bluuebunny/crossref_metadata_2025 huggingface dataset:
LongAxis: a MATLAB-based program for 3D quantitative analysis of epithelial cell shape and orientation
Authors: Carney Keith R. , Bryan Chase D. , Gordon Hannah B. , Kwan Kristen M.
Published: June 2019

Epithelial morphogenesis, a fundamental aspect of development, generates 3-dimensional tissue structures crucial for organ function. Underlying morphogenetic mechanisms are, in many cases, poorly understood, but mutations that perturb organ development can affect epithelial cell shape and orientation – difficult features to quantify in three dimensions. The basic structure of the eye is established via epithelial morphogenesis: in the embryonic optic cup, the retinal progenitor epithelium enwraps the lens. We previously found that loss of the extracellular matrix proteinlaminin-alpha1(lama1) led to mislocalization of apical polarity markers and apparent misorientation of retinal progenitors. We sought to visualize and quantify this phenotype, and determine whether loss of the apical polarity determinantpard3might rescue the phenotype. To this end, we developed LongAxis, a MATLAB-based program optimized for the retinal progenitor neuroepithelium. LongAxis facilitates 3-dimensional cell segmentation, visualization, and quantification of cell orientation and morphology. Using LongAxis, we find that retinal progenitors in thelama1−/−optic cup are misoriented and slightly less elongated. In thelama1;MZpard3double mutant, cells are still misoriented, but larger. Therefore, loss ofpard3does not rescue loss oflama1, and in fact uncovers a novel cell size phenotype. LongAxis enables population-level visualization and quantification of retinal progenitor cell orientation and morphology. These results underscore the importance of visualizing and quantifying cell orientation and shape in three dimensions within the retina.
Should virus capsids assemble perfectly? Theory and observation of defects
Authors: Spiriti Justin , Conway James F. , Zuckerman Daniel M.
Published: June 2019

Although published structural models of viral capsids generally exhibit a high degree of regularity or symmetry, structural defects might be expected because of the fluctuating environment in which capsids assemble and the requirement of some capsids for disassembly prior to genome delivery. Defective structures are observed in computer simulations, and are evident in single-particle cryoEM studies. Here, we quantify the conditions under which defects might be expected, using a statistical mechanics model allowing for ideal, defective, and vacant sites. The model displays a threshold in affinity parameters below which there is an appreciable population of defective capsids. Even when defective sites are not allowed, there is generally some population of vacancies. Analysis of single particles in cryoEM micrographs yields a confirmatory ≳15% of defective particles. Our findings suggest structural heterogeneity in virus capsids may be under-appreciated, and also points to a non-traditional strategy for assembly inhibition.
Split-gene drive system provides flexible application for safe laboratory investigation and potential field deployment
Authors: Del Amo Víctor López , Bishop Alena L. , Sánchez C. Héctor M. , Bennett Jared B. , Feng Xuechun , Marshall John M. , Bier Ethan , Gantz Valentino M.
Published: June 2019

CRISPR-based gene drives spread through populations bypassing the dictates of Mendelian genetics, offering a population-engineering tool for tackling vector-borne diseases, managing crop pests, and helping island conservation efforts; unfortunately, current technologies raise safety concerns for unintended gene propagation. Herein, we address this by splitting the two drive components, Cas9 and gRNAs, into separate alleles to form a novel trans-complementing split–gene-drive (tGD) and demonstrate its ability to promote super-Mendelian inheritance of the separate transgenes. This bi-component nature allows for individual transgene optimization and increases safety by restricting escape concerns to experimentation windows. We employ the tGD and a small– molecule-controlled version to investigate the biology of component inheritance and use our system to study the maternal effects on CRISPR inheritance, impaired homology on efficiency, and resistant allele formation. Lastly, mathematical modeling of tGD spread in a population shows potential advantages for improving current gene-drive technologies for field population modification.
Graphene Quantum Dot Oxidation Governs Noncovalent Biopolymer Adsorption
Authors: Jeong Sanghwa , Pinals Rebecca L. , Dharmadhikari Bhushan , Song Hayong , Kalluri Ankarao , Debnath Debika , Qi Wu , Ham Moon-Ho , Patra Prabir , Landry Markita P.
Published: June 2019

The graphene quantum dot (GQD) is a carbon allotrope with a planar surface amenable for functionalization and nanoscale dimensions that confer photoluminescent properties. Collectively, these properties render GQDs an advantageous platform for nanobiotechnology applications, including as optical biosensors and delivery platforms. In particular, noncovalent functionalization offers a route to reversible modification and preservation of the pristine GQD substrate. However, a clear paradigm for GQD noncovalent functionalization has yet to be realized. Herein, we demonstrate the feasibility of noncovalent polymer adsorption to the GQD surface, with a specific focus on single-stranded DNA (ssDNA). We study how GQD oxidation level affects the propensity for polymer adsorption by synthesizing and characterizing four types of GQD substrates and investigating noncovalent polymer association to these substrates. Distinct adsorption methods are developed for successful ssDNA attachment based upon the GQD’s initial level of oxidation. ssDNA adsorption to the GQD is confirmed by atomic force microscopy, by inducing ssDNA desorption, and with molecular dynamics simulations. ssDNA is determined to adsorb strongly to no-oxidation GQDs, weakly to low-oxidation GQDs, and not at all for heavily oxidized GQDs. We hypothesize that high GQD oxygen content disrupts the graphitic carbon domains responsible for stacking with the aromatic ssDNA bases, thus preventing the formation of stable polymer-GQD complexes. Finally, we develop a more generic adsorption platform and assess how the GQD system is tunable by modifying both the polymer sequence and type.
Processivity and Velocity for Motors Stepping on Periodic Tracks
Authors: Mugnai M.L. , Caporizzo M.A. , Goldman Y.E. , Thirumalai D.
Published: June 2019

