentiation are known. Here, we show that the C. elegans Forkhead transcription factor UNC-130 is required in only one of three convergent lineages that produce the same glial cell type. UNC-130 acts transiently as a repressor in progenitors and newly-born terminal cells to allow the proper specification of cells related by lineage rather than by cell type or function. Specification defects correlate with UNC-130:DNA binding, and UNC-130 can be functionally replaced by its human homolog, the neural crest lineage determinant FoxD3. We propose that, in contrast to terminal selectors that activate cell-type specific transcriptional programs in terminally differentiating cells, UNC-130 acts early and specifically in one convergent lineage to produce a cell type that also arises from molecularly distinct progenitors in other lineages.
Adaptation Within Embryonic and Neonatal Heart Environment Reveals Alternative Fates for Adult c-Kit+Cardiac Interstitial Cells
Authors: Wang Bingyan J. , Alvarez Roberto , Muliono Alvin , Sengphanith Sharon , Monsanto Megan M. , Weeks Joi , Sacripanti Roberto , Sussman Mark A. 
Published: September 2019

AbstractCardiac interstitial cells (CIC) perform essential roles in myocardial biology through preservation of homeostasis as well as response to injury or stress. Studies of murine CIC biology reveal remarkable plasticity in terms of transcriptional reprogramming and ploidy state with important implications for function. Despite over a decade of characterization andin vivoutilization of adult c-Kit+CIC (cCIC), adaptability and functional responses upon delivery to adult mammalian hearts remain poorly understood. Limitations of characterizing cCIC biology followingin vitroexpansion and adoptive transfer into the adult heart were circumvented by delivery of the donated cells into early cardiogenic environments of embryonic, fetal, and early postnatal developing hearts. These three developmental stages were permissive for retention and persistence, enabling phenotypic evaluation ofin vitroexpanded cCICs after delivery as well as tissue response following introduction to the host environment. Embryonic blastocyst environment prompted cCIC integration into trophectoderm as well as persistence in amniochorionic membrane. Delivery to fetal myocardium yielded cCIC perivascular localization with fibroblast-like phenotype, similar to cCICs introduced to postnatal P3 heart with persistent cell cycle activity for up to 4 weeks. Fibroblast-like phenotype of exogenously transferred cCICs in fetal and postnatal cardiogenic environments is consistent with inability to contribute directly toward cardiogenesis and lack of functional integration with host myocardium. In contrast, cCICs incorporation into extra-embryonic membranes is consistent with fate of polyploid cells in blastocysts. These findings provide insight into cCIC biology, their inherent predisposition toward fibroblast fates in cardiogenic environments, and remarkable participation in extra-embryonic tissue formation.
Data-based RNA-seq Simulations by Binomial Thinning
Authors: Gerard David 
Published: September 2019

AbstractWith the explosion in the number of methods designed to analyze bulk and single-cell RNA-seq data, there is a growing need for approaches that assess and compare these methods. The usual technique is to compare methods on data simulated according to some theoretical model. However, as real data often exhibit violations from theoretical models, this can result in un-substantiated claims of a method’s performance. Rather than generate data from a theoretical model, in this paper we develop methods to add signal to real RNA-seq datasets. Since the resulting simulated data are not generated from an unrealistic theoretical model, they exhibit realistic (annoying) attributes of real data. This lets RNA-seq methods developers assess their procedures in non-ideal (model-violating) scenarios. Our procedures may be applied to both single-cell and bulk RNA-seq. We show that our simulation method results in more realistic datasets and can alter the conclusions of a differential expression analysis study. We also demonstrate our approach by comparing various factor analysis techniques on RNA-seq datasets. Our tools are available in theseqgendiffR package on the Comprehensive R Archive Net-work:https://cran.r-project.org/package=seqgendiff.
A metabolic pathway for bile acid dehydroxylation by the gut microbiome
Authors: Funabashi Masanori , Grove Tyler L. , Pascal Victoria , Varma Yug , McFadden Molly E. , Brown Laura C. , Guo Chunjun , Medema Marnix H. , Almo Steven C. , Fischbach Michael A. 
Published: September 2019

