bluuebunny/crossref_metadata_2025 huggingface dataset:
Exposure to maternal obesityper seprograms sex-differences in pancreatic islets of the offspring
Authors: Nicholas L M , Nagao M , Kusinski L C , Fernandez-Twinn D S , Eliasson L , Ozanne S E
Published: March 2019

Maternal obesity increases type 2 diabetes (T2D) risk in the offspring. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of thein utero/early life environment on offspring islet function. Using a well-established mouse model of diet-induced obesity, we examined offspring islets before the onset of metabolic dysfunction. This allowed us to determine inherent changes, in males and females, which are distinct from the response of islets to an existing obesogenic, insulin resistant milieu hence identifying islet dysregulation reflecting very early manifestation of the disease before the onset of disrupted glucose homeostasis. Female offspring of obese dams displayed higher glucose-stimulated insulin secretion and mitochondrial respiration, increased expression of estrogen receptor α and decreased cleaved-caspase 3 and Bax:Bcl-2 reflecting reduced susceptibility to apoptosis. In contrast, male offspring of obese dams displayed compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration and increased “uncoupled” respiration and reduced docked insulin granules in β-cells. Thus, maternal obesity “programs” sex-differences in offspring islet function. Islets of female but not male offspring appear primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future T2D risk.
Chitosan films for microfluidic studies of single bacteria and perspectives for antibiotics susceptibility testing
Authors: Tréguier Julie , Bugnicourt Loic , Gay Guillaume , Diallo Mamoudou , Islam Salim , Toro Alexandre , David Laurent , Théodoly Olivier , Sudre Guillaume , Mignot Tâm
Published: March 2019

Single cell microfluidics is powerful to study bacteria and determine their susceptibility to antibiotics treatment. Glass treatment by adhesive molecules is a potential solution to immobilize bacterial cells and perform microscopy but traditional cationic polymers such as poly-lysine deeply affect bacterial physiology. In this work, we chemically characterized a class of chitosan polymers for their biocompatibility when adsorbed to glass. Chitosan chains of known length and composition allowed growth of Escherichia coli cells without any deleterious effects on cell physiology. Combined with a machine-learning approach, this method could measure the antibiotics susceptibility of a diversity of clinical strains in less than 1 hour and with higher accuracy than current methods. Last, chitosan polymers also supported growth of Klebsiella pneumoniae, another bacterial pathogen of clinical significance. The low cost of chitosan slides and their simple implementation makes them highly versatile for research as well as clinical use.
Human influences on antipredator behaviour in Darwin’s finches
Authors: Gotanda Kiyoko M.
Published: March 2019

1) Humans exert dramatic influences upon the environment, creating novel selective pressures to which organisms must adapt. On the Galapagos, humans have established a permanent presence and have altered selective pressures through influences such as invasive predators and urbanization, affecting iconic species such as Darwin’s finches.

2) Here, I ask two key questions: (i) does antipredator behaviour (e.g. FID) change depending on whether invasive predators are historically absent, present, or eradicated? and (ii) to what degree does urbanization affect antipredator behaviour? This study is one of the first to quantify antipredator behaviour in endemic species after the eradication of invasive predators. This will help to understand the consequences of invasive predator eradication and inform conservation measures.

3) I quantified flight initiation distance (FID), an antipredator behaviour, in Darwin’s finches, across multiple islands in the Galapagos that varied in the presence, absence, or successful eradication of invasive predators. On islands with human populations, I quantified FID in urban and non-urban populations of finches.

4) FID was higher on islands with invasive predators compared to islands with no predators. On islands from which invasive predators were eradicated ∼11 years previously, FID was also higher than on islands with no invasive predators. Within islands that had both urban and non-urban populations of finches, FID was lower in urban finch populations, but only above a threshold human population size. FID in larger urban areas on islands with invasive predators was similar to or lower than FID on islands with no history of invasive predators.

5) Overall, these results suggest that invasive predators can have a lasting effect on antipredator behaviour, even after eradication. Furthermore, the effect of urbanization can strongly oppose the effect of invasive predators, reducing antipredator behaviour to levels lower than found on pristine islands with no human influences. These results improve our understanding of human influences on antipredator behaviour which can help inform future conservation and management efforts on islands.
A Cas9 nanoparticle system with truncated Cas9 target sequences on DNA repair templates enhances genome targeting in diverse human immune cell types
Authors: Nguyen David N. , Roth Theodore L. , Li Jonathan , Chen Peixin Amy , Mamedov Murad R. , Vo Linda T. , Tobin Victoria , Apathy Ryan , Goodman Daniel , Shifrut Eric , Bluestone Jeffrey A. , Puck Jennifer M. , Szoka Francis C. , Marson Alexander
Published: March 2019