Processive molecular motors enable cargo transportation by assembling into dimers capable of taking several consecutive steps along a cytoskeletal filament. In the well-accepted hand-over-hand stepping mechanism the trailing motor detaches from the track and binds the filament again in leading position. This requires fuel consumption in the form of ATP hydrolysis, and coordination of the catalytic cycles between the leading and the trailing heads. However, alternative stepping mechanisms exist, including inchworm-like movements, backward steps, and foot stomps. Whether all of these pathways are coupled to ATP hydrolysis remains to be determined. Here, in order to establish the principles governing the dynamics of processive movement, we present a theoretical framework which includes all of the alternative stepping mechanisms. Our theory bridges the gap between the elemental rates describing the biochemical and structural transitions in each head, and the experimentally measurable quantities, such as velocity, processivity, and probability of backward stepping. Our results, obtained under the assumption that the track is periodic and infinite, provide expressions which hold regardless of the topology of the network connecting the intermediate states, and are therefore capable of describing the function of any molecular motor. We apply the theory to myosin VI, a motor that takes frequent backward steps, and moves forward with a combination of hand-over-hand and inchworm-like steps. Our model reproduces quantitatively various observables of myosin VI motility measured experimentally from two groups. The theory is used to predict the gating mechanism, the pathway for backward stepping, and the energy consumption as a function of ATP concentration.

Significance Statement

Molecular motors harness the energy released by ATP hydrolysis to transport cargo along cytoskeletal filaments. The two identical heads in the motor step alternatively on the polar track by communicating with each other. Our goal is to elucidate how the coordination between the two heads emerges from the catalytic cycles. To do so, we created a theoretical framework that allows us to relate the measurable features of motility, such as motor velocity, with the biochemical rates in the leading and trailing heads, thereby connecting biochemical activity and motility. We illustrate the efficacy of the theory by analyzing experimental data for myosin VI, which takes frequent backward steps, and moves forward by a hand-over-hand and inchworm-like steps.
Dynamics between horizontal gene transfer and acquired antibiotic resistance inS. Heidelberg followingin vitroincubation in broiler ceca
Authors: Oladeinde Adelumola , Cook Kimberly , Lakin Steven M. , Abdo Zaid , Looft Torey , Herrington Kyler , Zock Gregory , Lawrence Jodie Plumblee , Thomas Jesse C. , Beaudry Megan S. , Glenn Travis
Published: June 2019

The chicken gastrointestinal tract harbors taxa of microorganisms that play a role in the health and disease status of the host. The cecum is the part of the gut that carries the highest microbial densities, has the longest residence time of digesta and is a vital site for urea recycling and water regulation. Therefore, the cecum provides a rich environment for bacteria to horizontally transfer genes between one another via mobile genetic elements such as plasmids and bacteriophages. In this study, we used broiler chicken cecum as a model to investigate antibiotic resistance genes that can be transferredin vitrofrom ceca flora toSalmonella entericaserovar Heidelberg (S. Heidelberg). We used whole genome sequencing and resistome enrichment to decipher the interactions betweenS. Heidelberg, gut microbiome and acquired antibiotic resistance. After 48 h incubation of ceca under microaerophilic conditions, oneS. Heidelberg isolate was recovered with an acquired Inck2 plasmid (88 kb) encoding extended β-lactamase producing gene (blaCMY-2).In vitro, this plasmid was transferrable betweenE. coliandS. Heidelberg strains, but transfer was unsuccessful betweenS. Heidelberg strains. An in-depth genetic characterization of transferred plasmids suggests that they share significant homology with P1-like phages. This study contributes to our understanding of the dynamics between an important food-borne pathogen and the chicken gut microbiome.

Importance

S.Heidelberg is a clinically important serovar, linked to food-borne illness and among the top 5 serovars isolated from poultry in USA and Canada. Acquisition of new genetic material from microbial flora in the gastrointestinal tract of food animals, including broilers, may contribute to increased fitness of pathogens likeS.Heidelberg and may increase their level of antibiotic tolerance. Therefore, it is critical to gain a better understanding on the dynamic interactions that occur between important pathogens and the commensals present in the animal gut and other agroecosystems. In this study, we show that the native flora in the broiler ceca were capable of transferring mobile genetic elements carrying AmpC β-lactamase (blaCMY-2) gene to an important food-borne pathogenS. Heidelberg. The potential role for P1-like bacteriophage transduction was also discussed.
Early removal of senescent cells protects retinal ganglion cells loss in experimental ocular hypertension
Authors: Rocha Lorena Raquel , Nguyen Huu Viet Anh , Palomino La Torre Claudia , Xu Qianlan , Jabari Mary , Krawczyk Michal , Weinreb Robert N. , Skowronska-Krawczyk Dorota
Published: June 2019

Experimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimicks events occurring in human glaucoma. Senescence-related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to as the senescence-associated secretory phenotype (SASP). Emerging evidence suggests that the presence of these proinflammatory and matrix-degrading molecules has deleterious effects in a variety of tissues. In the current study, we demonstrated in a transgenic mouse model that early removal of senescent cells induced upon elevated intraocular pressure (IOP) protects unaffected RGCs from senescence and apoptosis. Visual evoked potential (VEP) analysis demonstrated that remaining RGCs are functional and that the treatment protected visual functions. Finally, removal of endogenous senescent retinal cells after IOP elevation by a treatment with senolytic drug dasatinib prevented loss of retinal functions and cellular structure. Senolytic drugs may have the potential to mitigate the deleterious impact of elevated IOP on RGC survival in glaucoma and other optic neuropathies.
Apolipoprotein M-bound sphingosine-1-phosphate regulates blood-brain barrier paracellular permeability and transcytosis
Authors: Janiurek Mette Mathiesen , Christoffersen Christina , Kucharz Krzysztof , Lauritzen Martin
Published: June 2019

ABTRACT

The blood-brain barrier (BBB) is formed by the endothelial cells lining cerebral microvessels. Here, we report that the BBB permeability is modified by apolipoprotein M (apoM)-bound sphingosine 1-phosphate (S1P). We used two-photon microscopy to monitor changes in BBB permeability in apoM-deficient mice (apoM−/−), showing significant increases in paracellular BBB permeability to small molecules without structural changes in junctional complexes between endothelial cells. Lack of apoM-bound S1P increased vesicle-mediated transfer of albumin across endothelium of brain pial and penetrating arterioles, whereas transcytosis in capillaries and venules remained unchanged. S1PR1 agonist SEW2871 rapidly normalized BBB permeability along both the paracellular and transcellular routes in apoM−/− mice. Thus, apoM-bound S1P maintains low paracellular BBB permeability for small molecules in all cerebral microvessels and low levels of adsorptive transcytosis in penetrating arterioles. Modulation of apoM/S1P-dependent signaling may be a novel strategy for the protection of brain endothelial cells to preserve the BBB function.
Alpha/Beta Hydrolase Domain-Containing Protein 2 regulates the rhythm of follicular maturation and estrous stages of the female reproductive cycle
Authors: Björkgren Ida , Chung Dong Hwa , Mendoza Sarah , Gabelev-Khasin Liliya , Modzelewski Andrew , He Lin , Lishko Polina V.
Published: June 2019

Therian female fertility is defined by a successful and strictly periodic ovarian cycle, which is under the control of gonadotropins and steroid hormones, particularly progesterone and estrogen. The latter two are produced by the ovaries that are engaged in controlled follicular growth, maturation and release of the eggs, i.e. ovulation. It is well known that steroid hormones regulate ovarian cycles via genomic signaling, by altering gene transcription and protein synthesis. However, despite this well-studied mechanism, steroid hormones can also signal via direct, non-genomic action, by binding to their membrane receptors. Here we show, that the recently discovered sperm membrane progesterone receptor α/β hydrolase domain-containing protein 2 (ABHD2) is highly expressed in mammalian ovaries where the protein plays a novel regulatory role in follicle maturation and the sexual cycle of females. Ablation ofAbhd2caused a dysregulation of the estrous cycle rhythm with females showing shortened luteal stages while remaining in the estrus stage for a longer time. Interestingly, the ovaries ofAbhd2knockout (KO) females resemble polycystic ovary morphology with a high number of atretic antral follicles that could be rescued with injection of gonadotropins. Such a procedure also allowedAbhd2KO females to ovulate a significantly increased number of mature and fertile eggs in comparison to their wild-type littermates. These results suggest a novel regulatory role of ABHD2 as an important factor in non-genomic steroid regulation of the female reproductive cycle.
ω-imidazolyl-alkyl derivatives as new preclinical drug candidates for NASH therapy
Authors: Diesinger Torsten , Lautwein Alfred , Buko Vyacheslav , Belonovskaya Elena , Lukivskaya Oksana , Naruta Elena , Kirko Siarhei , Andreev Viktor , Dvorsky Radovan , Buckert Dominik , Bergler Sebastian , Renz Christian , Müller-Enoch Dieter , Wirth Thomas , Haehner Thomas
Published: June 2019

Cytochrome P450 2E1 (CYP2E1) and its production of ROS play an essential role in the development and progression of inflammatory liver diseases such as alcoholic steatohepatitis. For this isoenzyme we have developed two new inhibitors - 12-imidazolyl-1-dodecanol (I-ol) and 1-imidazolyldodecane (I-an) - and wanted to test their effect on the related disease of non-alcoholic steatohepatitis (NASH). The fat-rich Lieber-DeCarli diet, which was administered over the entire experimental period of 16 weeks, was used for disease induction in the rat model, while the experimental substances were administered in parallel over the last four weeks. This high-calorie diet pathologically altered the ROS balance, the amount of adipocytokines, TNF-α and lipids as well as the activities of liver enzymes. Together with the histological examinations, the conclusion could be drawn that the diet led to the formation of NASH. I-ol and to a lesser extent I-an were able to shift the pathological values towards the normal range - despite continued administration of the noxious agent. I-ol, in particular, showed an extremely good tolerability in the acute toxicity study in rats. Thus, CYP2E1 appears to be a suitable drug target as well as I-ol and I-an promising drug candidates for the treatment of NASH.
SAPdb: A database of nanostructures formed by self-assembly of short peptides
Authors: Mathur Deepika , Kaur Harpreet , Dhall Anjali , Sharma Neelam , Raghava Gajendra P. S.
Published: June 2019

Background

Nanostructures generated by self-assembly of peptides yield nanomaterial that has many therapeutic applications, including drug delivery and biomedical engineering, due to their low cytotoxicity and higher uptake by targeted cells owing to their high affinity and specificity towards cell surface receptors. Despite the promising implications of this rapidly expanding field, there is no dedicated resource to study peptide nanostructures.

