bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Gene Expression in Erlotinib-Treated Fibroblasts
Authors: Wickersham Karen E. , Hodges Theresa K. , Edelman Martin J. , Song Yang , Nan Mintong , Dorsey Susan G.
Published: December 2018

Background

Therapies targeting the epidermal growth factor receptor (EGFR) result in a painful rash, the most common and debilitating toxicity among patients with non-small cell lung cancer (NSCLC) who take EGFR tyrosine kinase inhibitor (TKI) therapy; however, predicting the development and the severity of the rash is difficult.

Objective

The aim of this study was to examine how erlotinib—an EGFR TKI that NSCLC patients take to stop or slow tumor growth—altered the transcriptome of dermal fibroblasts.

Methods

Dermal fibroblasts (ATCC PCS-201-012) were seeded in cell culture flasks, grown under standard conditions, and transferred to cell culture dishes. Cells were treated once daily for 3 days with erlotinib 100 nM (n = 5), erlotinib 1 μM (n = 5), vehicle 1 μM (dimethyl sulfoxide) (n = 5), or no treatment (n = 5). Total RNA was extracted using a standard TRIzol method and hybridized using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Raw intensities generated from the arrays were normalized using a Robust Multiarray Average method and analyzed using analysis of variance in Limma R software. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis to identify canonical or noncanonical signaling pathways enriched in this dataset.

Results

We selected genes for investigation based on their potential role in wound healing (AQP3), rash development (CCL2), fibroblast activation (PALLD), cancer and cancer progression (GDF-15, SLC7A11, MMP12, and DIRAS3), and cell cycle control (CDC6). We were able to validate four of these genes by both Western blot analysis and quantitative polymerase chain reaction (MMP12, CCL2, CDC6, and SLC7A11).

Discussion

If found predictive of rash in future studies using patient samples, our findings may help to identify those at risk for severe rash so that (a) the dose of EGFR TKI therapy may be adjusted; (b) additional treatments for the rash can be developed; and/or (c) precise, patient-centered interventions can be developed so that patients with cancer can better self-manage their rash and adhere to EGFR TKI treatment.
Neuroglial Differentiation and Neoplasms in Testicular Germ Cell Tumors Lack Immunohistochemical Evidence of Alterations Characteristic of Their CNS Counterparts
Authors: Matoso Andres , Idrees Muhammad T. , Rodriguez Fausto J. , Ibrahim Junaid , Perrino Carmen M. , Ulbright Thomas M. , Epstein Jonathan I.
Published: December 2018

Overgrowth of neuroglial tissue is rare in testicular germ cell tumors and mostly reported as isolated cases. We retrospectively reviewed 13 cases of testicular germ cell tumors from 2 institutions from 1995 to 2018. Hematoxylin and eosin slides were collected and reviewed. Immunohistochemistry was performed in all cases with available material. The series included 4 primary tumors and 9 metastases, including 8 retroperitoneal and 1 axillary lymph node (LN). The average age was 34 (range: 19 to 54). Five of the LN dissections were postchemotherapy, with one a recurrence 5 years after the initial diagnosis. The average tumor size for primary tumors was 5.15 cm (range: 1.7 to 7.3) and for metastases was 6.4 cm (range: 0.6 to 15). The largest size of the neuroglial component was 4.5 cm in the primary tumors and 7.5 cm in metastatic sites. The neuroglial component in the primary site was associated with pure teratoma (n=2) and with a mixed germ cell tumor (teratoma, seminoma, and embryonal carcinoma) (n=2). Cases involving LNs were associated with teratoma (n=4), seminoma (n=2), rhabdomyosarcoma (n=2), primitive neuroectodermal tumors (n=1), and high-grade sarcoma (n=1) (some with >1 other component). Two cases were pure glial tumor. Histologically, the neuroglial components included low-grade astrocytoma (n=3) (both with microcysts formation and pilocytic features), gemistocytic astrocytomas (n=3), anaplastic astrocytoma (n=2), ganglioglioma (n=1), glioblastoma (n=2), gliosarcoma (n=1), and developing central nervous system (CNS) (n=2). By immunohistochemistry, 13/13 (100%) cases were GFAP(+), 10/10 (100%) cases showed retained ATRX, 10/10 were IDH1 pR132H (−), 5/10 (50%) were p53 (+). A single case 1/10 (10%) was BRAF p.V600E (+), but a mutation was not identified by polymerase chain reaction. Follow-up was available in 6 patients; 4 were confirmed to have received chemotherapy with BEP; 1 had a local recurrence and the patient with gliosarcoma developed a lung metastasis morphologically similar to the gliosarcoma of the retroperitoneum. In conclusion, neuroglial differentiation and neoplasms are rare in testicular germ cell tumors and are most commonly associated with teratomas; they can be seen in primary and metastatic sites. They exhibit the full range of neuroglial differentiation including developing CNS to gliomas/glioneuronal tumors WHO grades I-IV. None of the cases showed results consistent with ATRX, IDH or BRAF alterations, suggesting they have different oncogenic mechanisms than their CNS counterparts.
Perception of frequency modulation is mediated by cochlear place coding
Authors: Whiteford Kelly L. , Kreft Heather A. , Oxenham Andrew J.
Published: December 2018

