bluuebunny/crossref_metadata_2025 huggingface dataset:
The Spaces of Childhood
Authors: Gutman Marta , Clark Marci
Published: January 2019

Children’s places are an integral part of childhood because children are human beings who use, invent, experience, and make space. Space and childhood are mutually constitutive, with children’s spaces offering a measure of any society’s attitude toward children, both historically and in the present day. And yet the study of the physical spaces of childhood is an emerging field, forming a relatively new topic of interest to historians, architectural historians, geographers, ethnographers, and others who are invested in the study of children, childhood, and space. Cumulatively, the works cited in this bibliography deal with a range of ages, from birth to at least the teenage years—although who is considered a child varies with the social and historical context under consideration in each work. Some scholars investigate children as social actors in their own right, who use and interpret spaces on their own terms, inventing places for themselves and reinventing the settings that adults have made for them. For others, physical space offers a unique and useful lens to understanding childhood as an ideal imagined by adults and as a socially constructed condition, shaped by social class, race, gender, age, and so forth. Since space is also where childhood is lived, the material world is ripe for the study of lived experiences—of how children use, interpret, make, shape, and imagine space. One topic stands out in the new, exciting field of the spaces of childhood: space, childhood, children, and material culture in relationship to modernity. Spaces made for children have been pivotal to the construction of modernity in global society, as a world without places made specifically for children was transformed into one full of spaces made especially for them. Adults inscribed their objectives for modern children and their childhoods into modern physical spaces that isolated children from adults; accelerated the imposition of colonial structures of power, knowledge, and discipline on children; socialized children, directing them to gender-, race-, and class-specific futures in the adult world; and enabled consumption of special objects made specifically for boys and girls. These places also inscribed the ideal of the “good childhood,” one that is happy, free, and connected to nature, into the physical landscapes of modernizing cities. By demonstrating a child’s right to childhood, many places have become sites where children have been enabled to make their own decisions about consumption, play, and other aspects of their public and private lives.
Children as Perpetrators of Crime
Authors: McDiarmid Claire
Published: January 2019

Childhood studies recognizes that children are participants in society and questions accepted aspects of their disempowerment. It identifies what children do and, in so doing, recognizes their agency. In relation to the criminal law, this can create tension with the notion of the child as an innocent in need of protection coming into direct conflict with the concept of him/her as (responsible and wrongdoing) offender. This issue arises both in relation to the paradox of the individual child offender who embodies both characteristics simultaneously (McDiarmid 2007, cited under Youth Justice Including Rights-Based Approaches) and in relation to the polarized categorization of children into innocents and evildoers (Fionda 2005 and Rosier 2011, both cited under Innocence Versus Evil). For some, there appears to be little difficulty in accepting that children have the ability to commit, and to be accountable for, serious crimes; and an unquestioning acceptance of the child’s agency might accentuate this tendency. In fact, however, childhood studies offers a much richer perspective. Its application in relation to children as perpetrators of crime, therefore, offers the opportunity of placing behavior constituting a criminal act in the broader context of the child’s own social world. Its direct application in this area has been relatively limited, but the breadth of perspective it brings to issues of criminal responsibility is profound. In general, literature on children as perpetrators of crime applies childhood studies merely as one element in placing their criminal responsibility within the broader context of their lives and experiences. While there is a vast literature, then, on juvenile justice, only a small proportion directly (or even indirectly) engages with childhood studies. Childhood studies as a discipline has also engaged quite minimally with children who offend in a direct sense, but much of its literature offers a base from which to pursue questions of responsibility and agency that are central to this field.
The Hebrew Story in the Middle Ages
Authors: Yassif Eli
Published: January 2019

Hebrew narratives of the Middle Ages covers a period of about a thousand years, starting approximately from the Moslem invasions in the mid-7th century to mid-17th century. It also covers a great variety of cultural spaces, from Palestine to Babylon (Iraq), Europe, North Africa, and parts of the New World. It should be emphasized that Hebrew was not the only language in which narratives were created and disseminated in Jewish culture of the time; Aramaic, Judeo-Arabic, Yiddish, and Judeo-Spanish were among the Jewish dialects in which narratives were created. However, the following article will deal with Hebrew narratives only, which, like medieval Latin narrative, was the all-inclusive Jewish language that could establish communication between the various communities and cultural spaces. Hebrew narrative of the period is characterized by a great diversity. This is seen from the sources in which these narratives were included: collections of tales, historical chronicles, biblical and Talmudic interpretations, legal (halachic) codices, philosophical tractates; travel journals, sermons, mystical visions, and more. However, the world of Jewish storytelling in the Middle Ages stood for many years in the shadow of Hebrew poetry of the period, due to cultural and social Jewish ideologies of the 19th century, that continued into the 20th century. It was not until the late 1960s that this discipline was established as a legitimate branch of Jewish literature. Since then it became a full field of study: research of individual tales to full study of large collections of medieval Hebrew tales; critical editions of central books; studies of typical genres such as fables, exempla, legends, and demonological and fabulous tales; and studies of surveys of seminal archives and libraries as the Geniza and the Bodleian Library. Studies also center around the main stages and historical events of this long period: the establishment of Jewish medieval communities, the transfer of Jewish wisdom centers from the East to the West, the events around the Crusader movement, the expulsion from Spain in late 15th century: actually every major or local event in Jewish history of the time was followed by narratives of some kind. Hebrew narratives of the Middle Ages, was an essential part of Jewish culture of the period. It did not only react to the major historical events but also reflected important aspects of Jewish life that were not known from any other historical or legal sources. It also, and even more important, took part in the major debates and controversies that conducted Jewish life of the time, and reflected its diversity and changes.
Literati Culture
Authors: Roddy Stephen
Published: January 2019