Result

This study endeavours to create a dedicated repository of short peptides, which may prove to be the best models to study ordered nanostructures formed by peptide self-assembly. SAPdb has a repertoire of 1,049 entries of experimentally validated nanostructures formed by the self-assembling of small peptides. It includes 701 entries are of dipeptides, 328 entries belong to tripeptides, and 20 entries of single amino acid with some conjugated partners. Each entry encompasses comprehensive information about the peptide such as chemical modifications in the peptide sequences, the type of nanostructure formed, and experimental conditions like pH, temperature, and solvent required for the self-assembly of the peptide, etc. Further, our analysis has shown that the occurrence of aromatic amino acids favours the formation of self-assembling nanostructures, as indicated by a large number of entries in SAPdb contain aromatics amino acids. Besides, we have observed that these peptides form different nanostructures under different experimental conditions. SAPdb provides this comprehensive information in a hassle-free tabulated manner at a glance. User-friendly browsing, searching, and analysis modules are integrated for easy retrieval and comparison of data and examination of properties. We anticipate SAPdb to be a valuable repository for researchers engaged in the burgeoning arena of nanobiotechnology.

Availability

The database can be accessed on the web at https://webs.iiitd.edu.in/raghava/sapdb.
Targeting the Administration of Ecdysterone in Doping Control Samples
Authors: Parr Maria Kristina , Ambrosio Gabriella , Wuest Bernhard , Mazzarino Monica , de la Torre Xavier , Sibilia Francesca , Joseph Jan Felix , Diel Patrick , Botrè Francesco
Published: June 2019

Purpose

The phytosteroid ecdysterone was recently reported to enhance performance in sports and may thus be considered as a substance of relevance in anti-doping control. To trace back an administration of ecdysterone from urine samples analytical properties have been investigated to assess its integration into initial testing procedures (ITP) in doping control laboratories.

Methods

Analytical properties of ecdysterone were evaluated using GC-QTOF-MS and LC-QTOF-MS. Its metabolism and elimination in human were studied using urines collected after administration.

Results

The detectability of ecdysterone by GC-MS (after derivatization) and/or LC-MS(/MS) has been demonstrated and sample preparation methods were evaluated. Dilute-and-inject for LC-MS(/MS) or SPE using Oasis HLB for GC-MS or LC-MS were found most suitable, while liquid-liquid extraction was hampered by the high polarity of ecdysteroids.

Most abundantly, ecdysterone was detected in the post administration urines as parent compound besides the metabolite desoxy-ecdysterone. Additionally desoxy-poststerone was tentatively assigned as minor metabolite, however further investigations are needed.

Conclusion

An administration of ecdysterone can be targeted using existing procedures of anti-doping laboratories. Ecdysterone and desoxy-ecdysterone appeared as suitable candidates for integration in ITP. Using dilute-and-inject a detection of the parent compound was possible for more than two days after the administration of a single dose of ~50 mg.
Long-term activity drives dendritic branch elaboration of a C. elegans sensory neuron
Authors: Cohn Jesse A , Cebul Elizabeth R , Valperga Giulio , de Bono Mario , Heiman Maxwell G , Pierce Jonathan T
Published: June 2019

Neuronal activity often leads to alterations in gene expression and cellular architecture. The nematode Caenorhabditis elegans, owing to its compact translucent nervous system, is a powerful system in which to study conserved aspects of the development and plasticity of neuronal morphology. Here we focus on one sensory neuron in the worm, termed URX, which senses oxygen and signals tonically proportional to environmental oxygen. Previous studies have reported that URX has variable branched endings at its dendritic sensory tip. By controlling oxygen levels and analyzing mutants, we found that these branched endings grow over time as a consequence of neuronal activity. Furthermore, we observed that the branches contain microtubules, but do not appear to harbor the guanylyl cyclase GCY-35, a central component of the oxygen sensory transduction pathway. Interestingly, we found that although URX dendritic tips grow branches in response to long-term activity, the degree of branch elaboration does not correlate with oxygen sensitivity at the cellular or the behavioral level. Given the strengths of C. elegans as a model organism, URX may serve as a potent system for uncovering genes and mechanisms involved in activity-dependent morphological changes in neurons.
Simple spike dynamics of Purkinje cells in the macaque vestibulo-cerebellum reflect sensory prediction error
Authors: Laurens Jean , Angelaki Dora E.
Published: June 2019