Natural sounds convey information via frequency and amplitude modulations (FM and AM). Humans are acutely sensitive to the slow rates of FM that are crucial for speech and music. This sensitivity has been thought to rely on precise stimulus-driven auditory-nerve spike timing (time code), whereas a coarser code, based on variations in the cochlear place of stimulation (place code), represents faster FM. Here we test this longstanding theory in listeners with normal and impaired hearing, resulting in widely varying place-coding fidelity. Contrary to predictions, FM detection thresholds at slow and fast rates are highly correlated and closely related to the fidelity of cochlear place coding. We support this conclusion with additional data showing that place-based coding degrades at high modulation rates and in high spectral regions in ways that were previously interpreted as reflecting the limits of fine neural timing. The results suggest a unitary place-based neural code for FM.
Updating the in silico human surfaceome with meta-ensemble learning and feature engineering
Authors: Bojar Daniel
Published: December 2018

Next to being targeted by most available drugs, human proteins located in the plasma membrane are also responsible for a plethora of essential cellular functions, ranging from signaling to transport processes. In order to target and study these transmembrane proteins, their plasma membrane location has to be established. Yet experimental validation of the thousands of potential plasma membrane proteins is laborious and technically challenging. A recent study performed machine learning to classify surface and non-surface transmembrane proteins in human cells based on curated high-quality training data from the Cell Surface Protein Atlas (CSPA) and other databases, reporting a cross-validation prediction accuracy of 93.5% (1). Here, we report an improved version of the surfaceome predictor SURFY, SURFY2, using the same training data with a meta-ensemble classification approach involving feature engineering. SURFY2 yielded predictions with an accuracy score of 95.5% on a test dataset never seen before by the classifier. Importantly, we found several high-confidence re-classifications of disease-relevant proteins among the discrepant predictions between SURFY and SURFY2. To rationalize the prediction mechanism of SURFY2 and analyze differently classified transmembrane proteins we investigated classifier feature importances and data distributions between prediction sets. SURFY2 exhibited both an increased precision as well as recall compared to SURFY and delivers the best in silico human surfaceome up to now. This updated version of the surfaceome will instigate further advances in drug targeting and research on cellular signaling as well as transport processes.
Neuronal activity in the posterior cingulate cortex signals environmental information and predicts behavioral variability during routine foraging
Authors: Barack David L , Platt Michael L
Published: December 2018

Animals engage in routine behavior in order to efficiently navigate their environments. This routine behavior may be influenced by the state of the environment, such as the location and size of rewards. The neural circuits tracking environmental information and how that information impacts decisions to diverge from routines remains unexplored. To investigate the representation of environmental information during routine foraging, we recorded the activity of single neurons in posterior cingulate cortex (PCC) in monkeys searching through an array of targets in which the location of rewards was unknown. Outside the laboratory, people and animals solve such traveling salesman problems by following routine traplines that connect nearest-neighbor locations. In our task, monkeys also deployed traplining routines, but as the environment became better known, they diverged from them despite the reduction in foraging efficiency. While foraging, PCC neurons tracked environmental information but not reward and predicted variability in the pattern of choices. Together, these findings suggest that PCC mediates the influence of information on variability in choice behavior.
Effect of Compound Kushen Injection, a natural compound mixture, and its identified chemical components on migration and invasion of colon, brain and breast cancer cell lines
Authors: Nourmohammadi Saeed , Aung Thazin Nwe , Cui Jian , Pei Jinxin V. , De Ieso Michael Lucio , Harata-Lee Yuka , Qu Zhipeng , Adelson David L , Yool Andrea J
Published: December 2018

Cancer metastasis is a major cause of death. Traditional Chinese medicines (TCM) are promising sources of new anti-metastatic agents. Compound Kushen Injection (CKI), extracted from medicinal plants, Kushen (Sophora flavescens) and Baituling (Heterosmilax chinensis), contains a mixture of alkaloids and flavonoids known to disrupt cell cycle and induce apoptosis in breast cancer (MCF7). However, effects on cancer cell migration and invasion have remained unknown. CKI, fractionated mixtures, and single identified components were tested in migration assays with colon (HT-29, SW-480, DLD-1), brain (U-87 MG, U-251 MG), and breast (MDA-MB-231) cancer cell lines. Human embryonic kidney (HEK-293) and human foreskin fibroblast (HFF) served as non-cancerous controls. Wound closure, transwell invasion, and live cell imaging assays showed that CKI reduced motility in all eight cell lines. The greatest inhibition of migration occurred in HT-29 and MDA-MB-231, and the least in HEK-293. Fractionation and reconstitution of CKI showed that combinations of compounds were required for activity. Live cell imaging confirmed CKI strongly reduced migration of HT-29 and MDA-MB-231 cells, moderately slowed brain cancer cells, and had no effect on HEK-293. CKI uniformly blocked invasiveness through extracellular matrix. Apoptosis was increased by CKI in MDA-MB-231 cells but not in non-cancerous cells. Cell viability in CKI was unaffected in all cell lines. Transcriptomic analyses of MDA-MB-231 with and without CKI indicated down-regulated expression of actin cytoskeletal and focal adhesion genes, consistent with the observed impairment of cell migration. The pharmacological complexity of CKI is important for its effective block of cancer cell migration and invasion.
Mechanistic insights of the attenuation of quorum-sensing-dependent virulence factors of Pseudomonas aeruginosa: Molecular modeling of the interaction of taxifolin with transcriptional regulator LasR
Authors: Grabski Hovakim , Tiratsuyan Susanna
Published: December 2018

