bluuebunny/crossref_metadata_2025 huggingface dataset:
MicroRNA-141-3p/200a-3p target and may be involved in post-transcriptional repression of RNA decapping enzyme Dcp2 during renal development
Authors: Zhang Ming-Nan , Tang Qun-Ye , Li Rui-Min , Song Man-Gen
Published: June 2018

The RNA decapping enzyme Dcp2 is a crucial enzyme involved in the process of RNA turnover, which can post-transcriptionally regulate gene expression. Dcp2 has been found to be highly expressed in embryonic, but not adult, kidneys. Here we showed that Dcp2 mRNA was expressed, but Dcp2 proteins were absent, in mouse kidneys after postnatal day 10 (P10). In kidneys of adult Dcp2-IRES-EGFP knock-in mice, Dcp2 was undetectable but EGFP was expressed, indicating that Dcp2 mRNA was not completely silenced in adult kidneys. Using luciferase reporter assays, we found that miR-141-3p/200a-3p directly targeted the 3ʹ UTR of Dcp2 mRNA. Overexpression of miR-141-3p and miR-200a-3p downregulated endogenous Dcp2 protein expression. Furthermore, miR-141-3p and miR-200a-3p expression was low in embryonic kidneys but increased dramatically after P10 and was negatively correlated with Dcp2 protein expression during renal development. These results suggest miR-141-3p/200a-3p may be involved in post-transcriptional repression of Dcp2 expression during renal development.

Abbreviations: IRES: internal ribosome entry site; EGFP: enhanced green fluorescent protein; UTR: untranslated region
Concentric circles of South Africa’s climate diplomacy
Authors: Olutola Oluwole , Landsberg Chris
Published: June 2018

This paper adopts the logic of concentric circles to unpack the multilevel approach that characterizes South Africa’s interface with climate change. The post-1994 South Africa interacted with climate change at multiple levels. At some points, South Africa’s response to climate change is guided strictly by the dictates of its overriding national interests. At another, it is a question of either serving a continental ‘representative’ or ‘leading voice’ for groupings of major importance within the global South regarding climate change. Also, South Africa’s climate diplomacy on the global scene ranks relatively high when compared with the scenarios concerning other emerging and even a good number of industrialized economies. Therefore, it is not certain how the policy emphasis is shifting radially across the interest-chain of South Africa’s relations in the context of climate change. As a key finding, this paper argues that South Africa’s super-state posture leaves one to wonder how constructively altruistic is the country’s climate diplomacy.
Intersecting disciplinary frameworks: the architecture and ecology
of
the city
Authors: McGrath Brian
Published: June 2018

Introduction:
While many studies have explored the link between ecology and urban design, this paper examines two major conceptions that can promote deeper connections between architecture and ecological science.

Outcomes:
Rather than providing a comprehensive review, the paper explores in detail two frameworks that have not yet been exploited as foundations for a bridge between these fields. One is the seminal work of Aldo Rossi on the architecture of the city, as opposed to a more traditional architectural focus on specific buildings, lots, or specific clients. The complementary framework for ecological science is the ecology of the city, developed to support and explain a new era of more integrated social-ecological study of urban systems than had existed previously.

Discussion:
This paper draws heretofore unexamined parallels between architecture as represented by the work of Rossi and the ecology of the city as represented by the Baltimore School of Urban Ecology. The ecology of the city has become a widely used framing in the science of urban ecology, while the architecture of the city continues to influence a deeper understanding of the built environment as a whole. The parallels provided by the architecture of the city and the ecology of the city help to understand the historical interrelations between nature and culture.

Conclusion:
Intersecting the two conceptual frameworks of the architecture and ecology of the city can help satisfy the call for an actionable ecology for the  city. This call demands both disciplines integrate their conceptual frameworks with communities in the collective enterprise of creating urban ecosystem health, justice, and sustainability.
Comparison of standards for the calibration of voltage, current and resistance meters
Authors: Marais Louis , Yang Steven , Lam Brenda , Yue LIU , John Thomas , Negi P S , Sakuma Hiroaki , Watabe Eiji , Wey Chua Sze , Kumtawee Chalit , Pimsut Yaowaret
Published: June 2018

The 14th Meeting of the APMP Technical Committee on Electricity and Magnetism, held on 5 December 2011 in Kobe, Japan, decided to hold a comparison of standards for the calibration of voltage, current and resistance meters at the lowest attainable level of uncertainty. Our comparison, designated APMP.EM-S12, covered the parameters and ranges that would typically be measured during the calibration of digital multimeters in electrical laboratories. The instrument selected for the comparison was a Wavetek model 4950 Multifunction Transfer Standard.

Circulation of the travelling standard started in February 2015 and the comparison concluded in October 2016. Between each of the comparison rounds the travelling standard was returned to the National Measurement Institute, Australia (NMIA). The dependence of the instrument on temperature and humidity was determined before the start of the comparison. The drift of the instrument during the comparison was determined from measurements at the NMIA. Participant results were corrected for temperature and drift.

Comparison reference values were calculated from all participant results that survived outlier detection. Most of the results show good agreement with the comparison reference values.