Although the term literati culture (wenren wenhua) entered the Chinese lexicon only in the late 20th century, the aesthetic, moral, and intellectual pursuits it encompasses can be traced back nearly two millennia to the Wei-Jin era (220–420 ce). In its narrowest sense, it denotes the “four arts” (siyi) associated with cultured, literate males (wenren): music (especially the qin or guqin), the game of go (weiqi), calligraphy, and painting, as well as poetry and lyrical essays (especially xiaopin) associated with them. Literati culture is also usually construed to include connoisseurship of various categories of material objects, including tea and its implements, antique paintings and specimens of calligraphy, celebrated or rare manuscripts and book editions, rubbings taken from steles, ancient bronze vessels, and objets d’art associated with writing, such as ink stones or seals. During the mature phase of literati culture in the late Ming and Qing dynasties, this repertoire of practices further widened to include, inter alia, the collecting of any manner of rare or prized objects (both natural and man-made), garden design and architecture, the connoisseurship of the theater and its actors or other entertainers, and the espousal of philosophical ideals associated with leisure or reclusion. Given this expansive scope, scholarship has tended to treat this array of arts and avocations either through disciplinary lenses such as art history and material culture, or in terms of their associations with the principal intellectual vocations—literature (the so-called wenyuan or Garden of Literature) and textual scholarship (rulin or Forest of Scholarship)—that marked literati status. As the relatively elastic conception of literati culture has gained currency, however, cultural historians have increasingly studied these arts within the continuum of socioeconomic practices that marked membership in the elite, and also in light of the position of these arts in relation to more-demotic (tongsu) cultural forms. The growth of literati avocations and the writings about them after c. 1500 was stimulated by the surfeit of first- and second-tier examination holders, along with opportunities for patronage by wealthy merchants in the Yangzi delta region. Also evident in the late Ming and throughout the Qing is the influence of philological scholarship (kaozheng) on the classification or cataloguing of objects of various kinds. Finally, the statecraft-oriented (jingshi) scholarship and letters that flourished during the last century of Qing rule, and critiques of literati social preeminence relative to other vocations and social categories, stimulated the rethinking of the social and cultural institutions that perpetuated their dominance, which extended to the arts associated with the literati as well.
Antidepressant Use Among People Prescribed Opioids for Chronic Noncancer Pain
Authors: Gisev Natasa , Nielsen Suzanne , Campbell Gabrielle , Santo Thomas , Mant Andrea , Bruno Raimondo , Cohen Milton , Hall Wayne D , Larance Briony , Lintzeris Nicholas , Farrell Michael , Degenhardt Louisa
Published: January 2019

Objective

Although depression and chronic pain often coexist, few studies have examined antidepressant use among people with pain. This study examines the prevalence and characteristics associated with antidepressant use among people prescribed opioids for chronic noncancer pain (CNCP).

Design

Baseline data from a prospective cohort study.

Setting

Australian community.

Subjects

A total of 1166 people prescribed opioids for CNCP.

Methods

Baseline data collection consisted of a self-completed seven-day medication diary and telephone interview to collect information on sociodemographic characteristics and mental/physical health using validated questionnaires. Logistic regression was used to examine characteristics associated with antidepressant use, reporting adjusted odds ratios (AORs) and 95% confidence intervals (CIs).

Results

Of the 1166 participants, 668 (57.3%) were female, and the median (interquartile range) age was 59 (49–68) years. About half the cohort (N = 637, 54.6%) used antidepressants. Of these, 329 (51.7%) reported moderate to severe depression. Amitriptyline was the most commonly used antidepressant (17.3%). Factors independently associated with antidepressant use were being female (AOR = 1.47, 95% CI = 1.13–1.92), more years lived in pain (AOR = 1.01, 95% CI = 1.00–1.02), and use of nonopioid analgesics (AOR = 1.34, 95% CI = 1.01–1.78), benzodiazepines and related drugs (AOR = 1.84, 95% CI = 1.36–2.49), antiepileptics (AOR = 1.86, 95% CI = 1.38–2.51), and antipsychotics (AOR = 2.15, 95% CI = 1.22–3.77).