Pseudomonas aeruginosa is one of the most dangerous superbugs and is responsible for both acute and chronic infection. Current therapies are not effective because of biofilms that increase antibiotic resistance. Bacterial virulence and biofilm formation are regulated through a system called quorum sensing, which includes transcriptional regulators LasR and RhIR. These regulators are activated by their own natural autoinducers. Targeting this system is a promising strategy to combat bacterial pathogenicity. Flavonoids are very well known for their antimicrobial activity and taxifolin is one of them. It is also known that flavonoids inhibit Pseudomonas aeruginosa biofilm formation, but the mechanism of action is unknown. In the present study, we tried to analyse the mode of interactions of LasR with taxifolin. We used a combination of molecular docking, molecular dynamics simulations and machine learning techniques, which includes principal component and cluster analysis to study the interaction of the LasR protein with taxifolin. We show that taxifolin has two binding modes. One binding mode is the interaction with ligand binding domain. The second mode is the interaction with the "bridge", which is a cryptic binding site. It involves conserved amino acid interactions from multiple domains. Biochemical studies show hydroxyl group of ring A in flavonoids is necessary for inhibition. In our model the hydroxyl group ensures the formation of many hydrogen bonds during the second binding mode. Microsecond simulations also show the stability of the formed complex. This study may offer insights on how taxifolin inhibits LasR and the quorum sensing circuitry.
Rapamycin, an Immunosuppressant and mTORC1 Inhibitor, Triples the antidepressant Response Rate of Ketamine at 2 Weeks Following Treatment: A double-blind, placebo-controlled, cross-over, randomized clinical trial
Authors: Abdallah Chadi , Averill Lynnette A , Gueorguieva Ralitza , Goktas Selin , Purohit Prerana , Ranganathan Mohini , D'Souza Deepak Cyril , Formica Richard , Southwick Steven M , Duman Ronald S , Sanacora Gerard , Krystal John
Published: December 2018

BACKGROUND: Ketamine exerts rapid and robust antidepressant effects thought to be mediated by activation of the mechanistic target of rapamycin complex 1 (mTORC1). To test this hypothesis, depressed patients were pretreated with rapamycin, an mTORC1 inhibitor, prior to receiving ketamine. METHODS: Twenty-three patients suffering a major depressive episode were randomized to oral rapamycin (6 mg) or placebo, each was followed 2 hours later by ketamine 0.5 mg/kg in a double-blind cross-over design with treatment days separated by at least 2 weeks. Depression severity was assessed using Montgomery Asberg Depression Rating Scale (MADRS). Antidepressant response was defined as a MADRS improvement of 50% or more. RESULTS: Over the two-week follow-up, we found a significant treatment by time interaction (F(8,245) = 2.02, p = 0.04), reflecting prolonged antidepressant effects post rapamycin+ketamine treatment. At 2 weeks, we found a significantly higher response rate following rapamycin+ketamine (41%) compared to placebo+ketamine (13%, p = 0.04). However, rapamycin pretreatment did not alter the acute effects of ketamine. CONCLUSION: Unexpectedly, pretreatment with rapamycin prolonged rather than blocked the acute antidepressant effects of ketamine. This observation raises questions about the role of mTORC1 in the antidepressant effects of ketamine, raises the possibility that rapamycin may extend the benefits of ketamine, and thereby potentially sheds light on mechanisms that limit the duration of ketamine effects. The supplementing of ketamine with rapamycin may be a treatment strategy for reducing the frequency of ketamine infusions during maintenance treatment.
The mechanism of cross-talk between histone H2B ubiquitination and H3 methylation by Dot1L
Authors: Worden Evan J. , Hoffmann Niklas , Hicks Chad , Wolberger Cynthia
Published: December 2018

Methylation of histone H3, lysine 79 (H3K79), by Dot1L is a hallmark of actively transcribed genes that depends on monoubiquitination of H2B at lysine 120 (H2B-Ub), and is a well-characterized example of histone modification cross-talk that is conserved from yeast to humans. The mechanism by which H2B-Ub stimulates Dot1L to methylate the relatively inaccessible histone core H3K79 residue is unknown. The 3.0 Å resolution cryo-EM structure of Dot1L bound to ubiquitinated nucleosome reveals that Dot1L contains binding sites for both ubiquitin and the histone H4 tail, which establish two regions of contact that stabilize a catalytically competent state and positions the Dot1L active site over H3K79. We unexpectedly find that contacts mediated by both Dot1L and the H4 tail induce a conformational change in the globular core of histone H3 that reorients K79 from an inaccessible position, thus enabling this side chain to project deep into the active site in a position primed for catalysis. Our study provides a comprehensive mechanism of cross-talk between histone ubiquitination and methylation and reveals an unexpected structural plasticity in histones that makes it possible for histone-modifying enzymes to access residues within the nucleosome core.
Microglia are necessary for toxin-mediated demyelination and activation of microglia is sufficient to induce demyelination
Authors: Marzan Dave E. , West Brian L. , Salzer James L.
Published: December 2018