Virus-modified T cells are approved for cancer immunotherapy, but more versatile and precise genome modifications are needed for a wider range of adoptive cellular therapies1–4. We recently developed a non-viral CRISPR–Cas9 system for genomic site-specific integration of large DNA sequences in primary human T cells5. Here, we report two key improvements for efficiency and viability in an expanded variety of clinically-relevant primary cell types. We discovered that addition of truncated Cas9 target sequences (tCTS) at the ends of the homology directed repair (HDR) templates can interact with Cas9 ribonucleoproteins (RNPs) to ‘shuttle’ the template and enhance targeting efficiency. Further, stabilizing the Cas9 RNPs into nanoparticles with poly(glutamic acid) improved editing, reduced toxicity, and enabled lyophilized storage without loss of activity. Combining the tCTS HDR template modifications with polymer-stabilized nanoparticles increased gene targeting efficiency and viable cell yield across multiple genomic loci in diverse cell types. This system is an inexpensive, user-friendly delivery platform for non-viral genome reprogramming that we successfully applied in regulatory T cells (Tregs), γδ-T cells, B cells, NK cells, and primary and iPS-derived6 hematopoietic stem progenitor cells (HSPCs).
Folate deficiency facilitates coordination of KDM6A with p53 in response to DNA damage
Authors: Gao Jun , Zou Jizhen , Li Jianting , Zhang Yongfeng , Qiao Lina , Wang Fang , Bao Yihua , Hu Jin , Zhang Ting , Xie Qiu , Liu Changyun
Published: March 2019

Folate contributes to the accumulation of DNA strand breaks (DSBs) in the genome. Kdm6a plays a critical role in early embryogenesis but it is unknown whether Kdm6a is involved in the DNA damage response under folate deficiency. Here, we established a low folate environment for mouse embryonic cells using a folate antagonist (methotrexate, MTX). We found increased enrichment of DSBs in Kdm6a in MTX-treated cells, resulting in reduced Kdm6a expression. MTX treatment enriched KDM6A in the nonhomologous end-joining (NHEJ) repair pathway and controlled the expression of the Ku heterodimer (Ku70/80) and XRCC4. The activation of NHEJ repair pathway-associated genes under folate deficiency relied on the specific interaction between KDM6A and p53. p53 silencing increased Ku heterodimer expression. In addition, in a neural tube defect (NTD) mouse model and low folate neural tube defect human brain samples, KDM6A levels were also decreased and accompanied by over-expression of Ku80. Our findings highlight how alterations in folate levels affect KDM6A with respect to DNA breakage and DNA repair, offering a new insight into the molecular function of KDM6A.

Summary statement

Our study demonstrates for the first time that in mammals, Kdm6a and p53 have synergistic effects during DNA fragmentation repair.
3D Packing Defects in Lipid Membrane as a Function of Membrane Order
Authors: Tripathy Madhusmita , Srivastava Anand
Published: March 2019

Lipid membrane packing defects are considered as essential parameter that regulates specific membrane binding of several peripheral proteins. In absence of direct experimental characterization, lipid packing defects and their role in the binding of peripheral proteins are generally investigated through computational studies, which have been immensely successful in unraveling the key steps of the membrane-binding process. However, packing defects are calculated using 2-dimensional projections and the crucial information on their depths is generally overlooked. Here we present a simple yet computationally efficient algorithm, which identifies these defects in 3-dimensions. We employ the algorithm to understand the nature of packing defects in flat bilayer membranes exhibiting liquid-ordered (Lo), liquid-disordered (Ld) and co-existing Lo/Ld phases. Our results indicate the presence of shallower and smaller defects in the Lo phase membranes as compared to the defects in Ld and mixed Lo/Ld phase membranes. Such analyses can elucidate the molecular scale mechanisms that drive the preferential localization of certain proteins to either of the liquid phases or their interface. Moreover, on the methodology front, our analyses suggest that the projection based 2-dimensional calculation of packing defects might result in inaccurate quantification of their sizes - a very important feature for membrane association of protein motifs, thus advocating the importance of the 3-dimensional calculations.
Feedback loops in the Plk4–STIL–HsSAS6 network coordinate site selection for procentriole formation
Authors: Takao Daisuke , Watanabe Koki , Kuroki Kanako , Kitagawa Daiju
Published: March 2019

Centrioles are duplicated once in every cell cycle, ensuring the bipolarity of the mitotic spindle. Although the core components have been identified, how they cooperate to achieve high fidelity in centriole duplication remains poorly understood. Here, we show that in centriole duplication the accumulation of STIL and HsSAS6, components of the cartwheel structure, provides negative feedback in the centriolar dynamics of Plk4. By live-cell imaging of endogenously tagged proteins in human cells throughout the entire cell cycle, we quantitatively tracked the dynamics of the critical duplication factors: Plk4, STIL, and HsSAS6. Centriolar Plk4 peaks and then starts decreasing during the late G1 phase, which coincides with the accumulation of STIL at centrioles. Shortly thereafter, the HsSAS6 level increases steeply at the procentriole assembly site. We also show that both STIL and HsSAS6 are necessary for attenuating Plk4 levels. Furthermore, our mathematical modeling and simulation convincingly reproduce the dynamics of these three proteins at centrioles, and suggest that the STIL–HsSAS6 complex in the cartwheel has a negative feedback effect on centriolar Plk4. Combined, these findings illustrate how the dynamic behavior of and interactions between the critical duplication factors coordinate the centriole-duplication process.
Multiomics data analysis using tensor decomposition based unsupervised feature extraction --Comparison with DIABLO--
Authors: Taguchi Y-h.
Published: March 2019

