bluuebunny/crossref_metadata_2025 huggingface dataset:
Critical curvature localization in graphene. I. Quantum-flexoelectricity effect
Authors: Kothari Mrityunjay , Cha Moon-Hyun , Kim Kyung-Suk
Published: June 2018

Here, we report the discovery of a new, curvature-localizing, subcritical buckling mode that produces shallow-kink corrugation in multi-layer graphene. Our density functional theory (DFT) analysis reveals the mode configuration—an approximately 2 nm wide boundary layer of highly localized curvature that connects two regions of uniformly but oppositely sheared stacks of flat atomic sheets. The kink angle between the two regions is limited to a few degrees, ensuring elastic deformation. By contrast, a purely mechanical model of sandwich structures shows progressive supercritical curvature localization spread over a 50–100 nm wide boundary layer. Our effective-locality model of electromechanics reveals that coupling between atomic-layer curvature and electric-charge polarization, i.e. quantum flexoelectricity, leads to emergence of a boundary layer in which curvature is focused primarily within a 0.86 nm fixed band width. Both DFT and the model analyses show focused distributions of curvature and polarization exhibiting oscillating decay within the approximately 2 nm wide boundary layer. The results show that dipole–dipole interaction lowers the potential energy with such a distribution. Furthermore, this model predicts peak-polarization density approximately 0.12 e
-
 nm
−1
for 3° tilt angle. This high polarization concentration can be controlled by macroscopic deformation and is expected to be useful in studies of selective graphene-surface functionalization for various applications.
Cascading speciation among mutualists and antagonists in a tree–beetle–fungi interaction
Authors: Bracewell R. R. , Vanderpool D. , Good J. M. , Six D. L.
Published: June 2018

Cascading speciation is predicted to occur when multiple interacting species diverge in parallel as a result of divergence in one species promoting adaptive differentiation in other species. However, there are few examples where ecological interactions among taxa have been shown to result in speciation that cascades across multiple trophic levels. Here, we test for cascading speciation occurring among the western pine beetle (Dendroctonus brevicomis), its primary host tree (Pinus ponderosa), and the beetle's fungal mutualists (Ceratocystiopsis brevicomiandEntomocorticiumsp. B). We assembled genomes for the beetle and a fungal symbiont and then generated reduced representation genomic data (RADseq) from range-wide samples of these three interacting species. Combined with published data for the host tree, we present clear evidence that the tree, the beetle, and the fungal symbionts are all genetically structured into at least two distinct groups that have strongly codiverged with geographical isolation. We then combine our genomic results with diverse population and laboratory-based data to show evidence for reproductive isolation at each level of the cascade and for coevolution of both antagonistic and mutualistic species interactions within this complex network.
Tip-dating and homoplasy: reconciling the shallow molecular divergences of modern gharials with their long fossil record
Authors: Lee Michael S. Y. , Yates Adam M.
Published: June 2018

Simultaneously analysing morphological, molecular and stratigraphic data suggests a potential resolution to a major remaining inconsistency in crocodylian evolution. The ancient, long-snouted thoracosaurs have always been placed near the Indian gharial
Gavialis
, but their antiquity (
ca
72 Ma) is highly incongruous with genomic evidence for the young age of the
Gavialis
lineage (
ca
40 Ma). We reconcile this contradiction with an updated morphological dataset and novel analysis, and demonstrate that thoracosaurs are an ancient iteration of long-snouted stem crocodylians unrelated to modern gharials. The extensive similarities between thoracosaurs and
Gavialis
are shown to be an almost ‘perfect storm’ of homoplasy, combining convergent adaptions to fish-eating, as well resemblances between genuinely primitive traits (thoracosaurs) and atavisms (
Gavialis
). Phylogenetic methods that ignore stratigraphy (parsimony and undated Bayesian methods) are unable to tease apart these similarities and invariably unite thoracosaurs and
Gavialis.
However, tip-dated Bayesian approaches additionally consider the large temporal gap separating ancient (thoracosaurs) and modern (
Gavialis
) iterations of similar long-snouted crocodyliforms. These analyses robustly favour a phylogeny which places thoracosaurs basal to crocodylians, far removed from modern gharials, which accordingly are a very young radiation. This phylogenetic uncoupling of ancient and modern gharial-like crocs is more consistent with molecular clock divergence estimates, and also the bulk of the crocodylian fossil record (e.g. all unequivocal gharial fossils are very young). Provided that the priors and models attribute appropriate relative weights to the morphological and stratigraphic signals—an issue that requires investigation—tip-dating approaches are potentially better able to detect homoplasy and improve inferences about phylogenetic relationships, character evolution and divergence dates.
Imprint of parity and age at first birth on the genomic landscape of subsequent breast cancer
Authors: Nguyen Bastien , Venet David , Lambertini Matteo , Desmedt Christine , Salgado Roberto , Horlings Hugo , Rothé Françoise , Sotiriou Christos
Published: June 2018