Main text

To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/.

The final report has been peer-reviewed and approved for publication by the CCEM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
Results of the supplementary comparison (bilateral) of a fixed volume micropipette of 50 μl and a variable volume micropipette of 1000 μl (SIM.M.FF-S11) .
Authors: Batista E , Alberini M
Published: June 2018

The purpose of this comparison was to perform a bilateral comparison between IPQ—Portugal and INTI—Argentina, in order to test the agreement of their results and uncertainties in the calibration of micropipettes despite the different equipment used and calibration process. In order to access the stability of the micropipettes, INTI preformed two measurements: one at the beginning and another at the end of the comparison. The measurements were carried out from September 2017 to November 2017.

The type of micropipette suggested for this comparison was the single-channel piston pipette, which was the most common used in laboratories and easy to handle. Each laboratory had to calibrate a fixed volume micropipette of 50 μl and a variable volume micropipette of 1000 μl in 1000 μl , 500 μl , 100 μl . For the variable micropipette all results for both laboratories were consistent with the reference value obtained by the weighted mean.

The fixed micropipette was damaged during the transportation between laboratories and therefore the results cannot be used.

The value of the expanded uncertainty is quite similar for the higher volumes but there are some differences in the values of the uncertainty components. The uncertainty component that has a major contribution to the final uncertainty is the handling for IPQ and the temperature difference between water and pipette for INTI.

Main text

To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/.

The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).
Deligne Categories and the Limit of Categories Rep(GL(m|n))
Authors: Entova-Aizenbud Inna , Hinich Vladimir , Serganova Vera
Published: June 2018

For each integer $t$ a tensor category $\mathcal{V}_t$ is constructed, such that exact tensor functors $\mathcal{V}_t\rightarrow \mathcal{C}$ classify dualizable $t$-dimensional objects in $\mathcal{C}$ not annihilated by any Schur functor. This means that $\mathcal{V}_t$ is the “abelian envelope” of the Deligne category $\mathcal{D}_t=\operatorname{Rep}(GL_t)$. Any tensor functor $\operatorname{Rep}(GL_t)\longrightarrow \mathcal{C}$ is proved to factor either through $\mathcal{V}_t$ or through one of the classical categories $\operatorname{Rep}(GL(m|n))$ with $m-n=t$. The universal property of $\mathcal{V}_t$ implies that it is equivalent to the categories $\operatorname{Rep}_{\mathcal{D}_{t_1}\otimes \mathcal{D}_{t_2}}(GL(X),\epsilon )$, ($t=t_1+t_2$, $t_1$ not an integer) suggested by Deligne as candidates for the role of abelian envelope.
First constraints on the stellar mass function of star-forming clumps at the peak of cosmic star formation
Authors: Dessauges-Zavadsky Miroslava , Adamo Angela
Published: June 2018

Star-forming clumps dominate the rest-frame ultraviolet morphology of galaxies at the peak of cosmic star formation. If turbulence driven fragmentation is the mechanism responsible for their formation, we expect their stellar mass function to follow a power law of slope close to −2. We test this hypothesis performing the first analysis of the stellar mass function of clumps hosted in galaxies at $z$ ∼ 1–3.5. The clump sample is gathered from the literature with similar detection thresholds and stellar masses determined in a homogeneous way. To overcome the small number statistics per galaxy (each galaxy hosts up to a few tens of clumps only), we combine all high-redshift clumps. The resulting clump mass function follows a power law of slope ∼−1.7 and flattens at masses below $2\times 10^7\, \mathrm{M}_{\odot }$. By means of randomly sampled clump populations, drawn out of a power-law mass function of slope −2, we test the effect of combining small clump populations, detection limits of the surveys, and blending on the mass function. Our numerical exercise reproduces all the features observed in the real clump mass function confirming that it is consistent with a power law of slope ≃ − 2. This result supports the high-redshift clump formation through fragmentation in a similar fashion as in local galaxies, but under different gas conditions.
Optical Principles of Fluorescence-Guided Brain Tumor Surgery: A Practical Primer for the Neurosurgeon
Authors: Zhang Daniel Y , Singhal Sunil , Lee John Y K
Published: June 2018

Fluorescence-guided surgery is a rapidly growing field that has produced some of the most important innovations in surgical oncology in the past decade. These intraoperative imaging technologies provide information distinguishing tumor tissue from normal tissue in real time as the surgery proceeds and without disruption of the workflow. Many of these fluorescent tracers target unique molecular or cellular features of tumors, which offers the opportunity for identifying pathology with high precision to help surgeons achieve their primary objective of a maximal safe resection. As novel fluorophores and fluorescent probes emerge from preclinical development, a practical understanding of the principles of fluorescence remains critical for evaluating the clinical utility of these agents and identifying opportunities for further innovation. In this review, we provide an “in-text glossary” of the fundamental principles of fluorescence with examples of direct applications to fluorescence-guided brain surgery. We offer a detailed discussion of the various advantages and limitations of the most commonly used intraoperative imaging agents, including 5-aminolevulinic acid, indocyanine green, and fluorescein, with a particular focus on the photophysical properties of these specific agents as they provide a framework through which to understand the new agents that are entering clinical trials. To this end, we conclude with a survey of the fluorescent properties of novel agents that are currently undergoing or will soon enter clinical trials for the intraoperative imaging of brain tumors.
Endoscopic Resection of Hemorrhaged Third Ventricle Cavernous Malformation: 2-Dimensional Operative Video
Authors: Palandri Giorgio , Sorenson Thomas , Zucchelli Mino , Acciarri Nicola , Mantovani Paolo , Sturiale Carmelo
Published: June 2018