Conclusions

Antidepressant use is common among people with CNCP prescribed opioids. Those using antidepressants were more likely to use other psychotropic medicines concurrently, highlighting that they are a high-risk population requiring comprehensive assessment to optimize outcomes and reduce potential harms from polypharmacy.
An Experimental Test of the Host-Plant Range of Nonrecombinant Strains of North American Xylella fastidiosa subsp. multiplex
Authors: Nunney Leonard , Azad Hamid , Stouthamer Richard
Published: January 2019

Nonrecombinant strains of Xylella fastidiosa subsp. multiplex (those lacking evidence of significant intersubspecific homologous recombination) infect the xylem of a wide range of native and nonnative trees in North America. However, the degree to which different strains have a specialized host range remains poorly understood. We tested eight strains isolated from five different tree species (almond, olive, sweetgum, and plum in California and oak in Washington, DC). Experiments were conducted in greenhouses in Riverside, CA, and each strain was tested on 11 to 15 of the 17 plant species tested. Hosts infected by the most strains were plum (5 of 8 strains) and almond (4 of 8), while their congener peach was only infected by 1 of 8. No strains infected oleander or mulberry. All strains successfully infected their original host, with peach, olive (1 of 7), and sweetgum (2 of 6) only infected by such strains. Of the 90 total strain–novel-host combinations tested, 11 resulted in unambiguous infection, 2 gave ambiguous results, and the remaining 77 failed to result in symptoms or bacterial spread. All eight strains had a unique host range, including two pairs of strains with the same multilocus sequence typing sequence type, providing strong evidence of extensive plant-host specialization. There was little evidence that host relatedness was driving host specificity.
Medicaid Expansion and Prescription Trends
Authors: Cher Benjamin A.Y. , Morden Nancy E. , Meara Ellen
Published: January 2019

Background:

Opioid overdose deaths in the United States have climbed since 1999. In 2014, the Affordable Care Act prompted some states to expand Medicaid programs, providing low-cost prescription access to millions of Americans. Some have questioned whether Medicaid expansion might worsen the opioid crisis.

Objective:

To test the association between the expansion of state Medicaid programs and Medicaid-paid prescriptions of opioid pain relievers and opioid addiction therapies.

Research Design:

We analyzed the 2010–2016 Medicaid State Drug Utilization Data using a difference-in-differences regression approach, comparing prescriptions per enrollee between states that expanded Medicaid in 2014 and states that did not. We compared opioid pain relievers and opioid addiction therapies to 5 other commonly prescribed drug types important to the Medicaid expansion population (antidepressants, antihypertensives, diabetes medications, cholesterol treatments, and contraceptives) and to overall prescription volume. A secondary analysis compared opioid pain relievers and opioid addiction therapies, between states with high and low overdose death rates.

Results:

We found overall prescription use per enrollee was higher after 2014. Relative growth in opioid pain reliever prescriptions was modest compared with growth in medications for depression, hypertension, diabetes, and high cholesterol. Growth in prescriptions used to treat opioid use disorder greatly outpaced other drugs, suggesting important gains in access to addiction treatments; growth was higher in states with higher pre-2014 overdose death rates.

Conclusions:

Our results suggest Medicaid expansion benefited a population with unique needs, and that Medicaid expansion could be a valuable tool in addressing the opioid overdose epidemic.
Conscious perception of natural images is constrained by category-related visual features
Authors: Lindh Daniel , Sligte Ilja G. , Assecondi Sara , Shapiro Kimron L. , Charest Ian
Published: January 2019

Conscious perception is crucial for adaptive behaviour yet access to consciousness varies for different types of objects. The visual system comprises regions with widely distributed category information and exemplar-level representations that cluster according to category. Does this categorical organisation in the brain provide insight into object-specific access to consciousness? We address this question using the Attentional Blink (AB) approach with visual objects as targets. We find large differences across categories in the AB then employ activation patterns extracted from a deep convolutional neural network (DCNN) to reveal that these differences depend on mid- to high-level, rather than low-level, visual features. We further show that these visual features can be used to explain variance in performance across trials. Taken together, our results suggest that the specific organisation of the higher-tier visual system underlies important functions relevant for conscious perception of differing natural images.
Genetic Landscape of Electron Transport Chain Complex I Dependency in Acute Myeloid Leukemia
Authors: Baccelli Irène , Gareau Yves , Lehnertz Bernhard , Gingras Stéphane , Spinella Jean-François , Beautrait Alexandre , Corneau Sophie , Mayotte Nadine , Boivin Isabel , Girard Simon , MacRae Tara , Frechette Mélanie , Leveillé Koryne , Krosl Jana , Thiollier Clarisse , Lavallée Vincent-Philippe , Kanshin Evgeny , Bertomeu Thierry , Coulombe-Huntington Jasmin , St-Denis Corinne , Bordeleau Marie-Eve , Boucher Geneviève , Roux Philippe P. , Lemieux Sébastien , Tyers Mike , Thibault Pierre , Hébert Josée , Marinier Anne , Sauvageau Guy
Published: January 2019