Microgliosis is a prominent pathological feature in many neurological diseases including multiple sclerosis (MS). The precise role of microglia during demyelination, and the relative contributions of microglia vs. peripheral macrophages, are incompletely understood. Here, using a genetic fate mapping strategy, we identify microglia as predominant responders and key effectors of demyelination in the cuprizone (CUP) model. Pharmacological depletion of microglia demonstrates these cells are necessary for the demyelination, loss of oligodendrocytes, and reactive astrocytosis normally evident in this model. Electron microscopy (EM) and serial block face imaging show myelin sheaths remain intact in CUP treated mice depleted of microglia. However, these damaged myelin sheaths are lost upon-repopulation of microglia. Injection of colony-stimulating factor-1 to drive focal microgliosis in white matter is sufficient to induce focal demyelinationin vivo. These studies indicate activated microglia are required for demyelination that results from primary myelin pathology and are sufficient to induce demyelination directly.
Tarantula phylogenomics: A robust phylogeny of multiple tarantula lineages inferred from transcriptome data sheds light on the prickly issue of urticating setae evolution
Authors: Foley Saoirse , Lüddecke Tim , Cheng Dong-Qiang , Krehenwinkel Henrik , Künzel Sven , Longhorn Stuart J. , Wendt Ingo , von Wirth Volker , Tänzler Rene , Vences Miguel , Piel William H.
Published: December 2018

Mygalomorph spiders of the family Theraphosidae, known to the broader public as tarantulas, are among the most recognizable arachnids on earth due to their large size and widespread distribution. Their use of urticating setae is a notable adaptation that has evolved exclusively in certain New World theraphosids. Thus far, the evolutionary history of Theraphosidae remains poorly understood; theraphosid systematics still largely relies on morphological datasets, which suffer from high degrees of homoplasy, and traditional targeted sequencing of preselected genes failed to provide strong support for supra-generic clades (i.e. particularly those broader than subfamilies). In this study, we provide the first robust phylogenetic hypothesis of theraphosid evolution inferred from transcriptome data. A core ortholog approach was used to generate a phylogeny from 2460 orthologous genes across 25 theraphosid genera, representing all of the major theraphosid subfamilies, except Selenogyrinae. For the first time our phylogeny recovers a monophyletic group that comprises the vast majority of New World theraphosid subfamilies including Aviculariinae and Theraphosinae. Concurrently, we provide additional evidence for the integrity of questionable subfamilies, such as Poecilotheriinae and Psalmopoeinae, and support the non-monophyly of Ischnocolinae. The deeper relationships between almost all subfamilies are confidently inferred for the first time. We also used our phylogeny in tandem with published morphological data to perform ancestral state analyses on urticating setae. This revealed that the evolution of this important defensive trait might be explained by three equally parsimonious scenarios.
The Relation between Alpha/Beta Oscillations and the Encoding of Sentence induced Contextual Information
Authors: Terporten Rene , Schoffelen Jan-Mathijs , Dai Bohan , Hagoort Peter , Koesem Anne
Published: December 2018

Within the sensory domain, alpha/beta oscillations have been frequently linked to the prediction of upcoming sensory input. Here, we investigated whether oscillations at these frequency bands serve as a neural marker in the context of linguistic input prediction as well. Specifically, we hypothesized that if alpha/beta oscillations do index language prediction, their power should modulate during sentence processing, indicating stronger engagement of underlying neuronal populations involved in the linguistic prediction process. Importantly, the modulation should monotonically relate to the degrees of predictability of incoming words based on past context. Specifically, we expected that the more predictable the last word of a sentence, the stronger the alpha/beta power modulation. To test this, we measured neural responses with magnetoencephalography of healthy individuals (of either sex) during exposure to a set of linguistically matched sentences featuring three distinct levels of sentence context constraint (high, medium and low constraint). We observed fluctuations in alpha/beta power before last word onset, and also modulations in M400 amplitude after last word onset that are known to gradually relate to semantic predictability. In line with previous findings, the M400 amplitude was monotonically related to the degree of context constraint, with a high constraining context resulting in the strongest amplitude decrease. In contrast, alpha/beta power was non-monotonically related to context constraints. The strongest power decrease was observed for intermediate constraints, followed by high and low constraints. While the monotonous M400 amplitude modulation fits within a framework of prediction, the non-monotonous oscillatory results are not easily reconciled with this idea.
Augmin-mediated amplification of long-lived spindle microtubules directs plus-ends to kinetochores
Authors: David Ana F. , Roudot Philippe , Legant Wesley R. , Betzig Eric , Danuser Gaudenz , Gerlich Daniel W.
Published: December 2018