Cavernous malformations of the third ventricle are uncommon vascular lesions. Evidence suggests that cavernous malformations in this location might have a more aggressive natural history due to their risk of intraventricular hemorrhage and hydrocephalus.
1
The gold standard of treatment is considered to be microsurgical gross total resection of the lesion. However, with progressive improvement in endoscopic capabilities, several authors have recently advocated for the role of minimally-invasive neuroendoscopy for resecting intraventricular cavernous malformations.
2-4
In this timely intraoperative video, we demonstrate the gross total resection of a third ventricle cavernous malformation that presented with hemorrhage via a right-sided trans-frontal neuroendoscopic approach.
GPCR kinase 2–interacting protein‐1 protects against ischemia‐reperfusion injury of the spinal cord by modulating ASK1/JNK/p38 signaling
Authors: Chen Jian , Wang Qian , Zhou Wei , Zhou Zheng , Tang Peng‐Yu , Xu Tao , Liu Wei , Li Lin‐Wei , Cheng Lin , Zhou Zhi‐Min , Fan Jin , Yin Guo‐Yong
Published: June 2018

GPCR kinase 2–interacting protein‐1 (GIT1) is a scaffold protein that plays an important role in cell adaptation, proliferation, migration, and differentiation; however, the role of GIT1 in the regulation of neuronal death after spinal cord injury remains obscure. Here, we demonstrate that GIT1 deficiency remarkably increased neuronal apoptosis and enhanced JNK/p38 signaling, which resulted in stronger motor deficits by ischemia‐reperfusion in vivo, consistent with the finding of oxygen‐glucose deprivation/reoxygenation–induced neuronal injury in vitro. After treatment with JNK and p38 inhibitors, abnormally necroptotic cell death caused by GIT1 knockdown could be partially rescued, with the recovery of neuronal viability, which was still poorer than that in control neurons. Meanwhile, overactivation of JNK/p38 after GIT1 depletion was concomitant with excessive activity of apoptosis signal‐regulating kinase‐1 (ASK1) that could be abolished by ASK1 silencing in HEK293T cells. Finally, GIT1 could disrupt the oligomerization of ASK1 via interaction between the synaptic localization domain that contains the coiled‐coil (CC)‐2 domain of GIT1 and the C‐terminal CC domain of ASK1. It suppressed the autophosphorylation of ASK1 and led to decreasing activity of the ASK1/JNK/p38 pathway. These data reveal a protective role for GIT1 in neuronal damage by modulating ASK1/JNK/p38 signaling.—Chen, J., Wang, Q., Zhou, W., Zhou, Z., Tang, P.‐Y., Xu, T., Liu, W., Li, L.‐W., Cheng, L., Zhou, Z.‐M., Fan, J., Yin, G.‐Y. GPCR kinase 2‐interacting protein‐1 protects against ischemia‐reperfusion injury of the spinal cord by modulating ASK1/JNK/p38 signaling. FASEB J. 32, 6833–6847 (2018). www.fasebj.org
Concrete versus abstract forms of social concept: an fMRI comparison of knowledge about people versus social terms
Authors: Rice Grace E. , Hoffman Paul , Binney Richard J. , Lambon Ralph Matthew A.
Published: June 2018

The anterior temporal lobes (ATLs) play a key role in conceptual knowledge representation. The hub-and-spoke theory suggests that the contribution of the ATLs to semantic representation is (a) transmodal, i.e. integrating information from multiple sensorimotor and verbal modalities, and (b) pan-categorical, representing concepts from all categories. Another literature, however, suggests that this region's responses are modality- and category-selective; prominent examples include category selectivity for socially relevant concepts and face recognition. The predictions of each approach have never been directly compared. We used data from three studies to compare category-selective responses within the ATLs. Study 1 compared ATL responses to famous people versus another conceptual category (landmarks) from visual versus auditory inputs. Study 2 compared ATL responses to famous people from pictorial and written word inputs. Study 3 compared ATL responses to a different kind of socially relevant stimuli, namely abstract non-person-related words, in order to ascertain whether ATL subregions are engaged for social concepts more generally or only for person-related knowledge. Across all three studies a dominant bilateral ventral ATL cluster responded to
all
categories in
all
modalities. Anterior to this ‘pan-category’ transmodal region, a second cluster responded more weakly overall yet selectively for people, but did so equally for spoken names and faces (Study 1). A third region in the anterior superior temporal gyrus responded selectively to abstract socially relevant words (Study 3), but did not respond to concrete socially relevant words (i.e. written names; Study 2). These findings can be accommodated by the graded hub-and-spoke model of concept representation. On this view, the ventral ATL is the centre point of a bilateral ATL hub, which contributes to conceptual representation through transmodal distillation of information arising from multiple modality-specific association cortices. Partial specialization occurs across the graded ATL hub as a consequence of gradedly differential connectivity across the region.