Inhibition of oxidative phosphorylation (OXPHOS) is a promising therapeutic strategy in Acute Myeloid Leukemia (AML), but patients respond heterogeneously. Through chemically interrogation of 200 sequenced specimens, we identified Mubritinib as a strongin vitroandin vivoanti-leukemic compound, acting through ubiquinone-dependent inhibition of Electron Transport Chain complex I (ETC1). ETC1 targeting showed selective toxicity against a subgroup of chemotherapy-resistant leukemias exhibiting OXPHOS hyperactivity, high expression of mitochondrial activity-related genes, and mutations affectingNPM1, FLT3andDNMT3A. Altogether, our work thus identifies a novel ETC1 inhibitor with high clinical potential and reveals the landscape of OXPHOS dependency in AML.
A yeast phenomic model for the influence of Warburg metabolism on genetic buffering of doxorubicin
Authors: Santos Sean M. , Hartman John L.
Published: January 2019

Background

Saccharomyces cerevisiaerepresses respiration in the presence of adequate glucose, mimicking the Warburg effect, termed aerobic glycolysis. We conducted yeast phenomic experiments to characterize differential doxorubicin-gene interaction, in the context of respirationvs.glycolysis. The resulting systems level biology about doxorubicin cytotoxicity, including the influence of the Warburg effect, was integrated with cancer pharmacogenomics data to identify potentially causal correlations between differential gene expression and anti-cancer efficacy.

Methods

Quantitative high-throughput cell array phenotyping (Q-HTCP) was used to measure cell proliferation phenotypes (CPPs) of the yeast gene knockout/knockdown library, treated with escalating doxorubicin concentrations in fermentable and non-fermentable media. Doxorubicin-gene interaction was quantified by departure of the observed and expected phenotypes for the doxorubicin-treated mutant strain, with respect to phenotypes for the untreated mutant strain and both the treated and untreated reference strain. Recursive expectation-maximization clustering (REMc) and Gene Ontology-based analyses of interactions were used to identify functional biological modules that buffer doxorubicin cytotoxicity, and to characterize their Warburg-dependence. Yeast phenomic data was applied to cancer cell line pharmacogenomics data to predict differential gene expression that causally influences the anti-tumor efficacy, and potentially the anthracycline-associated host toxicity, of doxorubicin.

Results

Doxorubicin cytotoxicity was greater with respiration, suggesting the Warburg effect can influence therapeutic efficacy. Accordingly, doxorubicin drug-gene interaction was more extensive with respiration, including increased buffering by cellular processes related to chromatin organization, protein folding and modification, translation reinitiation, spermine metabolism, and fatty acid beta-oxidation. Pathway enrichment was less notable for glycolysis-specific buffering. Cellular processes exerting influence relatively independently, with respect to Warburg status, included homologous recombination, sphingolipid homeostasis, telomere tethering at nuclear periphery, and actin cortical patch localization. Causality for differential gene expression associated with doxorubicin cytotoxicity in tumor cells was predicted within the biological context of the phenomic model.

Conclusions

Warburg status influences the genetic requirements to buffer doxorubicin toxicity. Yeast phenomics provides an experimental platform to model the complexity of gene interaction networks that influence human disease phenotypes, as in this example of chemotherapy response. High-resolution, systems level yeast phenotyping is useful to predict the biological influence of functional variation on disease, offering the potential to fundamentally advance precision medicine.
Siliplant1 (Slp1) protein precipitates silica in sorghum silica cells
Authors: Kumar Santosh , Adiram-Filiba Nurit , Blum Shula , Sanchez-Lopez Javier Arturo , Tzfadia Oren , Omid Ayelet , Volpin Hanne , Heifetz Yael , Goobes Gil , Elbaum Rivka
Published: January 2019

Silicon is absorbed by plant roots as silicic acid. The acid moves with the transpiration stream to the shoot, and mineralizes as silica. In grasses, leaf epidermal cells called silica cells deposit silica in most of their volume by unknown mechanism.

Using bioinformatics tools, we identified a previously uncharacterized protein in sorghum (Sorghum bicolor), which we named Siliplant1 (Slp1). Silica precipitation activity in vitro, expression profile, and activity in precipitating biosilica in vivo were characterized.

Slp1 is a basic protein with seven repeat units rich in proline, lysine, and glutamic acid. A short peptide, repeating five times in the protein precipitated silica in vitro at a biologically relevant silicic acid concentration. Raman and NMR spectroscopies showed that the peptide attached the silica through lysine amine groups, forming a mineral-peptide open structure. We found Slp1 expression in immature leaf and inflorescence tissues. In the immature leaf active silicification zone, Slp1 was localized to the cytoplasm or near cell boundaries of silica cells. It was packed in vesicles and secreted to the paramural space. Transient overexpression of Slp1 in sorghum resulted in ectopic silica deposition in all leaf epidermal cell types.