Theories of cerebellar functions posit that the cerebellum implements forward models for online correction of motor actions and sensory estimation. As an example of such computations, a forward model compensates for a sensory ambiguity where the peripheral otolith organs in the inner ear sense both head tilts and translations. Here we exploit the response dynamics of two functionally-coupled Purkinje cell types in the caudal vermis to understand their role in this computation. We find that one population encodes tilt velocity, whereas the other, translation-selective, population encodes linear acceleration. Using a dynamical model, we further show that these signals likely represent sensory prediction error for the on-line updating of tilt and translation estimates. These properties also reveal the need for temporal integration between the tilt-selective velocity and translation-selective acceleration population signals. We show that a simple model incorporating a biologically plausible short time constant can mediate the required temporal integration.
Negligible-Cost and Weekend-Free Chemically Defined Human iPSC Culture
Authors: Kuo Hui-Hsuan , Gao Xiaozhi , DeKeyser Jean-Marc , Fetterman K. Ashley , Pinheiro Emily A. , Weddle Carly J. , Fonoudi Hananeh , Orman Michael V. , Romero-Tejeda Marisol , Jouni Mariam , Blancard Malorie , Magdy Tarek , Epting Conrad L. , George Alfred L. , Burridge Paul W.
Published: June 2019

Human induced pluripotent stem cell (hiPSC) culture has become routine, yet pluripotent cell media costs, frequent media changes, and reproducibility of differentiation have remained restrictive, limiting the potential for large-scale projects. Here, we describe the formulation of a novel hiPSC culture medium (B8) as a result of the exhaustive optimization of medium constituents and concentrations, establishing the necessity and relative contributions of each component to the pluripotent state and cell proliferation. B8 eliminates 97% of the costs of commercial media, made possible primarily by the in-lab generation of three E. coli-expressed, codon-optimized recombinant proteins: an engineered form of fibroblast growth factor 2 (FGF2) with improved thermostability (FGF2-G3); transforming growth factor β3 (TGFβ3) - a more potent TGFβ able to be expressed in E. coli; and a derivative of neuregulin 1 (NRG1) containing the EGF-like domain. The B8 formula is specifically optimized for fast growth and robustness at low seeding densities. We demonstrated the derivation and culture of 34 hiPSC lines in B8 as well as maintenance of pluripotency long-term (over 100 passages). This formula also allows a weekend-free feeding schedule without sacrificing growth rate or capacity for differentiation. Thus, this simple, cost-effective, and open source B8 media, will enable large hiPSC disease modeling projects such as those being performed in pharmacogenomics and large-scale cell production required for regenerative medicine.
Alcohol Increases Aggression in Flies
Authors: Park Annie , Tran Tracy , Scheuermann Elizabeth , Gutierrez Linda , Stojanik Christopher , Plyler Julian , Thompson Grace , Smith Dean , Atkinson Nigel S.
Published: June 2019

Alcohol-induced aggression is a destructive and widespread phenomenon, but we understand very little about the mechanisms that produce this behavior. We found that two different alcohol exposures potentiate aggression in male flies. (1) A pharmacologically relevant dose of alcohol increases aggression and decreases a goal-directed behavior in male flies. (2) In addition, the odor of alcohol itself enhances intermale aggression by potentiating olfactory signaling by cis-vaccenyl acetate (cVa), a volatile male pheromone. Characterizing these behaviors in the genetically tractable fruit fly can lead to a better understanding of the molecular correlates that regulate alcohol-induced aggression in humans and provide insights into an ethologically relevant behavior.

One Sentence Summary

We identified two pathways through which alcohol stimulates intermale aggression in flies; one acts by potentiating a male olfactory pheromone while the other is mediated by the systemic effects of alcohol.
Discovery of influenza drug resistance mutations and host therapeutic targets using a human airway chip
Authors: Si Longlong , Prantil-Baun Rachelle , Benam Kambez H , Bai Haiqing , Rodas Melissa , Burt Morgan , Ingber Donald E.
Published: June 2019

Here we demonstrate that influenza virus replication, host responses to infection, evolution through mutation or gene reassortment, and clinical efficacy of antiviral drugs can be reconstituted in a human Airway Chip microfluidic culture device. Modeling human-to-human transmission of infection in the continued presence of antiviral drugs on chips led to the emergence of clinically prevalent mutations responsible for amantadine- and oseltamivir-resistance, as well as the discovery of new resistance mutations. Analysis of infection responses resulted in identification of host therapeutic targets and demonstration that existing non-antiviral drugs may be repurposed to inhibit viral replication and synergize with antiviral therapeutics by targeting the host response to infection rather than the virus itself. This Influenza Chip may represent an alternative preclinical tool for development of new antiviral drugs and vaccines.

One Sentence Summary

New drug resistance mutations and potential tolerance-inducing therapeutics were discovered using an organ chip model of influenza infection.
Lis1 activates dynein motility by pairing it with dynactin
Authors: Elshenawy Mohamed M. , Kusakci Emre , Volz Sara , Baumbach Janina , Bullock Simon L. , Yildiz Ahmet
Published: June 2019