Background

Although parity and age at first birth are among the most known extrinsic factors that modulates breast cancer risk, their impact on the biology of subsequent breast cancer has never been explored in depth. In this study, we investigate the imprint of parity and age at first birth on the pattern of somatic mutations, somatic copy number alterations (SCNAs), transcriptomic profiles, and tumor infiltrating lymphocytes (TILs) levels of subsequent breast cancer.

Methods

A total of 313 patients with primary breast cancer with available whole genome and RNA sequencing data were included in this study. We used a multivariate analysis adjusted for age at diagnosis, pathological stage, molecular subtypes and histological subtypes. We compared nulliparous vs. parous, late parous vs. early parous, and nulliparous vs. pregnancy associated breast cancer (PABC) patients. Late and early parous patients were grouped by using the median age at first birth as a cut-off value. PABC was defined as patients diagnosed up to 10 years postpartum.

Results

Genomic alterations of breast cancer are associated with age at first birth but not parity status alone. Independently of clinicopathological features, early parous patients developed tumors characterized by a higher number of Indels (Padj = 0.002), a lower frequency of CDH1 mutations (1.2% vs. 12.7% Padj = 0.013), a higher frequency of TP53 mutations (50% vs. 22.5%; Padj = 0.010) and MYC amplification (28% vs. 7% Padj = 0.008), and a lower prevalence of mutational signature 2. PABC were associated with increased TILs infiltration (Padj = 0.0495).

Conclusions

These findings highlight an unprecedented link between reproductive history and the genomic landscape of subsequent breast cancer. With the rapid development of precision oncology, this work advocates that reproductive history should not be underestimated in future clinical studies of breast cancer.
The pyriproxyfen metabolite 4'OH- pyriproxyfen disrupts thyroid hormone signaling and enhances Musashi-1 levels in neuroprogenitors.
Authors: Spirhanzlova Petra , Le Mevel Sebastien , Wejaphikul Karn , Mughal Bilal , Gothie Jean-David , Sebillot Anthony , Butruille Lucille , Leemans Michelle , Visser Theo , Remaud Sylvie , Fini Jean-Baptiste , Demeneix Barbara
Published: June 2018

Epidemiological and experimental studies have raised questions as to whether the insecticide pyriproxyfen (PPF) could be implicated in the increased incidence of microcephaly associated with ZIKA infection during pregnancy. This pesticide is documented as a thyroid hormone (TH) disrupting chemical. We investigated whether environmentally relevant amounts of its main metabolite, 4'-OH-pyriproxyfen (4'-OH-PPF), modified TH signaling and early neuronal development. First, an in silico study revealed strong affinity of 4-OH-PPF to fit the ligand binding pocket of TH receptors (TRs). Further, in vitro assays on human cell lines showed 4'OH-PPF (> 3 mg/L ) to act as a TRα antagonist. Next, using a transgenic Xenopus TH-sensitive reporter system, Tg(thibz:GFP) tadpoles showed that 4'OH-PPF (> 10-7 mg/L) displayed TH-disruptive activity and reduced tadpole mobility (> 10-1 mg/L). Exposure to 4'OH-PPF significantly reduced Xenopus head size at levels equivalent to the maximum recommended daily intake of PPF (3x 10-1 mg/L). Most strikingly, in both the Xenopus system in vivo and in mouse neurosphere cultures, environmentally relevant concentrations of 4'OH-PPF increased expression of the gene that enables ZIKA replication: Musashi-1 (msi1) in neurogenic brain areas. We conclude that first, the PPF metabolite, 4'OH-PPF, disrupts thyroid signaling, neuronal development and behavior in Xenopus embryos, and second, that it increases Musashi-1 levels in neurogenic zones of both mouse and Xenopus, creating the potential to enhance viral replication. As PPF is used in areas with high microcephaly incidence and is readily broken down to 4'OH-PPF, these findings provide a plausible mechanism whereby PPF could, through induced changes in expression of Musashi-1, exacerbate the effects of ZIKA virus infection.
Functional connectivity reveals dissociable ventrolateral prefrontal mechanisms for the control of multilingual word retrieval
Authors: Branzi Francesca M. , Martin Clara D. , Carreiras Manuel , Paz-alonso Pedro M.
Published: June 2018