Our results show that Slp1 precipitates silica in sorghum silica cells.
Spontaneously emerging patterns in human visual cortex and their functional connectivity are linked to the patterns evoked by visual stimuli
Authors: Kim DoHyun , Livne Tomer , Metcalf Nicholas V. , Corbetta Maurizio , Shulman Gordon L.
Published: January 2019

The function of spontaneous brain activity is an important issue in neuroscience. Here we test the hypothesis that patterns of spontaneous activity code representational patterns evoked by stimuli and tasks. We compared in human visual cortex multi-vertex patterns of spontaneous activity to patterns evoked by ecological visual stimuli (faces, bodies, scenes) and low-level visual features (e.g. phase-scrambled faces). Specifically, we identified regions that preferred particular stimulus categories during localizer scans (e.g. extra-striate body area for bodies), measured multi-vertex patterns for each category during event-related task scans, and then correlated over vertices these stimulus-evoked patterns to the pattern measured on each frame of resting-state scans. The mean correlation coefficient was essentially zero for all regions/stimulus categories, indicating that resting multi-vertex patterns were not biased toward particular stimulus-evoked patterns. However, the spread of correlation coefficients between stimulus-evoked and resting patterns, i.e. both positive and negative, was significantly greater for the preferred stimulus category of an ROI (e.g. body category in body-preferring ROIs). The relationship between spontaneous and stimulus-evoked multi-vertex patterns also governed the temporal correlation or functional connectivity of patterns of spontaneous activity between individual regions (pattern-based functional connectivity). Resting patterns related to an object category fluctuated preferentially between ROIs preferring the same category, and patterns related to different categories fluctuated independently within their respective preferred ROIs (e.g. body- and scene-related multi-vertex patterns within body- and scene-preferring ROIs). These results support the general proposal that spontaneous multi-vertex activity patterns are linked to stimulus-evoked patterns, consistent with a representational function for spontaneous activity.
Recognizing off-sample mass spectrometry images with machine and deep learning
Authors: Ovchinnikova Katja , Kovalev Vitaly , Stuart Lachlan , Alexandrov Theodore
Published: January 2019

Motivation

Imaging mass spectrometry (imaging MS) is a powerful technology for revealing localizations of hundreds of molecules in tissue sections. However, imaging MS data is polluted with off-sample ions caused by caused by sample preparation, particularly by the MALDI matrix application. The presence of the off-sample ion images confounds and hinders metabolite identification and downstream analysis.

Results

We created a high-quality gold standard of 23238 manually tagged ion images from 87 public datasets from the METASPACE knowledge base. We developed several machine and deep learning methods for recognizing off-sample ion images. Deep residual learning performed the best with the F1 score of 0.97. Spatio-molecular biclustering method achieved the F1 scores of 0.96 and 0.93 in semi- and fully-automated scenarios, respectively. Molecular co-localization method achieved the F1 score of 0.90. We investigated the clusters of the DHB matrix, the most common MALDI matrix, and characterized parameters of a clusters combinatorial model. This work addresses an important issue in imaging MS and illustrates how public data, modern web technologies, and machine and deep learning open novel avenues in imaging MS.

Availability and Implementation

Data and source code are available at: https://github.com/metaspace2020/offsample.

Contact

theodore.alexandrov@embl.de
Kinesin-5 promotes microtubule nucleation and assembly by stabilizing a lattice-competent conformation of tubulin
Authors: Chen Geng-Yuan , Asenjo Ana B. , Chen Yalei , Mascaro Jake , Arginteanu David F. J. , Sosa Hernando , Hancock William O.
Published: January 2019

Besides sliding apart antiparallel microtubules during spindle elongation, the mitotic kinesin-5, Eg5 promotes microtubule polymerization, emphasizing its importance in mitotic spindle length control. Here, we characterize the Eg5 microtubule polymerase mechanism by assessing motor-induced changes in the longitudinal and lateral tubulin-tubulin bonds that form the microtubule lattice. Isolated Eg5 motor domains promote microtubule nucleation, growth and stability. Eg5 binds preferentially to microtubules over free tubulin, and colchicine-like inhibitors that stabilize the bent conformation of tubulin allosterically inhibit Eg5 binding, consistent with a model in which Eg5 induces a curved-to-straight transition in tubulin. Domain swap experiments establish that the family-specific Loop11, which resides near the nucleotide-sensing Switch-II domain, is necessary and sufficient for the polymerase activity of Eg5. Thus, we propose a microtubule polymerase mechanism in which Eg5 at the plus-end promotes a curved-to-straight transition in tubulin that enhances lateral bond formation and thereby promotes microtubule growth and stability.
Cross-talk of cellulose and mannan perception pathways leads to inhibition of cellulase production in several filamentous fungi
Authors: Hassan Lara , Lin Liangcai , Sorek Hagit , Goudoulas Thomas , Germann Natalie , Tian Chaoguang , Benz J. Philipp
Published: January 2019

It is essential for microbes to acquire information about their environment. Fungi use soluble degradation products of plant cell wall components to understand the substrate composition they grow on. Individual signaling pathways have been well described. However, the interconnections between pathways remain poorly understood. In the present work, we provide evidence of “confusion” due to cross-talk between the perception pathways for cellulose and the hemicellulose mannan in several filamentous fungi, leading to the inhibition of cellulase expression. We used the functional genomics tools available forNeurospora crassato investigate this signaling overlap at the molecular level. Cross-talk and competitive inhibition could be identified both during uptake by cellodextrin transporters and intracellularly. Importantly, the overlap is independent of CRE-1-mediated catabolite repression. These results provide novel insights into the regulatory networks of lignocellulolytic fungi and will contribute to the rational optimization of fungal enzyme production for efficient plant biomass depolymerization and utilization.
A hypomorphic allele of telomerase reverse transcriptase uncovers the minimal functional length of telomeres in Arabidopsis
Authors: Watson J. Matthew , Trieb Johanna , Troestl Martina , Renfrew Kyle , Mandakova Terezie , Shippen Dorothy E. , Riha Karel
Published: January 2019