This article is part of the theme issue ‘Varieties of abstract concepts: development, use and representation in the brain’.
Olfactory language and abstraction across cultures
Authors: Majid Asifa , Burenhult Niclas , Stensmyr Marcus , de Valk Josje , Hansson Bill S.
Published: June 2018

Olfaction presents a particularly interesting arena to explore abstraction in language. Like other abstract domains, such as time, odours can be difficult to conceptualize. An odour cannot be seen or held, it can be difficult to locate in space, and for most people odours are difficult to verbalize. On the other hand, odours give rise to primary sensory experiences. Every time we inhale we are using olfaction to make sense of our environment. We present new experimental data from 30 Jahai hunter-gatherers from the Malay Peninsula and 30 matched Dutch participants from the Netherlands in an odour naming experiment. Participants smelled monomolecular odorants and named odours while reaction times, odour descriptors and facial expressions were measured. We show that while Dutch speakers relied on concrete descriptors, i.e. they referred to odour sources (e.g.smells like lemon), the Jahai used abstract vocabulary to name the same odours (e.g.musty). Despite this differential linguistic categorization, analysis of facial expressions showed that the two groups, nevertheless, had the same initial emotional reactions to odours. Critically, these cross-cultural data present a challenge for how to think about abstraction in language.

This article is part of the theme issue ‘Varieties of abstract concepts: development, use and representation in the brain’.
Learning abstract words and concepts: insights from developmental language disorder
Authors: Ponari Marta , Norbury Courtenay Frazier , Rotaru Armand , Lenci Alessandro , Vigliocco Gabriella
Published: June 2018

Some explanations of abstract word learning suggest that these words are learnt primarily from the linguistic input, using statistical co-occurrences of words in language, whereas concrete words can also rely on non-linguistic, experiential information. According to this hypothesis, we expect that, if the learner is not able to fully exploit the information in the linguistic input, abstract words should be affected more than concrete ones. Embodied approaches instead argue that both abstract and concrete words can rely on experiential information and, therefore, there might not be any linguistic primacy. Here, we test the role of linguistic input in the development of abstract knowledge with children with developmental language disorder (DLD) and typically developing children aged 8–13. We show that DLD children, who by definition have impoverished language, do not show a disproportionate impairment for abstract words in lexical decision and definition tasks. These results indicate that linguistic information does not have a primary role in the learning of abstract concepts and words; rather, it would play a significant role in semantic development across all domains of knowledge.

This article is part of the theme issue ‘Varieties of abstract concepts: development, use and representation in the brain’.
NFAT5 participates in Inducible Nitric Oxide Synthase activation by hypoxia in MEF cells
Authors: Serman Yair , Fuentealba Rodrigo A. , Pasten Consuelo , Rocco Jocelyn , Ko Ben C. B. , Carrión Flavio , Irarrázabal Carlos E.
Published: June 2018

We previously described the protective role of NFAT5 during hypoxia, in an independent way of HIF-1α. Alternatively, inducible NO synthase (iNOS) is also induced by hypoxia. The aim of this study was to establish the NFAT5 target gene in mouse embryonic fibroblasts (MEF) cell stimulated by hypoxia. NFAT5, iNOS, NO level, aquaporin 1 (AQP1) and urea transporter 1 (UTA1) were induced by low oxygen levels in MEF cells. Additionally, NFAT5 and UTA1 were induced in reoxygenation (after 24hrs of hypoxia). NFAT5 transactivation domain (TAD) was induced during hypoxia and hypoxia/reoxygenation. Two MEF cells line independently produced for altered NFAT5 (Knockout and DBD-mutant) lost the iNOS and AQP1 induction by low oxygen. The iNOS induction was recovered in NFAT5-KO MEF cells, when recombinant NFAT5 protein expression was reconstituted, but not for NFAT5 DBD-mutant MEF cells, explained by its dominant negative effect. Finally, we found a negative feedback loop of iNOS effect over NFAT5 protein abundance. This work provides a relevant information about signaling pathway of NFAT5 during adaptive responses to oxygen depletion.
Cell type specific control of basolateral amygdala plasticity via feedforward inhibition
Authors: Guthman E. Mae , Ma Ming , Chu Philip , Baca Serapio M. , Restrepo Diego , Huntsman Molly M.
Published: June 2018

The basolateral amygdala (BLA) plays a vital role in associating specific sensory stimuli with salient valence information. Excitatory principal neurons (PNs) undergo plastic changes to encode this integrated sensory-valence information; however, local BLA inhibitory interneurons (INs) gate the plasticity of the PNs via feed forward inhibition (FFI). Despite extensive literature implicating parvalbumin expressing (PV+) INs in FFI in cortex and hippocampus, prior anatomical experiments in BLA implicate somatostatin expressing (Sst+) INs in BLA. In the present study, we combined patch clamp electrophysiology with chemogenetics, unsupervised cluster analysis, and predictive modeling and found that a previously unreported subpopulation of fast-spiking Sst+ INs mediate BLA FFI and gate plasticity.
Hyperparameter-free optimizer of stochastic gradient descent that incorporates unit correction and moment estimation
Authors: Yamada Kazunori D
Published: June 2018