ABSTRACTThe gut microbiota synthesize hundreds of molecules, many of which are known to impact host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at ~500 μM and are known to blockC. difficilegrowth1, promote hepatocellular carcinoma2, and modulate host metabolism via the GPCR TGR53. More broadly, DCA, LCA and their derivatives are a major component of the recirculating bile acid pool4; the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Despite the clear impact of DCA and LCA on host physiology, incomplete knowledge of their biosynthetic genes and a lack of genetic tools in their native producer limit our ability to modulate secondary bile acid levels in the host. Here, we complete the pathway to DCA/LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the 8-step conversion of cholic acid to DCA. We then engineer the pathway intoClostridium sporogenes, conferring production of DCA and LCA on a non-producing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool, and provide a road map for deorphaning and engineering pathways from the microbiome as a critical step toward controlling the metabolic output of the gut microbiota.
The CRY1 tail controls circadian timing by regulating its association with CLOCK:BMAL1
Authors: Parico Gian Carlo G. , Perez Ivette , Fribourgh Jennifer L. , Hernandez Britney N. , Lee Hsiau-Wei , Partch Carrie L. 
Published: September 2019

AbstractCircadian rhythms are generated by a transcription-translation feedback loop that establishes cell-autonomous biological timing of ~24-hours. A prevalent human variation in the core clock gene cryptochrome 1, Cry1Δ11, lengthens circadian period to cause Delayed Sleep Phase Disorder (DSPD). CRY1 has a 55 kDa photolyase homology region (PHR) followed by a ~100 residue tail that is intrinsically disordered; the Δ11 variant lacks a short segment encoded by Exon 11 within its tail. We show here that the disordered tail of CRY1 interacts directly with its PHR, and that Exon 11 is necessary and sufficient to disrupt the interaction between CRY1 and CLOCK, a subunit of the primary circadian transcription factor. Competition between PER2 and the tail for the CRY1 PHR suggests a regulatory role for the tail in the early morning, when CRY1 binds to CLOCK:BMAL1 on DNA independently of PER2. Discovery of this autoregulatory role for mammalian CRY1 highlights functional conservation with plant and insect cryptochromes, which also utilize PHR-tail interactions to reversibly control their activity.One Sentence SummaryThe disordered tail of the CRY1 protein regulates interactions between CRY1 and other core circadian rhythm proteins.
C17orf53 defines a novel pathway involved in inter-strand crosslink repair
Authors: Wang Chao , Chen Zhen , Su Dan , Tang Mengfan , Nie Litong , Zhang Huimin , Feng Xu , Wang Rui , Shen Xi , Srivastava Mrinal , McLaughlin Megan E. , Hart Glen Traver , Li Lei , Chen Junjie 
Published: September 2019

SummaryATR kinase is a master regulator of genome maintenance and participates in DNA replication and various DNA repair pathways. In a genome-wide screening for ATR-dependent fitness genes, we identified a previously uncharacterized gene, C17orf53, whose loss led to hypersensitivity to ATR inhibition. C17orf53 is conserved in vertebrate and is required for efficient cell proliferation. Loss of C17orf53 slowed down DNA replication and led to pronounced ICL repair defect. Further genetic analyses revealed that C17orf53 functions downstream in ICL repair pathway, probably by affecting the loading of repair factors such as RAD54. In addition, we showed that C17orf53 is a ssDNA- and RPA-binding protein, both of which are important for its functions in the cell. Taken together, C17orf53 is a novel component involved in ICL repair pathway.
Structural Pathway for Allosteric Activation of the Autophagic PI 3-Kinase Complex I
Authors: Young Lindsey N. , Goerdeler Felix , Hurley James H. 
Published: September 2019