Dividing cells reorganize their microtubule cytoskeleton into a bipolar spindle, which moves one set of sister chromatids to each nascent daughter cell. Early spindle assembly models postulated that spindle-pole-derived microtubules search the cytoplasmic space until they randomly encounter a kinetochore to form a stable attachment. More recent work uncovered several additional, centrosome-independent microtubule generation pathways, but the contributions of each pathway to spindle assembly have remained unclear. Here, we combined live microscopy and mathematical modeling to show that most microtubules nucleate at non-centrosomal regions in dividing human cells. Using a live-cell probe that selectively labels aged microtubule lattices, we demonstrate that the distribution of growing microtubule plus-ends can be almost entirely explained by Augmin-dependent amplification of long-lived microtubules. By ultra-fast 3D lattice light-sheet microscopy, we observed that this mechanism results in a strong directional bias of microtubule growth towards individual kinetochores. Our systematic quantification of spindle dynamics reveals highly coordinated microtubule growth during kinetochore-fiber assembly.
Cortical patterning of abnormal morphometric similarity in psychosis is associated with brain expression of schizophrenia related genes
Authors: Morgan Sarah E , Seidlitz Jakob , Whitaker Kirstie , Romero-Garcia Rafael , Clifton Nicholas E , Scarpazza Cristina , Amelsvoort Therese van , Marcelis Machteld , Os Jim van , Donohoe Gary , Mothersill David , Corvin Aiden , Pocklington Andrew , Raznahan Armin , McGuire Philip ,   The PSYSCAN Consortium, Vértes Petra E , Bullmore Edward T
Published: December 2018

Schizophrenia has been conceived as a disorder of brain connectivity but it is unclear how this network phenotype is related to the emerging genetics. We used morphometric similarity analysis of magnetic resonance imaging (MRI) data as a marker of inter-areal cortical connectivity in three prior case-control studies of psychosis: in total, N=185 cases and N=227 controls. Psychosis was associated with globally reduced morphometric similarity (MS) in all 3 studies. There was also a replicable pattern of case-control differences in regional MS which was significantly reduced in patients in frontal and temporal cortical areas, but increased in parietal cortex. Using prior brain-wide gene expression data, we found that the cortical map of case-control differences in MS was spatially correlated with cortical expression of a weighted combination of genes enriched for neu-robiologically relevant ontology terms and pathways. In addition, genes that were normally over-expressed in cortical areas with reduced MS were significantly up-regulated in a prior post mortem study of schizophrenia. We propose that this combination of neuroimaging and transcriptional data provides new insight into how previously implicated genes and proteins, as well as a number of unreported proteins in their vicinity on the protein interaction network, may interact to drive structural brain network changes in schizophrenia.
Measurement of junctional tension in epithelial cells at the onset of primitive streak formation in the chick embryo via non-destructive optical manipulation
Authors: Ferro Valentina , Chuai Manli , McGloin David , Weijer Cornelis
Published: December 2018

Oriented cell intercalations and cell shape changes are key determinants of large-scale epithelial cell sheet deformations occurring during gastrulation in many organisms. In several cases directional intercalation and cell shape changes have been shown to be associated with a planar cell polarity in the organisation of the actin-myosin cytoskeleton of epithelial cells. This polarised cytoskeletal organisation has been postulated to reflect the directional tension necessary to drive and orient directional cell intercalations. We have now further characterised and applied a recently introduced non-destructive optical manipulation technique to measure the tension in individual cell junctions in the epiblast of chick embryos in the early stages of primitive streak formation. We have measured junctional tension as a function of position and orientation. Junctional tension of mesendoderm cells, the tissue that drives the formation of the streak, is higher than tension of junctions of cells in other parts of the epiblast. Furthermore, in the mesendoderm junctional tension is higher in the direction of intercalation. The data are fitted best with a Maxwell model and we find that both junctional tension and relaxation time are dependent on myosin activity.
pVACtools: a computational toolkit to identify and visualize cancer neoantigens
Authors: Hundal Jasreet , Kiwala Susanna , McMichael Joshua , Miller Christopher A. , Wollam Alexander T. , Xia Huiming , Liu Connor J. , Zhao Sidi , Feng Yang-Yang , Graubert Aaron P. , Wollam Amber Z. , Neichin Jonas , Neveau Megan , Walker Jason , Gillanders William E , Mardis Elaine R. , Griffith Obi L. , Griffith Malachi
Published: December 2018

Identification of neoantigens is a critical step in predicting response to checkpoint blockade therapy and design of personalized cancer vaccines. We have developed an in silico sequence analysis toolkit - pVACtools, to facilitate comprehensive neoantigen characterization. pVACtools supports a modular workflow consisting of tools for neoantigen prediction from somatic alterations (pVACseq and pVACfuse), prioritization and selection using a graphical web-based interface (pVACviz) and design of DNA vector-based vaccines (pVACvector) and synthetic long peptide vaccines. pVACtools is available at pvactools.org.
Striatal volume and functional connectivity predict weight gain in early-phase psychosis
Authors: Homan Philipp , Argyelan Miklos , Fales Christina L. , DeRosse Pamela , Szeszko Philip , Robinson Delbert G. , Lencz Todd , Malhotra Anil K.
Published: December 2018