In the deep learning era, stochastic gradient descent is the most common method used for optimizing neural network parameters. Among the various mathematical optimization methods, the gradient descent method is the most naive. Adjustment of learning rate is necessary for quick convergence, which is normally done manually with gradient descent. Many optimizers have been developed to control the learning rate and increase convergence speed. Generally, these optimizers adjust the learning rate automatically in response to learning status. These optimizers were gradually improved by incorporating the effective aspects of earlier methods. In this study, we developed a new optimizer: YamAdam. Our optimizer is based on Adam, which utilizes the first and second moments of previous gradients. In addition to the moment estimation system, we incorporated an advantageous part of AdaDelta, namely a unit correction system, into YamAdam. According to benchmark tests on some common datasets, our optimizer showed similar or faster convergent performance compared to the existing methods. YamAdam is an option as an alternative optimizer for deep learning.
The immune checkpoint kick start: Optimization of neoadjuvant combination therapy using game theory
Authors: West Jeffrey , Robertson-Tessi Mark , Luddy Kimberly , Park Derek S. , Williamson Drew F.K. , Harmon Cathal , Khong Hung T. , Brown Joel , Anderson Alexander R.A.
Published: June 2018

An upcoming clinical trial at the Moffitt Cancer Center for women with stage 2/3 ER+breast cancer combines an aromatase inhibitor and a PD-L1 checkpoint inhibitor, and aims to lower a preoperative endocrine prognostic index (PEPI) that correlates with relapse-free survival. PEPI is fundamentally a static index, measured at the end of neoadjuvant therapy before surgery. We develop a mathematical model of the essential components of the PEPI score in order to identify successful combination therapy regimens that minimize both tumor burden and metastatic potential, based on time-dependent trade-offs in the system. We consider two molecular traits, CCR7 and PD-L1 which correlate with treatment response and increased metastatic risk. We use a matrix game model with the four phenotypic strategies to examine the frequency-dependent interactions of cancer cells. This game was embedded into an ecological model of tumor population growth dynamics. The resulting model predicts both evolutionary and ecological dynamics that track with changes in the PEPI score. We consider various treatment regimens based on combinations of the two therapies with drug holidays. By considering the trade off between tumor burden and metastatic potential, the optimal therapy plan was found to be a 1 month kick start of the immune checkpoint inhibitor followed by five months of continuous combination therapy. Relative to a protocol with both therapeutics given together from the start, this delayed regimen results in transient sub-optimal tumor regression while maintaining a phenotypic constitution that is more amenable to fast tumor regression for the final five months of therapy. The mathematical model provides a useful abstraction of clinical intuition, enabling hypothesis generation and testing of clinical assumptions.
LADL: Light-activated dynamic looping for endogenous gene expression control
Authors: Rege Mayuri , Kim Ji Hun , Valeri Jacqueline , Dunagin Margaret C. , Metzger Aryeh , Gong Wanfeng , Beagan Jonathan A. , Raj Arjun , Phillips-Cremins Jennifer E.
Published: June 2018

Mammalian genomes are folded into tens of thousands of long-range looping interactions1,2. The cause and effect relationship between looping and genome function is poorly understood, and the extent to which chromatin loops are dynamic on short time scales remains a fundamental unanswered question. Currently available strategies for loop engineering involve synthetic transcription factors tethered to dCas93,4 or zinc fingers5,6, which are constitutively expressed5,6 or induced on long time scales by the presence of a small molecule3. Here we report a new class of 3-D optoepigenetic tools for the directed rearrangement of 3-D chromatin looping on short time scales using blue light. We create synthetic architectural proteins by fusing the CIBN protein subunit from Arabidopsis thaliana with enzymatically dead Cas9 (dCas9). We target our light-activated dynamic looping system (LADL) to two genomic anchors with CRISPR guide RNAs and engineer their spatial co-localization via light-induced heterodimerization of the cryptochrome 2 (CRY2) protein with dCas9-CIBN. We apply LADL to redirect a stretch enhancer (SE) away from its endogenous Klf4 target gene and to the Zfp462 promoter. Looping changes occur as early as four hours after light induction. Using single molecule RNA FISH, we observe a LADL-induced increase in the total nascent Zfp462 transcripts and the number of Zfp462 alleles expressing simultaneously per cell. Moreover, LADL also increased synchronous Sox2 expression after reinforcement of a known Sox2-SE looping interaction. LADL facilitates loop synchronization across a large population of cells without exogenous chemical cofactors and can enable future efforts to engineer reversible and oscillatory looping on short time scales.
Multiobjective Strain Design: A Framework for Modular Cell Engineering
Authors: Garcia Sergio , Trinh Cong T.
Published: June 2018