AbstractAutophagy induction by starvation and stress involves the enzymatic activation of the class III phosphatidylinositol 3-kinase complex I (PI3KC3-C1). The inactive basal state of PI3KC3-C1 is maintained by inhibitory contacts between the VPS15 protein kinase and VPS34 lipid kinase domains that restrict the conformation of the VPS34 activation loop. Here, the pro-autophagic MIT domain-containing protein NRBF2 was used to map the structural changes leading to activation. Cryo-EM was used to visualize stepwise PI3KC3-C1 activating effects of binding the NRFB2 MIT domains. Binding of a single NRBF2 MIT domain to bends the helical solenoid of the VPS15 scaffold, displaces the protein kinase domain of VPS15, and releases the VPS34 kinase domain from the inhibited conformation. Binding of a second MIT stabilizes the VPS34 lipid kinase domain in an active conformation that has an unrestricted activation loop and is poised for access to membranes.
An integrated Asian human SNV and indel benchmark combining multiple sequencing methods
Authors: Huang Chuanfeng , Shao Libin , Qu Shoufang , Rao Junhua , Cheng Tao , Cao Zhisheng , Liu Sanyang , Hu Jie , Liang Xinming , Shang Ling , Chen Yangyi , Liang Zhikun , Zhang Jiezhong , Chen Peipei , Luo Donghong , Zhu Anna , Yu Ting , Zhang Wenxin , Fan Guangyi , Chen Fang , Huang Jie 
Published: September 2019

AbstractPrecision medicine of human requires an accurate and complete reference variant benchmark for different populations. A human standard cell line of NA12878 provides a good reference for part of the human populations, but it is still lack of a fine reference standard sample and variant benchmark for the Asians. Here, we constructed a stabilized cell line of a Chinese Han volunteer. We received about 4.16T clean data of the sample using eight sequencing strategies in different laboratories, including two BGI regular NGS platforms, three Illumina regular NGS platforms, two linked-read libraries, and PacBio CCS model. The sequencing depth and reference coverage of eight sequencing strategies have reached the saturation. We detected small variants of SNPs and Indels using the eight data sets and obtained eight variant sets by performing a series of strictly quality control. Finally, we got 3.35M SNPs and 349K indels supported by all of sequencing data, which could be considered as a high confidence standard small variant sets for the studies. Besides, we also detected 5,913 high quality SNPs located in the high homologous regions supported by both linked-reads and CCS data benefited by their long-range information, while these regions are recalcitrant to regular NGS data due to the limited mappability and read length. We compared the later SNPs against the public databases and 969 sites of them were novel SNPs, indicating these SNPs provide a vital complement for the variant database. Moreover, we also phased more than 99% heterozygous SNPs also supported by linked-reads and CCS data. This work provided an integrated Asians SNV and indel benchmark for the further basic studies and precision medicine.
The impact of pH onClostridioides difficilesporulation and physiology
Authors: Wetzel Daniela , McBride Shonna M. 
Published: September 2019