Despite the essential requirement of telomeric DNA for genome stability, the length of telomere tracts between species differs by up to four orders of magnitude, raising the question of the minimal length of telomeric DNA necessary for proper function. Here we address this question using a hypomorphic allele of the telomerase catalytic subunit, TERT. We show that although this construct partially restored telomerase activity to a tert mutant, telomeres continued to shorten over several generations, ultimately stabilizing at a bimodal size distribution. Telomeres on two chromosome arms were maintained at a length of 1kb, while the remaining telomeres were maintained at 400 bp. The longest telomeres identified in this background were also significantly longer in wild type populations, suggesting cis-acting elements on these arms either promote telomerase processivity or recruitment. Genetically disrupting telomerase processivity in this background resulted in immediate lethality. Thus, telomeres of 400 bp are both necessary and sufficient for Arabidopsis viability. As this length is the estimated minimal length for t-loop formation, our data suggest that telomeres long enough to form a t-loop constitute the minimal functional length.
Epigenetic deregulation of lamina-associated domains in Hutchinson-Gilford Progeria Syndrome
Authors: Köhler Florian , Bormann Felix , Raddatz Günter , Gutekunst Julian , Musch Tanja , Lyko Frank , Rodríguez-Paredes Manuel
Published: January 2019

Hutchinson-Gilford Progeria Syndrome (HGPS) is a progeroid disease characterized by the early onset of some classically age-related phenotypes including arthritis, loss of body fat and hair and atherosclerosis. Cells from affected individuals express a mutant version of the nuclear envelope protein Lamin A (termed Progerin) and have previously been shown to exhibit prominent chromatin changes. Here, we identify epigenetic deregulation of lamina-associated domains (LADs) as a central feature in the molecular pathology of HGPS. Using ATAC-see/-seq and Infinium MethylationEPIC BeadChip-mediated DNA methylation profiling, we demonstrate that dermal fibroblasts from HGPS patients exhibit both chromatin accessibility and DNA methylation changes that are enriched in LADs. Importantly, we further show that these epigenetic alterations are associated with HGPS-specific gene expression changes. Together, our results establish a central involvement of LADs in the epigenetic deregulation of HGPS and provide novel insight into the molecular changes associated with the disease.
SEMA4C is a novel target to limit osteosarcoma growth, progression, and metastasis
Authors: Smeester Branden A. , Slipek Nicholas J. , Pomeroy Emily J. , Bomberger Heather E. , Shamsan Ghaidan A. , Peterson Joseph J. , Crosby Margaret R. , Draper Garrett M. , Becklin Kelsie L. , Rahrmann Eric P. , McCarthy James B. , Odde David J. , Wood David K. , Largaespada David A. , Moriarity Branden S.
Published: January 2019

Semaphorins, specifically type IV, are important regulators of axonal guidance and have been increasingly implicated in poor prognoses in a number of different solid cancers. In conjunction with their cognate PLXNB family receptors, type IV members have been increasingly shown to mediate oncogenic functions necessary for tumor development and malignant spread. In this study, we investigated the role of semaphorin 4C (SEMA4C) in osteosarcoma growth, progression, and metastasis. We investigated the expression and localization of SEMA4C in primary osteosarcoma patient tissues and its tumorigenic functions in these malignancies. We demonstrate that overexpression of SEMA4C promotes properties of cellular transformation, while RNAi knockdown of SEMA4C promotes adhesion and reduces cellular proliferation, colony formation, migration, wound healing, tumor growth, and lung metastasis. These phenotypic changes were accompanied by reductions in activated AKT signaling, G1 cell cycle delay, and decreases in expression of mesenchymal marker genes SNAI1, SNAI2, and TWIST1. Lastly, monoclonal antibody blockade of SEMA4C in vitro mirrored that of the genetic studies. Together, our results indicate a multi-dimensional oncogenic role for SEMA4C in metastatic osteosarcoma and more importantly that SEMA4C has actionable clinical potential.
Chromokinesins NOD and KID Use Distinct ATPase Mechanisms and Microtubule Interactions to Perform a Similar Function
Authors: Walker Benjamin C. , Tempel Wolfram , Zhu Haizhong , Park Heewon , Cochran Jared C.
Published: January 2019