Diversity of cellular metabolism can be harnessed to produce a large space of molecules. However, development of optimal strains with high product titers, rates, and yields required for industrial production is laborious and expensive. To accelerate the strain engineering process, we have recently introduced a modular cell design concept that enables rapid generation of optimal production strains by systematically assembling a modular cell with an exchangeable production module(s) to produce target molecules efficiently. In this study, we formulated the modular cell design concept as a general multiobjective optimization problem with flexible design objectives derived from mass action. We developed algorithms and an associated software package, named ModCell2 to implement the design. We demonstrated that ModCell2 can systematically identify genetic modifications to design modular cells that can couple with a variety of production modules and exhibit a minimal tradeoff among modularity, performance, and robustness. Analysis of the modular cell designs revealed both intuitive and complex metabolic architectures enabling modular production of these molecules. We envision ModCell2 provides a powerful tool to guide modular cell engineering and sheds light on modular design principles of biological systems.
Parameter inference with analytical propagators for stochastic models of autoregulated gene expression
Authors: Veerman Frits , Popović Nikola , Marr Carsten
Published: June 2018

Stochastic gene expression in regulatory networks is conventionally modelled via the Chemical Master Equation (CME). As explicit solutions to the CME, in the form of so-called propagators, are oftentimes not readily available, various approximations have been proposed. A recently developed analytical method is based on a separation of scales that assumes significant differences in the lifetimes of mRNA and protein in the network, allowing for the efficient approximation of propagators from asymptotic expansions for the corresponding generating functions. Here, we showcase the applicability of that method to simulated data from a ‘telegraph’ model for gene expression that is extended with an autoregulatory mechanism. We demonstrate that the resulting approximate propagators can be applied successfully for Bayesian parameter inference in the non-regulated model; moreover, we show that, in the extended autoregulated model, autoactivation or autorepression may be refuted under certain assumptions on the model parameters. Our results indicate that the method showcased here may allow for successful parameter inference and model identification from longitudinal single cell data.
Accurate in vivo population sequencing uncovers drivers of within-host genetic diversity in viruses
Authors: Gelbart Maoz , Harari Sheri , Ben-Ari Ya’ara , Kustin Talia , Wolf Dana , Mandelboim Michal , Mor Orna , Pennings Pleuni , Stern Adi
Published: June 2018

Mutations fuel evolution and facilitate adaptation to novel environments. However, characterizing the spectrum of mutations in a population is obscured by high error rates of next generation sequencing. Here, we present AccuNGS, a novel in vivo sequencing approach that detects variants as rare as 1:10,000. Applying it to 46 clinical samples taken from early infections of the human-infecting viruses HIV, RSV and CMV, revealed large differences in within-host genetic diversity among virus populations. Haplotype reconstruction revealed that increased diversity was mostly driven by multiple transmitted/founder viruses in HIV and CMV samples. Conversely, we detected an abundance of defective virus genomes (DVGs) in RSV samples, including hyper-edited genomes, nonsense mutations and single point deletions. Higher proportions of DVGs correlated with increased viral loads, suggesting increased cellular co-infection rates, which enable DVG persistence. AccuNGS establishes a general platform that allows detecting DVGs, and in general, rare variants that drive evolution.
High-sensitivity c-reactive protein and total and saturated fat intake in adolescent students: a longitudinal study
Authors: Cândida de Lima Martins Camila , Emília Leite de Lima Ferreira Flávia , Cavalcanti de Almeida Aléssio Tony
Published: June 2018

Objective

The present study aimed to assess the relationship between hs-CRP concentrations and total and saturated fat intake in adolescents after a year of follow-up.

Methods

A longitudinal study carried out in the years 2014 and 2015 evaluated 408 adolescents from the municipal and state public schools of João Pessoa, Paraíba, between 10 and 14 years of age, who participated in the Longitudinal Study on Sedentary Behavior, Physical Activity, Eating Habits and Adolescent Health (LONCAAFS). Data were obtained on sociodemographic data, anthropometric nutritional status, physical activity and hs-CRP concentration. The consumption of total and saturated fats was evaluated from the 24 hour recall.

Results

The associations between concentrations of hs-CRP and total and saturated fat intake were performed by linear regression considering panel data, individual fixed effect, balanced bank, stratified by sex and BMI. The mean values of the hs-CRP variable were significantly different between the analyzed years (p = 0.024). The percentage of total and saturated fat consumption is within the recommended level in both years, with no significant difference (p> 0.05). No statistically significant associations were found between hs-CRP and total fat consumption (β = −0.19p = 0.582) and saturated fat (β = 0.20, p = 0.282).