Multiomics data analysis is the central issue of genomics science. In spite of that, there are not well defined methods that can integrate multomics data sets, which are formatted as matrices with different sizes. In this paper, I propose the usage of tensor decomposition based unsupervised feature extraction as a data mining tool for multiomics data set. It can successfully integrate miRNA expression, mRNA expression and proteome, which were used as a demonstration example of DIABLO that is the recently proposed advanced method for the integrated analysis of multiomics data set.
Pharmacologically diverse antidepressant drugs disrupt the interaction of BDNF receptor TRKB and the endocytic adaptor AP-2
Authors: Fred Senem Merve , Laukkanen Liina , Brunello Cecilia A , Vesa Liisa , Goos Helka , Cardon Iseline , Moliner Rafael , Maritzen Tanja , Varjosalo Markku , Casarotto Plinio C , Castrén Eero
Published: March 2019

Antidepressant drugs activate TRKB (tropomyosin-related kinase B), however it remains unclear whether these compounds employ a common mechanism for achieving this effect. We found by using mass spectrometry that the interaction of several proteins with TRKB was disrupted in the hippocampus of fluoxetine-treated animals (single intraperitoneal injection), including members of the AP-2 complex (adaptor protein complex-2) involved in vesicular endocytosis. The interaction of TRKB with the cargo-docking mu subunit of the AP-2 complex (AP2M) was disrupted by both acute and repeated fluoxetine treatment. However, while the coupling between full length TRKB and AP2M was disrupted by fluoxetine, the interaction between AP2M and the TRKB C-terminal peptide was resistant to this drug, indicating that the binding site targeted by fluoxetine must lie outside of the TRKB:AP2M interface. In addition to fluoxetine, other pharmacologically diverse antidepressants imipramine, rolipram, phenelzine, ketamine, and the ketamine metabolite 2R,6R-hydroxynorketamine (RR-HNK) also decreased the interaction between TRKB:AP2M in vitro, as measured by ELISA. Silencing the expression of AP2M in MG87.TRKB cell line led to increased surface positioning of TRKB and to a higher response to BDNF (brain-derived neurotrophic factor), observed as the levels of active TRKB. Moreover, animals haploinsufficient for the Ap2m1 gene displayed increased levels of active TRKB in vivo, as well as an enhanced cell surface expression of the receptor in cultured hippocampal neurons.

Taken together, our data suggests that disruption of the TRKB:AP2M interaction is an effect shared by several antidepressants with diverse chemical structures and canonical modes of action.
Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility
Authors: Nishimura Kaoru , Dioguardi Elisa , Nishio Shunsuke , Villa Alessandra , Han Ling , Matsuda Tsukasa , Jovine Luca
Published: March 2019

Interaction between sperm and the egg zona pellucida (ZP) is the first step of mammalian fertilization, and ZP component ZP1 is important for fertility by covalently cross-linking ZP filaments into a matrix. Like ZP4, a structurally-related subunit absent in the mouse, ZP1 is predicted to contain an N-terminal ZP-N domain of unknown function. Characterization of ZP1 proteins carrying mutations from infertile patients suggests that, unlike in the mouse, filament cross-linking by ZP1 is crucial for human ZP assembly. We map the function of ZP1 to its ZP-N1 domain and determine crystal structures of ZP-N1 homodimers from a chicken homolog of ZP1. These reveal that ZP filament cross-linking is highly plastic and can be modulated by ZP1 fucosylation and, potentially, zinc sparks. Moreover, we show that ZP4 ZP-N1 forms non-covalent homodimers in chicken but not human. Together, these data identify human ZP1 cross-links as a promising target for non-hormonal contraception.
During hippocampal inactivation, grid cells maintain their synchrony, even when the grid pattern is lost
Authors: Almog Noam , Tocker Gilad , Bonnevie Tora , Moser Edvard , Moser May-Britt , Derdikman Dori
Published: March 2019

The grid cell network in the MEC has been subject to thorough testing and analysis, and many theories for their formation have been suggested. To test some of these theories we re-analyzed data from Bonnevie et al. (2013), in which the hippocampus was inactivated and grid cells were recorded in the MEC, to investigate whether the firing associations of grid cells depend on hippocampal inputs. Specifically, we examined temporal and spatial correlations in the firing times of simultaneously recorded grid cells before and during hippocampal inactivation. Our analysis revealed evidence of network coherence in grid cells even in the absence of hippocampal input to the MEC, both in regular grid cells and in those that became head-direction cells after hippocampal inactivation. This favors models which suggest that phase relations between grid cells in the MEC are dependent on intrinsic connectivity within the MEC.
Damage to the Right Insula Disrupts the Perception of Affective Touch
Authors: Kirsch Louise P. , Besharati Sahba , Papadaki Christina , Crucianelli Laura , Bertagnoli Sara , Ward Nick , Moro Valentina , Jenkinson Paul M. , Fotopoulou Aikaterini
Published: March 2019