Background: Second-generation antipsychotic drugs (SGAs) are essential in the treatment of psychotic disorders, but are well-known for inducing substantial weight gain and obesity. Critically, weight gain may reduce life expectancy for up to 20-30 years in patients with psychotic disorders, and prognostic biomarkers are generally lacking. The dorsal striatum, rich in dopamine D2 receptors which are antagonized by antipsychotic medications, plays a key role in the human reward system and in appetite regulation, suggesting that altered dopamine activity in the striatal reward circuitry may be responsible for increased food craving and resultant weight gain.
Methods: Here, we measured striatal volume and striatal resting state functional connectivity at baseline, and weight gain over the course of 12 weeks of antipsychotic treatment in 81 patients with early-phase psychosis. We also included a sample of 58 healthy controls. Weight measurements were completed at baseline, and then weekly for 4 weeks, and every 2 weeks until week 12. We used linear mixed models to compute individual weight gain trajectories. Striatal volume and whole-brain striatal connectivity were then calculated for each subject, and used to assess the relationship between striatal structure and function and individual weight gain in multiple regression models.
Outcomes: Patients had similar baseline weights and body mass indices (BMI) compared to healthy controls. There was no evidence that prior drug exposure or duration of untreated psychosis correlated with baseline BMI. Higher left putamen volume and lower frontopolar connectivity predicted magnitude of weight gain in patients, and these effects multiplied when the structure-function interaction was considered.
Interpretation: These results provide evidence for a synergistic effect of striatal structure and function on antipsychotics-induced weight gain. Lower fronto-striatal connectivity, implicated in less optimal long-term decision making, was associated with more weight gain, and this relationship was stronger for higher compared to lower left putamen volumes.
Use of F2 bulks in training sets for genomic prediction of combining ability and hybrid performance
Authors: Technow Frank
Published: December 2018

Developing training sets for genomic prediction in hybrid crops requires producing hybrid seed for a large number of entries. In autogamous crop species (e.g., wheat, rice, rapeseed, cotton) this requires elaborate hybridization systems to prevent self-pollination and presents a significant impediment to the implementation of hybrid breeding in general and genomic selection in particular. An alternative to F1 hybrids are bulks of F2 seed from selfed F1 plants (F1:2). Seed production for F1:2 bulks requires no hybridization system because the number of F1 plants needed for producing enough F1:2 seed for multi-environment testing can be generated by hand-pollination. This study evaluated the suitability of F1:2 bulks for use in training sets for genomic prediction of F1 level general combining ability and hybrid performance, under different degrees of divergence between heterotic groups and modes of gene action, using quantitative genetic theory and simulation of a genomic prediction experiment. The simulation, backed by theory, showed that F1:2 training sets are expected to have a lower prediction accuracy relative to F1 training sets, particularly when heterotic groups have strongly diverged. The accuracy penalty, however, was only modest and mostly because of a lower heritability, rather than because of a difference in F1 and F1:2 genetic values. It is concluded that resorting to F1:2 bulks is, in theory at least, a promising approach to remove the significant complication of a hybridization system from the breeding process.
Systematic Mapping of cell Wall Mechanics in the Regulation of Cell Morphogenesis
Authors: Davì Valeria , Guo Haotian , Tanimoto Hirokazu , Barett Katia , Couturier Etienne , Boudaoud Arezki , Minc Nicolas
Published: December 2018

Walled cells of plants, fungi and bacteria, come with a large range of shapes and sizes, which are ultimately dictated by the mechanics of their cell wall. This stiff and thin polymeric layer encases the plasma membrane and protects the cells mechanically by opposing large turgor pressure derived stresses. To date, however, we still lack a quantitative understanding for how local and/or global mechanical properties of the wall support cell morphogenesis. Here, we combine super-resolution imaging, and laser-mediated wall relaxation, to quantitate subcellular values of wall thickness (h) and bulk elastic moduli (Y) in large populations of live mutant cells and conditions affecting cell diameter in the rod-shaped model fission yeast. We find that lateral wall stiffness, defined by the surface modulus, σ=hY, robustly scales with cell diameters. This scaling is valid in tens of mutants covering various functions, within the population of individual isogenic strains, along single misshaped cells, and even across the fission yeasts clade. Dynamic modulations of cell diameter by chemical and/or mechanical means suggest that the cell wall can rapidly adapt its surface mechanics, rendering stretched wall portions stiffer than unstretched ones. Size-dependent wall stiffening constrains diameter definition and limits size variations, and may also provide and efficient mean to keep elastic strains in the wall below failure strains potentially promoting cell survival. This quantitative set of data impacts our current understanding of the mechanics of cell walls, and its contribution to morphogenesis.
Molecular epidemiology and high mortality of Crimean-Congo hemorrhagic fever in Oman: a re-emerging infection
Authors: Al-Abri Seif , Hewson Roger , Al-Kindi Hanan , Al-Abaidani Idris , Al-Jardani Amina , Al-Maani Amal , Almahrouqi Samira , Atkinson Barry , Al-Wahaibi Adil , Al-Rawahi Bader , Bawikar Shyam , Beeching Nicholas J
Published: December 2018

Background

Crimean-Congo hemorrhagic fever (CCHF) is a serious disease with a high fatality rate reported in many countries. The first case of CCHF in Oman was detected in 1995 and serosurveys have suggested widespread infection of humans and livestock throughout the country.

Methodology

Cases of CCHF reported to the Ministry of Health (MoH) of Oman between 1995 and 2017 were retrospectively reviewed. Diagnosis was confirmed by serology and/or molecular tests in Oman. Stored RNA from recent cases was studied by sequencing the complete open reading frame (ORF) of the viral S segment at Public Health England, enabling phylogenetic comparisons to be made with other S segments of strains obtained from the region.