Conclusion

The study did not present significant evidence on the relationship between the concentrations of hs-CRP and the consumption of total and saturated fats, as one year of follow-up may not have promoted evident changes in the levels of hs-CRP in adolescents.
The role of matrilineality in shaping patterns of Y chromosome and mtDNA sequence variation in southwestern Angola
Authors: Oliveira Sandra , Hübner Alexander , Fehn Anne-Maria , Aço Teresa , Lages Fernanda , Pakendorf Brigitte , Stoneking Mark , Rocha Jorge
Published: June 2018

Southwestern Angola is a region characterized by contact between indigenous foragers and incoming food-producers, involving genetic and cultural exchanges between peoples speaking Kx’a, Khoe-Kwadi and Bantu languages. Although present-day Bantu-speakers share a patrilocal residence pattern and matrilineal principle of clan and group membership, a highly stratified social setting divides dominant pastoralists from marginalized groups that subsist on alternative strategies and have previously been though to have pre-Bantu origins. Here, we compare new high-resolution sequence data from 2.3 Mb of the non-recombining Y chromosome (NRY) from 170 individuals with previously reported mitochondrial genomes (mtDNA), to investigate the population history of seven representative southwestern Angolan groups (Himba, Kuvale, Kwisi, Kwepe, Twa, Tjimba, !Xun) and to study the causes and consequences of sex-biased processes in their genetic variation. We found no clear link between the formerly Kwadi-speaking Kwepe and pre-Bantu eastern African migrants, and no pre-Bantu NRY lineages among Bantu-speaking groups, except for small amounts of “Khoisan” introgression. We therefore propose that irrespective of their subsistence strategies, all Bantu-speaking groups of the area share a male Bantu origin. Additionally, we show that in Bantu-speaking groups, the levels of among-group and between-group variation are higher for mtDNA than for NRY. These results, together with our previous demonstration that the matriclanic systems of southwestern Angolan Bantu groups are genealogically consistent, suggest that matrilineality strongly enhances both female population sizes and interpopulation mtDNA variation.
Commitments by the Biopharmaceutical Industry to Clinical Trial Transparency: The Evolving Environment
Authors: Baronikova Slavka , Purvis Jim , Southam Eric , Beeso Julie , Winchester Christopher C , Panayi Antonia
Published: June 2018

Background

Sponsors of clinical trials have ethical obligations to register protocols, to report study results and to comply with applicable legal requirements.

Objective

To evaluate public commitments to trial disclosure and rates of disclosure by members and non-members of the European Federation of Pharmaceutical Industries and Associations (EFPIA) and/or the Pharmaceutical Research and Manufacturers of America (PhRMA).

Study selection

Websites of the top 50 biopharmaceutical companies by 2015 sales were searched for statements relating to trial data disclosure. Disclosure of trial results completed by biopharmaceutical industry and non-industry sponsors of at least 30 trials (2006–2015) was assessed using TrialsTracker.

Findings

Among the top 50 companies, 30 were EFPIA/PhRMA members and 20 were non-members, of which 26 and none, respectively, had a statement on their website committing to the disclosure of trials data. Of 29 377 trials in TrialsTracker, 9511 were industry-sponsored (69 companies) and 19 866 were non-industry-sponsored (254 institutions). The overall mean disclosure rate was 55%, with higher rates for industry (74%) than for non-industry sponsors (46%). Of the 30 companies within the top 50 with data in TrialsTracker, the mean disclosure rate was 76% (77% for EFPIA/PhRMA members [n = 25] versus 67% for non-members [n = 5]).

Conclusions

Most of the top 50 biopharmaceutical companies have publicly committed to the disclosure of trial data. Industry sponsors have responded to the ethical and legal demands of trial disclosure to a greater extent than non-industry sponsors, and now disclose three quarters of their trials.
Allostery and cooperativity in multimeric proteins: bond-to-bond propensities in ATCase
Authors: Hodges Maxwell , Barahona Mauricio , Yaliraki Sophia N.
Published: June 2018

Aspartate carbamoyltransferase (ATCase) is a large dodecameric enzyme with six active sites that exhibits allostery: its catalytic rate is modulated by the binding of various substrates at distal points from the active sites. A recently developed method, bond-to-bond propensity analysis, has proven capable of predicting allosteric sites in a wide range of proteins using an energy-weighted atomistic graph obtained from the protein structure and given knowledge only of the location of the active site. Bond-to-bond propensity establishes if energy fluctuations at given bonds have significant effects on any other bond in the protein, by considering their propagation through the protein graph. In this work, we use bond-to-bond propensity analysis to study different aspects of ATCase activity using three different protein structures and sources of fluctuations. First, we predict key residues and bonds involved in the transition between inactive (T) and active (R) states of ATCase by analysing allosteric substrate binding as a source of energy perturbations in the protein graph. Our computational results also indicate that the effect of multiple allosteric binding is non linear: a switching effect is observed after a particular number and arrangement of substrates is bound suggesting a form of long range communication between the distantly arranged allosteric sites. Second, cooperativity is explored by considering a bisubstrate analogue as the source of energy fluctuations at the active site, also leading to the identification of highly significant residues to the T↔R transition that enhance cooperativity across active sites. Finally, the inactive (T) structure is shown to exhibit a strong, non linear communication between the allosteric sites and the interface between catalytic subunits, rather than the active site. Bond-to-bond propensity thus offers an alternative route to explain allosteric and cooperative effects in terms of detailed atomistic changes to individual bonds within the protein, rather than through phenomenological, global thermodynamic arguments.
More are better, but the details matter: combinations of multiple Fresnel zone plates for improved resolution and efficiency in X-ray microscopy
Authors: Li Kenan , Jacobsen Chris
Published: June 2018