Specific, peripheral C-tactile afferents contribute to the perception of tactile pleasure, but the brain areas involved in their processing remain debated. We report the first human lesion study on the perception of C-tactile touch (N = 59), revealing that posterior and anterior right insula lesions reduce tactile, contralateral and ipsilateral pleasantness sensitivity, respectively. These findings are consistent with a posterior-to-anterior pattern of integration of interoceptive information in the frontoinsular junction.
Bacteriophage adherence to mucus mediates preventive protection against pathogenic bacteria
Authors: Almeida Gabriel MF , Laanto Elina , Ashrafi Roghaieh , Sundberg Lotta-Riina
Published: March 2019

Metazoan mucosal surfaces are major interfaces between the organism and environment. These surfaces have been proposed to host bacteriophages in a symbiotic relationship with metazoans. Considering the so far poorly understood phage–mucus interaction and its role in ecological interactions and for mucosal bacterial infections, empirical evidence and model systems need to be established. Here, using the fish pathogenFlavobacterium columnareand rainbow trout (Oncorhynchus mykiss), we show that phages infecting the pathogen are capable of binding to primary mucus layers and protecting fish from infections. Furthermore, exposure to mucus changes the bacterial phenotype by increasing bacterial virulence and susceptibility to phage infections. Tests using other phage–bacterium pairs suggest that the relevance of mucus for bacteria and phages may be widespread in the biosphere. Therefore, interactions of bacteria and phages inside the mucus environment may be important for disease and evolution, and this phenomenon has significant potential to be exploited for preventive phage therapy approaches.
Contingent Convergence: The ability to detect convergent genomic evolution is dependent on population size and migration
Authors: Whiting James R. , Fraser Bonnie A.
Published: March 2019

Outlier scans, in which the genome is scanned for signatures of selection, have become a prominent tool in studies of local adaptation, and more recently studies of genetic convergence in natural populations. However, such methods have the potential to be confounded by features of demographic history, such as population size and migration, which are considerably varied across natural populations. In this study, we use forward-simulations to investigate and illustrate how several measures of genetic differentiation commonly used in outlier scans (FST, DXYand Δπ) are influenced by demographic variation across multiple sampling generations. In a factorial design with 16 treatments, we manipulate the presence/absence of founding bottlenecks (N of founding individuals), protracted bottlenecks (proportional size of diverging population) and migration rate between two populations with ancestral and derived phenotypic optima. Our results illustrate known constraints of individual measures associated with reduced population size and a lack of migration; but notably we demonstrate how relationships between measures are similarly dependent on demography. We find that false-positive signals of convergent evolution (the same simulated outliers detected in independent treatments) are attainable as a product of similar demographic treatment, and that outliers across different measures (particularly FSTand DXY) can occur with little influence of selection. Taken together, we show how underappreciated, yet quantifiable measures of demographic history can influence commonly employed methods for detecting selection.
Library Preparation and Sequencing Platform Introduce Bias in Metagenomic-Based Characterizations of Microbiomes
Authors: Poulsen Casper S. , Ekstrøm Claus T. , Aarestrup Frank M. , Pamp Sünje J.
Published: March 2019

Metagenomics is increasingly used to describe microbial communities in biological specimens. Ideally, the steps involved in the processing of the biological specimens should not change the microbiome composition in a way that it could lead to false interpretations of inferred microbial community composition. Common steps in sample preparation include sample collection, storage, DNA isolation, library preparation, and DNA sequencing. Here we assess the effect of three library preparation kits and two DNA sequencing platforms. Of the library preparation kits, one involved a polymerase chain reaction (PCR) step (Nextera), and two were PCR-free (NEXTflex and KAPA). We sequenced the libraries on Illumina HiSeq and NextSeq platforms. As example microbiomes, we assessed two pig fecal samples and two sewage samples of which aliquots were stored at different storage conditions (immediate processing and storage at −80°C). All DNA isolations were performed in duplicate, totaling 80 samples excluding controls. We found that both library preparation and sequencing platform had systematic effects on the inferred microbial community composition. The different sequencing platforms introduced more variation than library preparation and freezing the samples. The results highlight that all sample processing steps need to be considered when comparing studies. Standardization of sample processing is key to generate comparable data within a study, and comparisons of differently generated data, such as in a meta-analysis, should be performed cautiously.