Lissencephaly-1 (Lis1) is a key cofactor for dynein-mediated intracellular transport towards the minus-ends of microtubules (MTs). It remains unclear whether Lis1 serves as an inhibitor or an activator of mammalian dynein motility. Here we use single-molecule imaging and optical trapping to show that Lis1 does not directly alter the stepping and force production of individual dynein motors assembled with dynactin and a cargo adaptor. Instead, Lis1 binding releases dynein from its auto-inhibited state and thereby promotes the formation of an active complex with dynactin. Lis1 also favors recruitment of two dyneins to dynactin, resulting in increased velocity, higher force production and more effective competition against kinesin in a tug-of-war. Lis1 dissociates from motile complexes, indicating that its primary role is to orchestrate the assembly of the transport machinery. These results provide a mechanistic explanation for why Lis1 is required for efficient transport of many dynein-associated cargoes in cells.
High-resolution structural genomics reveals new therapeutic vulnerabilities in glioblastoma
Authors: Johnston Michael J. , Nikolic Ana , Ninkovic Nicoletta , Guilhamon Paul , Cavalli Florence M.G. , Seaman Steven , Zemp Franz J. , Lee John , Abdelkareem Aly , Ellestad Katrina , Murison Alex , Kushida Michelle M. , Coutinho Fiona J. , Ma Yussanne , Mungall Andrew J. , Moore Richard , Marra Marco A. , Taylor Michael D. , Dirks Peter B. , Pugh Trevor J. , Morrissy Sorana , St Croix Bradley , Mahoney Douglas J. , Lupien Mathieu , Gallo Marco
Published: June 2019

We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating sub-5-kb resolution 3D genome maps by in situ Hi-C. Contact maps at sub-5-kb resolution allow identification of individual DNA loops, domain organization, and large-scale genome compartmentalization. We observed differences in looping architectures among GSCs from different patients, suggesting that 3D genome architecture is a further layer of inter-patient heterogeneity for glioblastoma. Integration of DNA contact maps with chromatin and transcriptional profiles identified specific mechanisms of gene regulation, including the convergence of multiple super enhancers to individual stemness genes within individual cells. We show that the number of loops contacting a gene correlates with elevated transcription. These results indicate that stemness genes are hubs of interaction between multiple regulatory regions, likely to ensure their sustained expression. Regions of open chromatin common among the GSCs tested were poised for expression of immune-related genes, including CD276. We demonstrate that this gene is co-expressed with stemness genes in GSCs and that CD276 can be targeted with an antibody-drug conjugate to eliminate self-renewing cells. Our results demonstrate that integrated structural genomics data sets can be employed to rationally identify therapeutic vulnerabilities in self-renewing cells.
Protein crystal structure determination with the crystallophore, a nucleating and phasing agent
Authors: Engilberge Sylvain , Wagner Tristan , Santoni Gianluca , Breyton Cécile , Shima Seigo , Franzetti Bruno , Riobé Francois , Maury Olivier , Girard Eric
Published: June 2019

Obtaining crystals and solving the phase problem remain major hurdles encountered by bio-crystallographers in their race to obtain new high-quality structures. Both issues can be overcome by the crystallophore, Tb-Xo4, a lanthanide-based molecular complex with unique nucleating and phasing properties. This article presents examples of new crystallization conditions induced by the presence of Tb-Xo4. These new crystalline forms bypass crystal defects often encountered by crystallographers, such as low-resolution diffracting samples or crystals with twinning. Thanks to Tb-Xo4's high phasing power, the structure determination process is greatly facilitated and can be extended to serial crystallography approaches.
Synthesis, crystal structure and studies on the interaction with albumin of a new silver(I) complex based on 2-(4-nitrobenzenesulfonamido)benzoic acid
Authors: Bomfim Filho Lucius Flavius Ourives , Rocha Cleidivania , Rodrigues Bernardo Lages , Beraldo Heloisa , Teixeira Leticia Regina
Published: June 2019

In the present work, the two-dimensional (2D) polymer poly[[μ4-2-(4-nitrobenzenesulfonamido)benzoato-κ4
O
1:O
1:O
1′:N
6]silver(I)] (AgL), [Ag(C13H9N2O6S)]
n
, was obtained from 2-(4-nitrobenzenesulfonamido)benzoic acid (HL), C13H10N2O6S. FT–IR, 1H and 13C{1H} NMR spectroscopic analyses were used to characterize both compounds. The crystal structures of HL and AgL were determined by single-crystal X-ray diffraction. In the structure of HL, O—H...O hydrogen bonds between neighbouring molecules result in the formation of dimers, while the silver(I) complex shows polymerization associated with the O atoms of three distinct deprotonated ligands (L
−). Thus, the structure of the Ag complex can be considered as a coordination polymer consisting of a one-dimensional linear chain, constructed by carboxylate bridging groups, running parallel to the b axis. Neighbouring polymeric chains are further bridged by Ag—C monohapto contacts, resulting in a 2D framework. Fingerprint analysis of the Hirshfeld surfaces show that O...H/H...O hydrogen bonds are responsible for the most significant contacts in the crystal packing of HL and AgL, followed by the H...H and O...C/C...O interactions. The Ag...Ag, Ag...O/O...Ag and Ag...C/C...Ag interactions in the Hirshfeld surface represent 12.1% of the total interactions in the crystal packing. Studies of the interactions of the compounds with human serum albumin (HSA) indicated that both HL and AgL interact with HSA.
Crystal structure of the glycoside hydrolase PssZ from Listeria monocytogenes
Authors: Wu Huijun , Qiao Shuai , Li Defeng , Guo Lu , Zhu Meijun , Ma Luyan Z.
Published: June 2019