Findings

Of 88 cases of CCHF, 4 were sporadic in 1995 and 1996, then none occurred until 2011. From 2011-2017, incidence has steadily increased and 19 (23.8%) of 80 cases clustered around Eid Al Adha. The median (range) age was 33 (15-68) years and 79 (90%) were male. The major risk for infection was contact with animals and/or butchering in 73/88 (83%) and only one case was related to tick bites alone. Severe cases were over-represented: 64 (72.7%) had a platelet count < 50 x 109/L and 32 (36.4%) died. There was no intrafamilial spread or healthcare-associated infection. The viral S segments from 11 patients presenting in 2013 and 2014 were all grouped in Asia 1 (IV) lineage.

Conclusions

CCHF is well-established throughout Oman, with a single strain of virus present for at least 20 years. Most patients are men involved in animal husbandry and butchery. The high mortality suggests that there is substantial under-diagnosis of milder cases. Preventive measures have been introduced to reduce risks of transmission to animal handlers and butchers and to maintain safety in healthcare settings.
Mother to child blocking of hepatitis B virus and post vaccination serological test in Qinghai province
Authors: Xiaojun Ma , Wensheng Ba , Zengping Hao , Puren Li , Jianhai Zhao , Xitao Ai , Xianglu Zhu , Kezhong A , Xueqin Yang , Yanmei Ma , Zhongjiu Li , Lianwei Li , Bingju Guan , Xianglan Li , Shourong Zhang , Zhen Li , Jinhua Zhao , Juan Ma , So SAMUEL , Jianmin Zhang
Published: December 2018

Background
In 2016, Qinghai Province and the Asian Liver Center of Stanford University in the United States cooperated to carry out a one-year project of hepatitis B mother-to-child blockade and post-immunization serological test in our province. Through this study, we evaluated the current situation of hepatitis B maternal and infant blockade and the effect of maternal and infant blockade in multi-ethnic areas of Qinghai Province.

Methods

From May 1, 2016 to April 30, 2017, all pregnant women who gave birth in Qinghai Province were screened for HBsAg. For pregnant women who were screened for HBsAg positive, the medical staff had a detailed understanding of the history and treatment of hepatitis B, and provided scientific nutritional support and guidance. Free hepatitis B immunoglobulin (100 units) injections were given to newborns born to HBsAg-positive mothers within 12 hours after birth, and three doses of hepatitis B vaccination were given. All newborns born to HBsAg-positive mothers were followed up from 1 to 3 months after complete immunization of HBIG and HepB. The County (district) CDC was responsible for rapid fingertip blood screening, screening for HBsAg-positive children, collecting 3ml of venous blood for quantitative detection of HBsAg.

Results

During the study period, 61381 pregnant women were hospitalized, 6027 (97.79%) pregnant women were screened for HBsAg. 1912 pregnant women were detected positive for HBsAg, with a positive rate of 3.19%. The HepB vaccine rate was 97.11% in live infants within 24 hours. The vaccination rate of hepatitis B vaccine was 94.78% and the injection rate of HBIG was 97.15% in 12-hour live delivery children of HBsAg positive mothers. A total of 864 newborns born to HBsAg positive mothers were followed up. Fast fingertip blood test was performed 1-3 months after HBIG injection and whole course hepatitis B vaccination. The positive rate of HBsAg was 5.21%. 34 positive serum samples were detected by chemiluminescent immunoassay in the laboratory of provincial CDC. The coincidence rate of HBsAg positive was 82.35%, and that of HBV DNA positive was 79.41%. Fifty-seven children with HBV surface antibody negative were detected and vaccinated with HBV vaccine free of charge in the whole course according to the national immunization program.

Conclusion

The infection rate of hepatitis B among women of childbearing age in Qinghai province is 3.19%, and the blocking rate of mother and infant is 94.79%. It is still necessary to strengthen the injection of hepatitis B vaccine and HBIG for positive mothers and children.
Spatio-temporal variation of skeletal Mg-calcite in Antarctic marine calcifiers in a global change scenario
Authors: Figuerola Blanca , Gore Damian , Johnstone Glenn , Stark Jonathan
Published: December 2018

Human driven changes such as increases in oceanic CO2, global warming and pollution may negatively affect the ability of marine calcifiers to build their skeletons/shells, especially in polar regions. Here we address, for the first time, spatio-temporal variability of skeletal Mg-calcite using bryozoan and serpulid species as models in a recruitment experiment of settlement tiles in East Antarctica. Mineralogies were determined using X-ray diffractometry for 754 specimens belonging to six bryozoan species (four cheilostome and two cyclostome species) and two serpulid species from around Casey Station. All species had calcitic skeletons. Intra- and interspecific variability in wt% MgCO3 in calcite among most species contributed to the biggest source of variation overall. Therefore, biological processes seem to be the main factor controlling the skeletal Mg-calcite in these taxa. However, spatial variability found in wt% MgCO3 in calcite could also reflect local impacts such as freshwater input and contaminated sediments. The vulnerability of these species to global change is also examined and those species with high-Mg calcite skeletons and low thermal tolerance (e.g. Beania erecta) could be particularly sensitive to near-future global ocean chemistry changes.
The α-tubulin of Laodelphax striatellus facilitates the passage of rice stripe virus (RSV) and enhances horizontal transmission
Authors: Li Yao , Chen Danyu , Hu Jia , Zhang Lu , Xiang Yin , Liu Fang ,   Yao Li, Danyu Chen, Jia Hu, Lu Zhang, Yin Xiang, Fang Liu
Published: December 2018