Importance

Previous research has reported effects of sample storage conditions and DNA isolation procedures on metagenomics-based microbiome composition; however, the effect of library preparation and DNA sequencing in metagenomics has not been thoroughly assessed. Here, we provide evidence that library preparation and sequencing platform introduce systematic biases in the metagenomic-based characterization of microbial communities. These findings suggest that library preparation and sequencing are important parameters to keep consistent when aiming to detect small changes in microbiome community structure. Overall, we recommend that all samples in a microbiome study are processed in the same way to limit unwanted variations that could lead to false conclusions. Furthermore, if we are to obtain a more holistic insight from microbiome data generated around the world, we will need to provide more detailed sample metadata, including information about the different sample processing procedures, together with the DNA sequencing data at the public repositories.
Isolation of lactic acid bacteria capable of reducing environmental alkyl and fatty acid hydroperoxides, and the effect of their oral administration on oxidative-stressed nematodes and rats
Authors: Watanabe Akio , Yamaguchi Takuro , Murota Kaeko , Ishii Tadaaki , Terao Junji , Okada Sanae , Tanaka Naoto , Kimata Shinya , Abe Akira , Suzuki Tomonori , Uchino Masataka , Niimura Youichi
Published: March 2019

Reinforcement of hydroperoxide-eliminating activity in the intestines and colon should prevent associated diseases. We previously isolated a lactic acid bacterium,Pediococcus pentosaceusBe1, that facilitates a 2-electron reduction of hydrogen peroxide to water. In this study, we successfully isolated an alternative lactic acid bacterium,Lactobacillus plantarumP1-2, that can efficiently reduce environmental alkyl hydroperoxides and fatty acid hydroperoxides to their corresponding hydroxy derivatives through a 2-electron reduction. Each strain exhibited a wide concentration range with regard to the environmental reducing activity for each hydroperoxide. Given this, the two lactic acid bacteria were orally administered to the oxygen-sensitive short-lived nematode mutant, and this resulted in a significant expansion of its lifespan. This observation suggests thatP. pentosaceusBe1 andL. plantarumP1-2 inhibit internal oxidative stress. To determine the specific organs involved in this response, we performed a similar experiment in rats, involving induced lipid peroxidation by iron-overloading. We observed that onlyL. plantarumP1-2 inhibited colonic mucosa lipid peroxidation in rats with induced oxidative stress.
Facile assembly of an affordable miniature multicolor fluorescence microscope made of 3D-printed parts enables detection of single cells
Authors: Tristan-Landin Samuel B. , Gonzalez-Suarez Alan M. , Jimenez-Valdes Rocio J. , Garcia-Cordero Jose L.
Published: March 2019

Fluorescence microscopy is one of the workhorses of biomedical research and laboratory diagnosis; however, their cost, size, maintenance, and fragility has prevented their adoption in developing countries or low-resource settings. Although significant advances have decreased their size, cost and accessibility, their designs and assembly remain rather complex. Here, inspired on the simple mechanism from a nut and a bolt we report the construction of a portable fluorescence microscope that operates in bright field mode and in three fluorescence channels: UV, green, and red. It is assembled in under 10 min from only six 3D printed parts and basic electronic components that can be readily purchased in most locations or online for US $85. Adapting a microcomputer and a touch LCD screen, the microscope can capture time-lapse images and videos. We characterized its resolution and illumination conditions and benchmarked its performance against a high-end fluorescence microscope by tracking a biological process in single cells. We also demonstrate its application to image cells inside a microfluidic device in bright-field and fluorescence mode. Our microscope fits in a CO2 chamber and can be operated in time-lapse mode. Our portable microscope is ideal in applications where space is at a premium, such as lab-on-a-chips or space missions, and can find applications in clinical research, diagnostics, telemedicine and in educational settings.
Knowledge and awareness of cervical cancer in Southwestern Ethiopia is lacking: a descriptive analysis
Authors: Saleem Atif , Bekele Alemayehu , Fitzpatrick Megan B. , Mahmoud Eiman A. , Lin Athena W. , Velasco H. Eduardo , Rashed Mona M.
Published: March 2019

Purpose

Cervical cancer remains the second most common cancer and cancer-related death among women in Ethiopia. This is the first study, to our knowledge, describing the demographic, and clinicopathologic characteristics of cervical cancer cases in a mainly rural, Southwestern Ethiopian population with a low literacy rate to provide data on the cervical cancer burden and help guide future prevention and intervention efforts.

Methods

A descriptive analysis of 154 cervical cancer cases at the Jimma University Teaching Hospital in Southwestern Ethiopia from January 2008 – December 2010 was performed. Demographic and clinical characteristics were obtained from patient questionnaires and cervical punch biopsies were histologically examined.

Results

Of the 154 participants with a histopathologic diagnosis of cervical cancer, 95.36% had not heard of cervical cancer and 89.6% were locally advanced at the time of diagnosis. Moreover, 86.4% of participants were illiterate, and 62% lived in a rural area.

Conclusion

A majority of the 154 women with cervical cancer studied at the Jimma University Teaching Hospital in Southwestern Ethiopia were illiterate, had not heard of cervical cancer and had advanced disease at the time of diagnosis. Given the low rates of literacy and knowledge regarding cervical cancer in this population which has been shown to correlate with a decreased odds of undergoing screening, future interventions to address the cervical cancer burden here must include an effective educational component.
Efficiency of protein synthesis inhibition depends on tRNA and codon compositions
Authors: Rudorf Sophia
Published: March 2019

Regulation and maintenance of protein synthesis are vital to all organisms and are thus key targets of attack and defense at the cellular level. Here, we mathematically analyze protein synthesis for its sensitivity to the inhibition of elongation factor EF-Tu and/or ribosomes in dependence of the system’s tRNA and codon compositions. We find that protein synthesis reacts ultrasensitively to a decrease in the elongation factor’s concentration for systems with an imbalance between codon usages and tRNA concentrations. For well-balanced tRNA/codon compositions, protein synthesis is impeded more effectively by the inhibition of ribosomes instead of EF-Tu. Our predictions are supported by re-evaluated experimental data as well as by independent computer simulations. Not only does the described ultrasensitivity render EF-Tu a distinguished target of protein synthesis inhibiting antibiotics. It may also enable persister cell formation mediated by toxin-antitoxin systems. The strong impact of the tRNA/codon composition provides a basis for tissue-specificities of disorders caused by mutations of human mitochondrial EF-Tu as well as for the potential use of EF-Tu targeting drugs for tissue-specific treatments.