Biofilms are microbial communities that are embedded in the extracellular matrix. The exopolysaccharide (EPS) is a key component of the biofilm matrix that maintains the structure of the biofilm and protects the bacteria from antimicrobials. Microbial glycoside hydrolases have been exploited to disrupt biofilms by breaking down EPSs. PssZ has recently been identified as a glycoside hydrolase that can disperse aggregates of Listeria monocytogenes. In this study, the crystal structure of PssZ has been determined at 1.6 Å resolution. PssZ belongs to glycoside hydrolase family 8 and adopts a classical (α/α)6-barrel fold. This architecture forms a deep groove which may serve as the substrate-binding pocket. The conserved catalytic residues (Glu72, Trp110, Asn119, Phe167, Tyr183 and Asp232) are localized at the centre of the groove. This crystal structure will help to improve the understanding of the hydrolytic mechanism of PssZ and its application as a biofilm disrupter.
Crystal structures of two CuII compounds: catena-poly[[chloridocopper(II)]-μ-N-[ethoxy(pyridin-2-yl)methylidene]-N′-[oxido(pyridin-3-yl)methylidene]hydrazine-κ4
N,N′,O:N′′] and di-μ-chlorido-1:4κ2
Cl:Cl-2:3κ2
Cl:Cl-dichlorido-2κCl,4κCl-bis[μ3-ethoxy(pyridin-2-yl)methanolato-1:2:3κ3
O:N,O:O;1:3:4κ3
O:O:N,O]bis[μ2-ethoxy(pyridin-2-yl)methanolato-1:2κ3
N,O:O;3:4κ3
N,O:O]tetracopper(II)
Authors: Sall Ousmane , Tamboura Farba Bouyagui , Sy Adama , Barry Aliou Hamady , Thiam Elhadj Ibrahima , Gaye Mohamed , Ellena Javier
Published: June 2019

Two CuII complexes [Cu(C14H13N4O2)Cl]
n
, I, and [Cu4(C8H10NO2)4Cl4]
n
, II, have been synthesized. In the structure of the mononuclear complex I, each ligand is coordinated to two metal centers. The basal plane around the CuII cation is formed by one chloride anion, one oxygen atom, one imino and one pyridine nitrogen atom. The apical position of the distorted square-pyramidal geometry is occupied by a pyridine nitrogen atom from a neighbouring unit, leading to infinite one-dimensional polymeric chains along the b-axis direction. Each chain is connected to adjacent chains by intermolecular C—H...O and C—H...Cl interactions, leading to a three-dimensional network structure. The tetranuclear complex II lies about a crystallographic inversion centre and has one core in which two CuII metal centers are mutually interconnected via two enolato oxygen atoms while the other two CuII cations are linked by a chloride anion and an enolato oxygen. An open-cube structure is generated in which the two open-cube units, with seven vertices each, share a side composed of two CuII ions bridged by two enolato oxygen atoms acting in a μ3-mode. The CuII atoms in each of the two CuO3NCl units are connected by one μ2-O and two μ3-O atoms from deprotonated hydroxyl groups and one chloride anion to the three other CuII centres. Each of the pentacoordinated CuII cations has a distorted NO3Cl square-pyramidal environment. The CuII atoms in each of the two CuO2NCl2 units are connected by μ2-O and μ3-O atoms from deprotonated alcohol hydroxy groups and one chloride anion to two other CuII ions. Each of the pentacoordinated CuII cations has a distorted NO2Cl2 square-pyramidal environment. In the crystal, a series of intramolecular C—H...O and C—H...Cl hydrogen bonds are observed in each tetranuclear monomeric unit, which is connected to four tetranuclear monomeric units by intermolecular C—H...O hydrogen bonds, thus forming a planar two-dimensional structure in the (\overline{1}01) plane.
Crystal structure of (E)-N-cyclohexyl-2-(2-hydroxy-3-methylbenzylidene)hydrazine-1-carbothioamide
Authors: Arafath Md. Azharul , Kwong Huey Chong , Adam Farook
Published: June 2019

The asymmetric unit of the title compound, C15H21N3OS, comprises of two crystallographically independent molecules (A and B). Each molecule consists of a cyclohexane ring and a 2-hydroxy-3-methylbenzylidene ring bridged by a hydrazinecarbothioamine unit. Both molecules exhibit an E configuration with respect to the azomethine C=N bond. There is an intramolecular O—H...N hydrogen bond in each molecule forming an S(6) ring motif. The cyclohexane ring in each molecule has a chair conformation. The benzene ring is inclined to the mean plane of the cyclohexane ring by 47.75 (9)° in molecule A and 66.99 (9)° in molecule B. The mean plane of the cyclohexane ring is inclined to the mean plane of the thiourea moiety [N—C(=S)—N] by 55.69 (9) and 58.50 (8)° in molecules A and B, respectively. In the crystal, the A and B molecules are linked by N—H...S hydrogen bonds, forming `dimers'. The A molecules are further linked by a C—H...π interaction, hence linking the A–B units to form ribbons propagating along the b-axis direction. The conformation of a number of related cyclohexanehydrazinecarbothioamides are compared to that of the title compound.
5-Methyl-1,3-phenylene bis[5-(dimethylamino)naphthalene-1-sulfonate]: crystal structure and DFT calculations
Authors: Duangthongyou Tanwawan , Rattanakam Ramida , Chainok Kittipong , Suramitr Songwut , Tuntulani Thawatchai , Wannalerse Boontana
Published: June 2019