Fresnel zone plates used for X-ray nanofocusing face high-aspect-ratio nanofabrication challenges in combining narrow transverse features (for high spatial resolution) along with extended optical modulation along the X-ray beam direction (to improve efficiency). The stacking of multiple Fresnel zone plates along the beam direction has already been shown to offer improved characteristics of resolution and efficiency when compared with thin single zone plates. Using multislice wave propagation simulation methods, here a number of new schemes for the stacking of multiple Fresnel zone plates are considered. These include consideration of optimal thickness and spacing in the axial direction, and methods to capture a fraction of the light otherwise diffracted into unwanted orders, and instead bring it into the desired first-order focus. The alignment tolerances for stacking multiple Fresnel zone plates are also considered.
Multiscale X-ray imaging using ptychography
Authors: Sala Simone , Kuppili Venkata S. C. , Chalkidis Stefanos , Batey Darren J. , Shi Xiaowen , Rau Christoph , Thibault Pierre
Published: June 2018

The success of ptychography and other imaging experiments at third-generation X-ray sources is apparent from their increasingly widespread application and the improving quality of the images they produce both for resolution and contrast and in terms of relaxation of experimental constraints. The wider availability of highly coherent X-rays stimulates the development of several complementary techniques which have seen limited mutual integration in recent years. This paper presents a framework in which some of the established imaging techniques – with particular regard for ptychography – are flexibly applied to tackle the variable requirements occurring at typical synchrotron experiments. In such a framework one can obtain low-resolution images of whole samples and smoothly zoom in on specific regions of interest as they are revealed by switching to a higher-resolution imaging mode. The techniques involved range from full-field microscopy, to reach the widest fields of view (>mm), to ptychography, to achieve the highest resolution (<100 nm), and have been implemented at the I13 Coherence Branchline at Diamond Light Source.
Estimating the efficiency of Greek banking system during the last decade of world economic crisis
Authors: Sompolos Zois , Mavri Maria
Published: June 2018

Purpose

The purpose of this paper is to examine the efficiency of the four largest Greek banking organizations for the period 2004–2014, including both a period of strong economic growth and a period of economic crisis and recession, which is still plaguing the Greek economy and more specifically the Greek banking sector.

Design/methodology/approach

The study incorporates the application of financial ratio analysis and the data envelopment analysis (DEA) in order to calculate the technical efficiency of Greek financial institutions. More specifically, a two-stage output-oriented DEA model is developed in order to estimate the global efficiency of banks. The banking function is considered as consisting of two stages in series, a service/operational efficiency and a profitability efficiency. In both output-oriented models, methods of constant returns to scale and variable returns to scale were applied.

Findings

The results show that in terms of operational efficiency, banks started from a low rate of return in 2004, which improved until 2008, which marked the peak of operational efficiency. By 2010, the operating efficiency varied with downward trend until 2012–2013. In terms of profitability efficiency, the image is clearer, since the impact the financial crisis had on bank’s profit efficiency led, by 2012, to a plunge in the average efficiency by 30–40 percent.

Originality/value

A multi-stage DEA process, input oriented, was used in order to estimate changes in the performance and efficiency of banking system. The period 2004–2014 has not been examined until recently and all previous studies used the output-oriented DEA model.
Organizational logic to prioritize between the elements of triple bottom line
Authors: Rodriguez Rocio , Svensson Goran , Eriksson David
Published: June 2018

Purpose

The purpose of this paper is to assess both private and public organizations in order to compare the similarities and differences between the organizational priority logic of TBL elements. The research objective is, therefore, to describe the organizational logic, so as to prioritize between economic, social and environmental elements of the triple bottom line (TBL). The approach is also to describe the common denominators and differentiators between private and public organizations.

Design/methodology/approach

Based on judgmental sampling and in-depth interviews of executives at private and public hospitals in Spain. Data were collected from the directors of communication of private hospitals, and from the executive in charge of corporate social responsibility of public hospitals.

Findings

The organizational logic for prioritizing the elements of TBL differs between private and public hospitals. The economic element of TBL is crucial to survival for private hospitals. Compliance with the legal requirements and certifications of the environmental element is the major concern for public hospitals. Private and public hospitals would both pay considerably greater attention to the social element of TBL, if there were no judicial and economic restrictions.

Research limitations/implications

This study differs from previous ones in terms of exploring the interfaces and relationships between TBL elements, which focus on the organizational logic to prioritize between the elements of TBL. There are both common denominators and differentiators between private and public hospitals, when it comes to the priority logic of TBL elements.

Practical implications

The priority logic of determining the most important TBL element it is mainly about satisfying organizational needs and societal demands. Determining the second most important TBL element is mostly about organizational preferences and what it wants to achieve. Determining the least important TBL element it is about the organizational mindset for and with respect to the future.

Originality/value

This study contributes to determining the appropriate organizational priority logic of the TBL elements, as well as common denominators and differentiators between private and public organizations. It also contributes to explaining the organizational reasoning as to why one TBL element may be prioritized over another, an issue which has not been addressed in existing theory and previous studies.