Author Summary

We predict and analyze the response of differently composed protein synthesis systems to the inhibition of elongation factor EF-Tu and/or ribosomes. The study reveals a strong interdependency of a protein synthesis system’s composition and its susceptibility to inhibition. This interdependency defines a generic mechanism that provides a common basis for a variety of seemingly unrelated phenomena including, for example, persister cell formation and tissue-specificity of certain mitochondrial diseases. The described mechanism applies to simple artificial translation systems as well as to complex protein synthesis in vivo.
Quantification of biomolecular dynamics inside real and synthetic nuclear pore complexes using time-resolved atomic force microscopy
Authors: Stanley George J. , Akpinar Bernice , Shen Qi , Ellis Fisher Patrick D. , Lusk C. Patrick , Lin Chenxiang , Hoogenboom Bart W.
Published: March 2019

Over the past decades, atomic force microscopy (AFM) has emerged as an increasingly powerful tool to study the dynamics of biomolecules at nanometre length scales. However, the more stochastic the nature of such biomolecular dynamics, the harder it becomes to distinguish them from AFM measurement noise. Rapid, stochastic dynamics are inherent to biological systems comprising intrinsically disordered proteins. One role of such proteins is in the formation of the transport barrier of the nuclear pore complex (NPC): the selective gateway for macromolecular traffic entering or exiting the nucleus. Here, we use AFM to observe the dynamics of intrinsically disordered proteins from two systems: the transport barrier of native NPCs, and the transport barrier of a mimetic NPC made using a DNA origami scaffold. Analysing data recorded with 50-200 ms temporal resolution, we highlight the importance of drift correction and appropriate baseline measurements in such experiments. In addition, we describe an auto-correlation analysis to quantify time scales of observed dynamics and to assess their veracity — an analysis protocol that lends itself to the quantification of stochastic fluctuations in other biomolecular systems. The results reveal the surprisingly slow rate of stochastic, collective transitions inside mimetic NPCs, highlighting the importance of FG-nup cohesive interactions.
A temperature-controlled single-crystal growth cell for the in situ measurement and analysis of face-specific growth rates
Authors: Turner T. D. , Nguyen T. T. H. , Nicholson P. , Brown G. , Hammond R. B. , Roberts K. J. , Marziano I.
Published: March 2019

The design and construction of a growth cell for the precision measurement of face-specific single-crystal growth rates are presented. Accurate mechanical drawings in SolidWorks of the cell and individual components are provided, together with relevant construction models. A general methodology for its use in the measurement of single-crystal growth rates and their underpinning growth mechanism is presented and illustrated with representative data provided for the crystal growth of the {011} and {001} faces of RS-ibuprofen single crystals grown in ethanolic solutions. Analysis of these data highlights the utility of the methodology in morphological model development and crystallization process design.
Structural evolution of La2Ti2O7at elevated temperatures
Authors: Ishizawa Nobuo , Ninomiya Keisuke , Wang Jun
Published: March 2019

Structural evolution of a La2Ti2O7ferroelectric compound possessing perovskite-type slabs at elevated temperatures was investigated using the single-crystal X-ray diffraction technique. The monoclinic low-temperature phase (L) transformed into the orthorhombic high-temperature phase (H)viaan incommensurately modulated phase (IC) between ∼989 and ∼1080 K. The L–IC transition was considered to be of the first order, with the L+IC two-phase co-existing region between ∼989 and ∼1027 K. The structure of IC was determined from the (3+1)-dimensional superspace representation with a modulation vectorq= αao(α ≃ 0.49), whereaois thea-axis vector of the basic cell. The structural modulation originated from the variation of the tilt angle of the TiO6octahedra in the perovskite-type slab in association with small positional displacements of La atoms. The IC–H transition took place at ∼1080 K and was close to the second order. During the IC–H transition, nanoscale flat plate domains having either a cell twin of the L-type structural modules or a cell twin of the alternating H- and L-type structural modules began to appear in the approximant structure of IC. The thickness of the flat plate domains then grew rapidly along the modulation vector in proportion to (½ − α)−1as α approached ½ with decreasing temperature. In the two-phase L+IC co-existing region, the IC phase consisting of the two types of cell twins was gradually replaced with the low-temperature monoclinic phase L, which is not cell twinned but rather twinned macroscopically by the L-type structural modules.
Chemical and structural variability in cubic spinel oxides
Authors: Bosi Ferdinando
Published: March 2019