The title compound, C31H30N2S2O6, possesses crystallographically imposed twofold symmetry with the two C atoms of the central benzene ring and the C atom of its methyl substituent lying on the twofold rotation axis. The two dansyl groups are twisted away from the plane of methylphenyl bridging unit in opposite directions. The three-dimensional arrangement in the crystal is mainly stabilized by weak hydrogen bonds between the sulfonyl oxygen atoms and the hydrogen atoms from the N-methyl groups. Stacking of the dansyl group is not observed. From the DFT calculations, the HOMO–LUMO energy gap was found to be 2.99 eV and indicates n→π* and π→π* transitions within the molecule.
Holes in wrist patches improve wearing comfort
Authors: Klous Lisa , Bergmann Tiest Wouter , Dorst Pim van , van der Linde Matthijs , Daanen Hein
Published: June 2019

Purpose

The purpose of this paper was to investigate whether small holes in an impermeable patch at the wrist improve perceived comfort during exercise.

Design/methodology/approach

Nine male participants participated in this study. During the experiment, participants cycled 60 W in a hot room (35°C, 30 percent relative humidity) while an impermeable 20 cm2 patch was located on the ventral side of one wrist and at the same time a patch of identical shape with 5 mm diameter holes (17.7 percent uncovered) on the other wrist. The participants could not see the patches. Participants were forced to choose which patch they perceived as more comfortable. Chest and arm skin temperature, thermal comfort, thermal sensation and wetness perception were assessed.

Findings

Participants preferred 5 mm holes over no holes (p=0.017). Chest skin temperature (p=0.018) but not arm skin temperature correlates with this preference. Thermal comfort, thermal sensation and wetness perception did not differ significantly between patches. It is concluded that patches with 5 mm holes are preferred over impermeable patches during work in the heat in particular when the torso skin is warm.

Originality/value

The wrist is a preferred location for smart wearables. Generally, wrist bands are made of air-impermeable materials leading to sensation of wetness and discomfort. This study has shown that manufacturers should consider to make small holes in their wrist bands to optimize wearing comfort.
Using Vertically Integrated Projects to embed research-based education for sustainable development in undergraduate curricula
Authors: Strachan Scott Munro , Marshall Stephen , Murray Paul , Coyle Edward J. , Sonnenberg-Klein Julia
Published: June 2019

Purpose

This paper aims to share the University of Strathclyde’s experience of embedding research-based education for sustainable development (RBESD) within its undergraduate curricula through the use of an innovative pedagogy called Vertically Integrated Projects (VIP), originated at Georgia Institute of Technology.

Design/methodology/approach

This paper discusses how aligning VIP with the SDG framework presents a powerful means of combining both research-based education (RBE) and education for sustainable development (ESD), and in effect embedding RBESD in undergraduate curricula.

Findings

The paper reports on the University of Strathclyde’s practice and experience of establishing their VIP for Sustainable Development programme and presents a reflective account of the challenges faced in the programme implementation and those envisaged as the programme scales up across a higher education institution (HEI).

Research limitations/implications

The paper is a reflective account of the specific challenges encountered at Strathclyde to date after a successful pilot, which was limited in its scale. While it is anticipated these challenges may resonate with other HEIs, there will also be some bespoke challenges that may not be discussed here.

Practical implications

This paper offers a practical and scalable method of integrating SDG research and research-based education within undergraduate curricula.

Social implications

The paper has the potential to deliver SDG-related impact in target communities by linking research-based teaching and learning with community outreach.

Originality/value

The alignment of VIP with the SDG research area is novel, with no other FE institutions currently using this approach to embed SDG research-based teaching within their curricula. Furthermore, the interdisciplinary feature of the VIP programme, which is critical for SDG research, is a Strathclyde enhancement of the original model.
A fragility approach to sustainability – researching effects of education
Authors: Platje Joost (Johannes) , Will Markus , Van Dam Ynte K.
Published: June 2019

Purpose

Management education trainers are increasingly called upon to train students to devise interventions for sustainable development in business settings. Due to the dominant reductionist paradigm, these interventions may lead to unwanted side effects. Teaching students about unacknowledged feedback loops in complex systems should prevent them from choosing “the most obvious” intervention without considering unwanted side effects.The current study aims to report the effects of teaching a systems perspective, applied to transport systems, on students’ opinions and expressed paradigms. The following questions are addressed: Do students adhere to the techno-centric paradigm, believing technology, innovation and growth can solve all types of threats for sustainable development, while neglecting low probability, high impact events? Are paradigms held by students coherent? Can teaching lead to a change in opinions and paradigms held by students?

Design/methodology/approach

Measures for several systems concepts (i.e. functional stupidity, paradigms and fragility) are taken across a wide sample of university students. Posttests of some key items are taken for a subsample that followed a sustainability and systems perspective in a course on transport economics.

Findings

A large share of students think that technology can solve different types of problems in sustainable development (a kind of weak sustainability), but their paradigms tend to be a mix of conflicting opinions. Though student opinions on topics that were explicitly treated in the course have changed, neither a wider paradigm shift nor significantly more coherent paradigms can be confirmed.

Originality/value

The results show that even though students can be taught about the unwanted side effects and limitations on specific techno-fix interventions, this does not automatically translate into a critical mind-set toward techno-fixing in general.