Rice stripe virus (RSV), causal agent of rice stripe disease, is transmitted by the small brown planthopper (SBPH, Laodelphax striatellus) in a persistent manner. The midgut and salivary glands of SBPH are the first and last barriers in viral circulation and transmission, respectively; however, the precise mechanisms used by RSV to cross these organs and re-inoculate rice have not been fully elucidated. We obtained full-length cDNA of L. striatellus α-tubulin 2 (LsTUB) and found that RSV infection increased the level of LsTUB in vivo. Furthermore, LsTUB was shown to bind the RSV nonstructural protein 3 (NS3) in vitro. RNAi was used to reduce LsTUB expression, which caused a significant reduction in RSV titer, NS3 expression, RSV inoculation rates, and transmission to healthy plants. Electrical penetration graphs (EPG) showed that LsTUB knockdown by RNAi did not impact SBPH feeding; therefore, the reduction in RSV inoculation rate was likely caused by the decrease in RSV transmission. These findings suggest that LsTUB mediates the passage of RSV through midgut and salivary glands and leads to successful horizontal transmission.
Intrinsic polarization cues interfere with pheromone gradient sensing in S. cerevisiae
Authors: Vasen Gustavo , Colman Lerner Alejandro
Published: December 2018

Polarity decisions are central to many processes, including mitosis and chemotropism. In S. cerevisiae, budding and mating projection (MP) formation use an overlapping system of cortical landmarks that converge on the small G-protein Cdc42. However, pheromone gradient sensing must override the Rsr1-dependent internal polarity cues used for budding. Using this model system, we asked what happens when intrinsic and extrinsic spatial cues are misaligned. Is there competition, or collaboration? By live cell microscopy and microfluidics technics we uncovered three previously overlooked features of this signaling system. First, the cytokinesis-associated polarization patch serves as a polarity landmark independently of all known cues. Second, the Rax1-Rax2 complex functions as novel pheromone promoted polarity cue in the distal pole of the cells. Finally, we showed that internal cues remain active during pheromone gradient tracking and that they interfere with this process biasing the location of MPs, since yeast defective in internal cue utilization align significantly better than wild- type with artificially generated pheromone gradients.
Structural basis for activation of Dot1L methyltransferase on the nucleosome by histone H2BK120 ubiquitylation
Authors: Anderson Cathy J , Baird Matthew R , Hsu Allen , Barbour Emily H , Koyama Yuka , Borgnia Mario J , McGinty Robert K
Published: December 2018

Histone H3 lysine 79 (H3K79) methylation is enriched on actively transcribed genes, and its misregulation is a hallmark of leukemia. Methylation of H3K79, which resides on the structured disk face of the nucleosome, is mediated by the Dot1L methyltransferase. Dot1L activity is part of a trans-histone crosstalk pathway, requiring prior histone H2B ubiquitylation of lysine 120 (H2BK120ub) for optimal activity. However, the molecular details describing both how Dot1L binds to the nucleosome and why Dot1L is activated by H2BK120 ubiquitylation are unknown. Here we present the cryo-EM structure of Dot1L bound to a nucleosome reconstituted with a site-specifically ubiquitylated H2BK120. The structure reveals that Dot1L engages the nucleosome acidic patch using an arginine anchor and occupies a conformation poised for methylation. Ubiquitin directly interacts with Dot1L and is positioned as a clamp on the nucleosome interacting region of Dot1L. Using our structure, we identify point mutations that disrupt the nucleosome-specific and ubiquitin-dependent activities of Dot1L. This study establishes a path to better understand Dot1L function in normal and leukemia cells.
Regulation of MLL/COMPASS stability through its proteolytic cleavage by taspase1 as a possible approach for clinical therapy of leukemia
Authors: Zhao Zibo , Wang Lu , Volk Andrew G. , Birch Noah W. , Stoltz Kristen L. , Bartom Elizabeth T. , Marshall Stacy A. , Rendleman Emily J. , Nestler Carson M. , Shilati Joseph , Schiltz Gary E. , Crispino John D. , Shilatifard Ali
Published: December 2018

Chromosomal translocations of the Mixed-lineage leukemia 1 (MLL1) gene generate MLL chimeras that drive the pathogenesis of acute myeloid and lymphoid leukemia. The untranslocated MLL1 is a substrate for proteolytic cleavage by the endopeptidase threonine aspartase 1 (taspase1); however, the biological significance of MLL1 cleavage by this endopeptidase remains unclear. Here, we demonstrate that taspase1-dependent cleavage of MLL1 results in the destabilization of MLL. Upon loss of taspase1, MLL1 association with chromatin is markedly increased due to the stabilization of its unprocessed version, and this stabilization of the uncleaved MLL1 can result in the displacement of MLL chimeras from chromatin in leukemic cells. Casein kinase II (CKII) phosphorylates MLL1 proximal to the taspase1 cleavage site, facilitating its cleavage, and pharmacological inhibition of CKII blocks taspase1-dependent MLL1 processing, increases MLL1 stability, and results in the displacement of the MLL chimeras from chromatin. Accordingly, inhibition of CKII in a MLL-AF9 mouse model of leukemia delayed leukemic progression in vivo. This study provides insights into the direct regulation of the stability of MLL1 through its cleavage by taspase1, which can be harnessed for targeted therapeutic approaches for the treatment of aggressive leukemia as the result of MLL translocations.