The empirical relations between cubic spinel oxides of different compositions were investigated using data from 349 refined crystal structures. The results show that the spinel structure is able to tolerate many constituents (at least 36) by enlarging and decreasing the tetrahedra and octahedra. This is reflected in a large variation in tetrahedral and octahedral bond distances. The oxygen positional parameter (u) may be regarded as a measure of the distortion of the spinel structure from cubic close packing or of the angular distortion of the octahedron. The distortion can best be explained in terms of ionic potential (IP), which merges the size and charge properties of an ion. Sterically induced distortion depends on ion size, whereas electrostatically induced distortion is caused by cation–cation repulsion across faces of tetrahedra and shared edges of octahedra. The strong correlations between theuparameter and the IP at theTandMsites are consistent with the main role played by the both charge and size. Large distortions (u≫ 0.27) result in oxygen–oxygen distances of the octahedron shorter than 2.50 Å, which would lead to structural instability because of increased non-bonded repulsion forces between the oxygen atoms.
A new hybrid analytical model based on winding function theory for analysis of surface mounted permanent magnet motors
Authors: Faiz Jawad , Rezaee-Alam Farhad
Published: March 2019

Purpose

The purpose of this paper is to present an improved winding function theory (IWFT) for performance analysis of surface mounted permanent magnet (SMPM) motors, which can precisely and simultaneously consider the impacts of stator slotting, the winding distribution, the magnetic flux density within PMs because of the armature reaction, the PM magnetization angle and the magnetic saturation,.

Design/methodology/approach

To obtain this improved analytical model, the conformal mappings (CMs) are introduced to calculate the relative complex permeance of slotted air-gap, which is used to obtain the function of slotted air-gap length. The equivalent magnetizing current model is used to extract the equivalent winding function for each PM pole. For retaining the basic assumption of WFT, the magnetic saturation is also considered by a proper increase in the air-gap length in the front of the stator teeth.

Findings

A new hybrid analytical model (HAM) based on WFT is presented in this paper, which can simultaneously and accurately consider the effects of slotting, the magnetic saturation, the variation of PM operating point and the winding distribution. In fact, IWFT removes all the drawbacks of the conventional WFT. Moreover, IWFT is more user-friendly and faster than other analytical and numerical techniques.

Practical implications

The obtained HAM can be used for design, optimization and fault diagnosis in electric machines.

Originality/value

This paper presents a new HAM for accurate modeling the SMPM motors, which includes different considerations of electromagnetic modeling. This new HAM can also be used for modeling the other electric motors.
The influences of contract structure, contracting process, and service complexity on supplier performance
Authors: Zou Wenting , Brax Saara A. , Vuori Mervi , Rajala Risto
Published: March 2019

Purpose

To build a more comprehensive understanding of factors affecting the success of service contracting, the purpose of this paper is to investigate the influences of service complexity, contract structure and contracting process on the buyer-perceived supplier performance in business-to-business (B2B) services.

Design/methodology/approach

A research model is developed based on transaction cost economics and the research on service contracting. The model is tested by the survey data collected. Professional focus groups on LinkedIn are used to generate the list of potential respondents. The sample consists of 177 purchasing professionals from 25 countries.

Findings

The results indicate that three major contract dimensions and follow-up management practices positively influence buyer-perceived supplier performance. Furthermore, service complexity amplifies the effects of incentives designed in the contract and the buyer’s follow-up contract management on perceived supplier performance.

Research limitations/implications

The sample consists of respondents from 25 countries and provides good geographic coverage. However, the results should be generalized with caution because not all countries were represented equally.

Practical implications

The study suggests a framework and guidelines for purchasing managers to improve the design and management of service contracts to secure good performance from their supplier.

Originality/value

This paper contributes to understanding the performance-enhancing aspects of designing and monitoring service contracts in B2B contexts. It also adds to the knowledge of the role of service complexity in successful B2B service purchasing.
Policy implementation under stress
Authors: Fjeldstad Odd-Helge , Ali Merima , Katera Lucas
Published: March 2019

Purpose

Inter-organisational cooperation in revenue collection has received limited attention in the tax administration literature. Recent experiences from Tanzania offer a unique opportunity to examine opportunities and challenges facing such cooperation between central and local government agencies in a developing country context. The administration of property taxes (PT) in Tanzania has been oscillating between decentralised and centralised collection regimes. This paper aims to examine how inter-organisational cooperation affected implementation of the reforms.

Design/methodology/approach

The study draws on data from a variety of sources of information collected during a series of fieldworks over the past decade. Semi-structured interviews were conducted with a wide range of stakeholders, including senior managers and operational staff of the national and municipal tax administrations. The interviews focused on the background and objectives of the property tax reforms, working relations between the central and local government revenue administrations, technical and administrative challenges and innovations, and changes over time with respect to revenue enhancement and implementation of the reforms. Relevant tax legislation and regulations, budget speeches and reports were reviewed.