Chromokinesins NOD and KID have similar DNA binding domains and functions during cell division, while their motor domain sequences show significant variations. It has been unclear whether these motors have similar structure, chemistry, and microtubule interactions necessary to follow a similar mechanism of force mediation. We used biochemical rate measurements, cosedimentation, and structural analysis to investigate the ATPase mechanisms of the NOD and KID core domains. These experiments and analysis revealed that NOD and KID have different ATPase mechanisms, microtubule interactions, and catalytic domain structures. The ATPase cycles of NOD and KID have different rate limiting steps. The ATPase rate of NOD was robustly stimulated by microtubules albeit its microtubule affinity was weakened in all nucleotide bound states. KID bound microtubules tightly in all nucleotide states and remained associated with the microtubule for more than 100 cycles of ATP hydrolysis before dissociating. The structure of KID was most similar to conventional kinesin (KIF5). Key differences in the microtubule binding region and allosteric communication pathway between KID and NOD are consistent with our biochemical data. Our results support the model that NOD and KID utilize distinct mechanistic pathways to achieve the same function during cell division.
Geometric control of frequency modulation of cAMP oscillations due to Ca2+-bursts in dendritic spines
Authors: Ohadi D. , Rangamani P.
Published: January 2019

The spatiotemporal regulation of cAMP and its dynamic interactions with other second messengers such as calcium are critical features of signaling specificity required for neuronal development and connectivity. cAMP is known to contribute to long-term potentiation and memory formation by controlling the formation and regulation of dendritic spines. Despite the recent advances in biosensing techniques for monitoring spatiotemporal cAMP dynamics, the underlying molecular mechanisms that attribute to the subcellular modulation of cAMP remain unknown. In the present work, we model the spatio-temporal dynamics of calcium-induced cAMP signaling pathway in dendritic spines. Using a 3D reaction-diffusion model, we investigate the effect of different spatial characteristics of cAMP dynamics that may be responsible for subcellular regulation of cAMP concentrations. Our model predicts that the volume-to-surface ratio of the spine, regulated through the spine head size, spine neck size, and the presence of physical barriers (spine apparatus) is an important regulator of cAMP dynamics. Furthermore, localization of the enzymes responsible for the synthesis and degradation of cAMP in different compartments also modulates the oscillatory patterns of cAMP through exponential relationships. Our findings shed light on the significance of complex geometric and localization relationships for cAMP dynamics in dendritic spines.
β-catenin has an ancestral role in cell fate specification but not cell adhesion
Authors: Salinas-Saavedra Miguel , Wikramanayake Athula H. , Martindale Mark Q
Published: January 2019

The ß-catenin protein has two major known functions in animal cells. It keeps epithelial tissue homeostasis by its connection with Adherens Junctions (AJ), and it serves as a transcriptional cofactor along with Lef/Tcf to enter the nucleus and regulate target genes of the Wnt/ß-catenin (cWnt) signaling pathway. To assess the ancestral role of ß-catenin during development we examined its distribution and function in the ctenophoreMnemiopsis leidyi(one of the earliest branching animal phyla) by using ctenophore-specific antibodies and mRNA injection. We found that ß-catenin protein never localizes to cell-cell contacts during embryogenesis as it does in other metazoans, most likely because ctenophore-cadherins do not have the cytoplasmic domain required for interaction with the catenin proteins. Downregulation of zygoticMlß-catenin signaling led to the loss of endodermal and mesodermal tissues indicating that nuclear ß-catenin may have a deep role in germ-layer evolution. Our results indicate that the ancestral role for ß-catenin was in the cell-fate specification and not in cell adhesion and also further emphasizes the critical role of this protein in the evolution of tissue layers in metazoans.
Stimulation of phospholipase Cβ1 by Gαq promotes the assembly of stress granule proteins
Authors: Qifti Androniqi , Jackson Lela , Singla Ashima , Garwain Osama , Scarlata Suzanne
Published: January 2019

During adverse conditions, mammalian cells regulate protein production by sequestering the translational machinery in membrane-less organelles known as stress granules. Here, we found that activation of the G protein subunit Gαq promoted the formation of particles that contained stress granule proteins through a mechanism linked to the presence of phospholipase Cβ1 (PLCβ1) in the cytosol. In experiments with PC12 and A10 cells, we showed that under basal conditions, cytosolic PLCβ1 bound to stress granule associated proteins, including PABPC1, eIF5A, and Ago2. Knockdown of cytosolic PLCβ1 with siRNA or promoting its relocalization to the plasma membrane by activating Gαq resulted in the formation of particles containing the stress granule markers, PABPC1, G3BP1, and Ago2. Our studies showed that the composition of these particles resemble those formed under osmotic stress and are distinct from those formed by other stresses. Our results fit a simple thermodynamic model in which cytosolic PLCβ1 solubilizes stress granule proteins such that its movement to activated Gαq releases these particles to enable the formation of stress granules. Together, our data are suggestive of a link between Gαq-coupled signals and protein translation through stress granule formation.
Computation of stationary distributions in stochastic models of cellular processes with molecular memory
Authors: Zhang Jiajun , Zhou Tianshou
Published: January 2019

Modeling stochastic dynamics of intracellular processes has long rested on Markovian (i.e., memoryless) hypothesis. However, many of these processes are non-Markovian (i.e., memorial) due to, e.g., small reaction steps involved in synthesis or degradation of a macroscopic molecule. When interrogating aspects of a cellular network by experimental measurements (e.g., by singlemolecule and single-cell measurement technologies) of network components, a key need is to develop efficient approaches to simulate and compute joint distributions of these components. To cope with this computational challenge, we develop two efficient algorithms: stationary generalized Gillespie algorithm and stationary generalized finite state projection, both being established based on a stationary generalized chemical master equation. We show how these algorithms can be combined in a streamlined procedure for evaluation of non-Markovian effects in a general cellular network. Stationary distributions are evaluated in two models of constitutive and bursty gene expressions as well as a model of genetic toggle switch, each considering molecular memory. Our approach significantly expands the capability of stochastic simulation to investigate gene regulatory network dynamics, which has the potential to advance both understanding of molecular systems biology and design of synthetic circuits.