ABSTRACTClostridioides difficileis a pathogenic bacterium that infects the human colon to cause diarrheal disease. Growth of the bacterium is known to be dependent on certain bile acids, oxygen levels and nutrient availability in the intestine, but how the environmental pH can influenceC. difficileis mostly unknown. Previous studies indicated thatC. difficilemodulates the intestinal pH, and prospective cohort studies have found a strong association between a more alkaline fecal pH andC. difficileinfection. Based on these data we hypothesized thatC. difficilephysiology can be affected by various pH conditions. In this study, we investigated the impact of a range of pH conditions onC. difficileto assess potential effects on growth, sporulation, motility and toxin production in the strains 630∆ermand R20291. We observed pH-dependent differences in sporulation rate, spore morphology and viability. Sporulation frequency was lowest under acidic conditions, and differences in cell morphology were apparent at low pH. In alkaline environments,C. difficilesporulation was greater for strain 630∆erm, whereas R20291 produced relatively high levels of spores in a broad range of pH conditions. Rapid changes in pH during exponential growth impacted sporulation similarly among the strains. Furthermore, we observed an increase inC. difficilemotility with increases in pH, and strain-dependent differences in toxin formation under acidic conditions. The data demonstrate that pH is an important parameter that affectsC. difficilephysiology and may reveal relevant insights into the growth and dissemination of this pathogen.IMPORTANCEClostridioides difficileis an anaerobic bacterium that causes gastrointestinal disease.C. difficileforms dormant spores, which can survive harsh environmental conditions, allowing their spread to new hosts. In this study, we determine how intestinally relevant pH conditions impactC. difficilephysiology in the two divergent strains, 630∆erm and R20291. Our data demonstrate that low pH conditions reduceC. difficilegrowth, sporulation, and motility. However, toxin formation and spore morphology are differentially impacted in the strains at low pH. In addition, we observed that alkaline environments reducedC. difficilegrowth, but increased cell motility. When pH was adjusted rapidly during growth, we observed similar impacts on both strains. This study provides new insights into the phenotypic diversity ofC. difficilegrown under the diverse pH conditions present in the intestinal tract, and demonstrates similarities and differences in the pH responses of differentC. difficileisolates.
A genetic algorithm approach for balancing two-sided assembly lines with setups
Authors: Delice Yilmaz 
Published: September 2019

Purpose
This paper aims to discuss the sequence-dependent forward setup time (FST) and backward setup time (BST) consideration for the first time in two-sided assembly lines. Sequence-dependent FST and BST values must be considered to compute all of the operational times of each station. Thus, more realistic results can be obtained for real-life situations with this new two-sided assembly line balancing (ALB) problem with setups consideration. The goal is to obtain the most suitable solution with the least number of mated stations and total stations.

Design/methodology/approach
The complex structure it possesses has led to the use of certain assumptions in most of the studies in the ALB literature. In many of them, setup times have been neglected or considered superficially. In the real-life assembly process, potential setup configurations may exist between each successive task and between each successive cycle. When two tasks are in the same cycle, the setup time required (forward setup) may be different from the setup time required if the same two tasks are in consecutive cycles (backward setup).

Findings
Algorithm steps have been studied in detail on a sample solution. Using the proposed algorithm, the literature test problems are solved and the algorithm efficiency is revealed. The results of the experiments revealed that the proposed approach finds promising results.

Originality/value
The sequence-dependent FST and BST consideration is applied in a two-sided assembly line approach for the first time. A genetic algorithm (GA)-based algorithm with ten different heuristic rules was used in this proposed model.
The strategic and operational landscape of emergency services in the UK
Authors: Murphy Peter , Wankhade Paresh , Lakoma Katarzyna 
Published: September 2019

Purpose
The organisational and service delivery landscape of the emergency services in the UK has been rapidly changing and is facing further change in the foreseeable future. The purpose of this paper is to examine recent and ongoing organisational changes in the policy development, service delivery and regulatory landscape of the emergency services, in order to capture the overall picture and potential opportunities for improvement or further investigation.

Design/methodology/approach
This general review utilises the characteristics of the three domains of a national framework, namely, policy development, service delivery and public assurance, and uses these characteristics as lenses to examine the three main blue light emergency services of police, fire and ambulances.

Findings
What emerges in the organisational landscape and conceptual maps for the police and even more so for the Fire and Rescue Service, is the immaturity of many of the organisations in the policy and the public assurance domains while the service delivery organisations have remained relatively stable. In the relatively neglected ambulance services, we find the NHS’s recent Ambulance Response Programme has considerable potential to improve parts of all three domains.

Research limitations/implications
The review is limited to the UK and primarily focussed on England.

Practical implications
The review identifies opportunities for improvement, potential improvement and further research.

Originality/value
Although the National Audit Office has attempted in the past to provide organisational landscape reviews of individual emergency services, this contemporary comparative review of all three services using a common model is unique. It provides considerable new insights for policy makers, service delivers and regulators.