Findings

Two lessons of broader relevance for policy implementation and PT administration are highlighted. First, institutional trust matters. Top-down reform processes, ambiguity related to the rationale behind the reforms and lack of consultations on their respective roles and expectations have acted as barriers to constructive working relationships between the local and central government revenue agencies. Second, administrative constraints, reflected in poor preparation, outdated property registers and valuation rolls and inadequate incentives for the involved agencies to cooperate hampered the implementation of the reforms.

Originality/value

This paper contributes to the literature on inter-organisational cooperation in revenue collection through a detailed case study of property tax reforms in a developing country context. It also contributes to the literature on policy implementation by identifying political and administrative factors challenging the reform process. In line with this literature, the study shows that policy implementation is not necessarily a coherent process. Instead, it is frequently fragmented and disrupted by changes in policy formulation and access to adequate resources.
China–Pakistan economic corridor and maritime security collaboration
Authors: Chang Yen-Chiang , Khan Mehran Idris
Published: March 2019

Purpose

This study aims to explore why marine development and maritime security in Pakistan are significant and what the Chinese concerns are. Therefore, the objective of this research is to analyse a growing Pak–China bilateral interests, particularly at Gwadar, to achieve the geostrategic objectives of China–Pakistan Economic Corridor (CPEC).

Design/methodology/approach

The study adopts a qualitative means to discuss the significance of China’s ambitions towards the CPEC project concerning strategic deep-sea management and maritime regulations in the region, with a particular focus on the Gwadar Port.

Findings

The paper concludes that the Gwadar Port is a critical element for maritime security in the whole region. The study also provides an analysis of national and international, security and legal challenges associated with CPEC.

Originality/value

Most of the potential outcomes have already been discussed in public, though a limited academic discussion is available on the legal aspects. It is particularly so with regard to the development and capacity building in the maritime sector of Pakistan under this project. This study aims to explore why marine development and maritime security in Pakistan is significant and what the Chinese concerns are.
Clinical and radiological outcomes of infantile hemangioma treated with oral propranolol: A long‐term follow‐up study
Authors: Yu Zhang , Cai Ren , Chang Lei , Qiu Yajing , Chen Xuanfeng , Chen Qianyi , Ma Gang , Jin Yunbo , Lin Xiaoxi
Published: March 2019

Infantile hemangiomas (IH) undergo rapid growth during early infancy followed by gradual involution. After involution, a part of IH remain as residual lesions. Since 2008, oral propranolol has been widely used in the treatment of IH. However, long‐term outcome of IH treated with propranolol remains unknown. This study aimed to investigate the sequelae of IH treated with propranolol. In this study, propranolol was given at a dose of 2 mg/kg per day at the age of 3.8 ± 2.5 months and follow‐up visits were arranged to continue at least through the age of 4 years. Types of sequela were recorded and classified as four degrees (“none”, “minimal”, “significant” and “severe” at last visit), then subsequent therapy was evaluated with the help of magnetic resonance imaging (MRI). A total of 73 patients with complete follow up were enrolled in the study. The most common types of sequela were telangiectasia, fibrofatty tissue and erythema. Significant and severe sequelae were observed in 72.4% of treated IH; superficial IH led to more but not significantly significant and severe sequelae than mixed IH (P > 0.05). Despite propranolol treatment, surgery was still needed in 37.5% of IH at a mean age of 70.3 months, and for the main reason of surgery, fibrofatty or hemangioma residua, MRI was useful for us to choose an appropriate surgical procedure.
Novel haloarchaeal viruses from Lake Retba infecting Haloferax and Halorubrum species
Authors: Mizuno Carolina M. , Prajapati Bina , Lucas‐Staat Soizick , Sime‐Ngando Telesphore , Forterre Patrick , Bamford Dennis H. , Prangishvili David , Krupovic Mart , Oksanen Hanna M.
Published: March 2019

The diversity of archaeal viruses is severely undersampled compared with that of viruses infecting bacteria and eukaryotes, limiting our understanding on their evolution and environmental impacts. Here, we describe the isolation and characterization of four new viruses infecting halophilic archaea from the saline Lake Retba, located close to Dakar on the coast of Senegal. Three of the viruses, HRPV10, HRPV11 and HRPV12, have enveloped pleomorphic virions and should belong to the family Pleolipoviridae, whereas the forth virus, HFTV1, has an icosahedral capsid and a long non‐contractile tail, typical of bacterial and archaeal members of the order Caudovirales. Comparative genomic and phylogenomic analyses place HRPV10, HRPV11 and HRPV12 into the genus Betapleolipovirus, whereas HFTV1 appears to be most closely related to the unclassified Halorubrum virus HRTV‐4. Differently from HRTV‐4, HFTV1 encodes host‐derived minichromosome maintenance helicase and PCNA homologues, which are likely to orchestrate its genome replication. HFTV1, the first archaeal virus isolated on a Haloferax strain, could also infect Halorubrum sp., albeit with an eightfold lower efficiency, whereas pleolipoviruses nearly exclusively infected autochthonous Halorubrum strains. Mapping of the metagenomic sequences from this environment to the genomes of isolated haloarchaeal viruses showed that these known viruses are underrepresented in the available viromes.