Author summary

Cellular systems are driven by interactions between subsystems via time-stamped discrete events, involving numerous components and reaction steps and spanning several time scales. Such biochemical reactions are subject to inherent noise due to the small numbers of molecules. Also, they could involve several small steps, creating a memory between individual events. Delineating these molecular stochasticity and memory of biomolecular networks are continuing challenges for molecular systems biology. We present a novel approach to compute the probability distribution in stochastic models of cellular processes with molecular memory based on stationary generalized chemical master equation. We map a stochastic system with memory onto a Markovian model with effective reaction propensity functions. This formulation enables us to efficiently develop algorithms under the Markovian framework, and thus systematically analyze how molecular memories regulate stochastic behaviors of biomolecular networks. Here we propose two representative algorithms: stationary generalized Gillespie algorithm and stationary generalized finite state projection algorithm. The former generate realizations with Monte Carlo simulation, but the later compute approximations of the probability distribution by solving a truncated version of stochastic process. Our approach is demonstrated by applying it to three different examples from systems biology: generalized birth-death process, a stochastic toggle switch model, and a 3-stage gene expression model.
Re-investigation and correct symmetry of Ca3CoAl4O10
Authors: Kahlenberg Volker
Published: January 2019

A re-investigation of the crystal structure of tricalcium cobalt(II) tetraaluminate, Ca3CoAl4O10, using single-crystal X-ray diffraction data, revealed orthorhombic (Pbcm) symmetry. The present contribution corrects the results of a previous X-ray powder diffraction study [Vazquez et al. (2002). J. Solid State Chem.
166, 191–196] where this phase has been described in an unnecessarily low space-group symmetry (Pbc21). The compound belongs to the group of tetrahedral framework structures. The distribution of the aluminium and cobalt ions among the centres of the four different tetrahedra within the asymmetric unit has been studied in detail. Charge compensation is achieved by the incorporation of two symmetrically independent calcium ions located in voids of the tetrahedral framework. Ca3CoAl4O10 is isotypic with Ca3MgAl4O10.
Ethyl 6′-cyano-7′-(p-tolyl)-1′,6′,7′,7a′-tetrahydro-3′H-spiro[indeno[1,2-b]quinoxaline-11,5′-pyrrolo[1,2-c]thiazole]-6′-carboxylate
Authors: Muthuselvi C. , Muthu M. , Athimoolam S. , Ravikumar B. , Pandiarajan S. , Srinivasan N. , Krishnakumar R. V.
Published: January 2019

The title compound, C31H26N4O2S, crystallizes in a triclinic centrosymmetric lattice with two molecules in the unit cell. The five-membered thiazole and pyrrolidine rings adopt twisted and envelope conformations, respectively. The methoxyphenyl and indenoquinoxaline planes are oriented with a dihedral angle of 88.1 (1)° to each other. The crystal structure features C—H...N, C—H...O and C—H...S intermolecular interactions forming two R
2
2(16) ring motifs and a C(11) and two C
2
2(14) chain motifs. The –CH3 group of the ethyl side chain is disordered over two positions with site occupancies of 0.55 and 0.45.
Allyl 6-amino-5-cyano-2-methyl-4-phenyl-4H-pyran-3-carboxylate
Authors: Krishnan G. Anantha , Kumar C. Udhaya , Mohandas T. , Pillai M. Velayutham , Sakthivel P.
Published: January 2019

In the title compound, C17H16N2O3, the 4H-pyran ring adopts a boat conformation. In the crystal, N—H...N and N—H...O interactions link the molecules, forming an infinite ribbon running along the a-axis direction with N—H...N interactions forming centrosymmetric R
2
2(12) graph-set motifs. The allyl side chain is disordered over two sets of sites with occupancies of 0.720 (7) and 0.280 (7).
Tris(1,10-phenanthroline-κ2
N,N′)cobalt(II) bis(2,4,5-tricarboxybenzoate) monohydrate
Authors: Zhong Kai-Long , Cao Guo-Qing , Song Wei , Ni Chao
Published: January 2019

In the complex cation of the title salt, [Co(C12H8N2)3](C10H5O8)2·H2O, the CoII cation is situated on a twofold rotation axis and is coordinated in a distorted octahedral manner by six N atoms from three chelating 1,10-phenanthroline (phen) ligands. In the crystal, the non-coordinating 2,4,5-tricarboxybenzoate anions interact with each other via O—H...O hydrogen bonds, generating a two-dimensional network parallel to (100). Adjacent sheets are connected by waterO—H...Ocarboxylate hydrogen bonds, resulting in a three-dimensional network structure that surrounds the complex cations.