A fundamental cognitive operation involved in speech production is word retrieval from the mental lexicon, which in monolinguals is supported by dissociable ventro-lateral prefrontal cortex (vlPFC) mechanisms associated with proactive and reactive control. This functional magnetic resonance imaging (fMRI) study established whether in multilinguals word retrieval is supported by the same prefrontal mechanisms, and whether proactive modulation consists in suppression of the non-target lexicon. Healthy multilingual volunteers participated in a task that required them to name pictures alternatively in their dominant and less-dominant language. Two crucial variables were manipulated: the cue-target interval (CTI) to either engage (long CTI) or prevent proactive control processes (short CTI), and the cognate status of the pictures to-be-named (non-cognates versus cognates) to capture the presence of selective pre-activation of the target language. Results support the two-process account of vlPFC and indicate that multilinguals engage in proactive control to prepare the target language. This proactive modulation, enacted by anterior vlPFC, is achieved by boosting the activation of lexical representations of the target language. Control processes supported by mid-vlPFC and left inferior parietal lobe together, are similarly engaged in pre-and post-word retrieval, possibly exerted on phonological representations to reduce cross-language interference.

Significance Statement

Word retrieval in monolingual speech production is enacted by left ventro-lateral prefrontal cortex (vlPFC) supporting controlled access to conceptual representations (proactive control), and left mid-vlPFC supporting post-retrieval lexical selection (reactive control). In this functional magnetic resonance imaging (fMRI) study we demonstrate that multilingual word retrieval is supported by similar prefrontal mechanisms. However, differently from monolinguals, multilingual speakers retrieve words by applying proactive control on lexical representations to reduce cross-language interference. Alternatively to what it has been proposed by one of the most influential models, here we show that this proactive modulation is achieved by boosting the activation of lexical representations of the target language.
Roles of motion perception and visual acuity for driving hazard perception
Authors: Moharrer Mojtaba , Tang Xiaolan , Luo Gang
Published: June 2018

PURPOSE

There are many visually impaired people who can drive legally with bioptic telescope. Drawing on the experience of drivers with reduced vision, this study investigated the role of motion perception and visual acuity in driving, under simulated low visual acuity.

METHODS

Twenty normally sighted participants took part in a driving hazard perception (HP) test, in four different conditions: with/without motion interruption and with/without simulated low visual acuity. In interrupted motion conditions a mask frame was inserted between every frame of the driving videos. In simulated low visual acuity conditions, participants wore glasses with diffusing filters that lowered their visual acuity to 20/120 on average. Participants’ response time, hazard detection rates, and HP scores, which combined response time and detection rate, were compared.

RESULTS

Repeated measure ANOVA revealed that the HP scores significantly declined from 20.46 to 16.82 due to the motion mask (F(1,19)= 9.343, p = 0.006). However, simulated low visual acuity did not affect HP scores (F(1,19) = 1.807, p = 0.195). The interaction between vision and mask was not significant (F(1,19) = 1. 295, p = 0.269). The decline in score was mostly due to significant decrease in detection rate, from 0.80 to 0.64, due to the motion mask (F(1,19) = 16.686, p = 0.001).

CONCLUSIONS

In this experimental setting, human observers relied largely on motion information for detecting driving hazards, rather than high visual acuity. This finding might help explain how visually impaired drivers can compensate for their impaired vision during driving.
The Effects of Varying Gravito-inertial Stressors on Grip Strength and Hemodynamic Responses Across Gender
Authors: White Olivier , Barbiero Marie , Goswami Nandu
Published: June 2018

The body behaves as a global system with many interconnected subsystems. While the effects of a gravitational change on body responses have been extensively studied in isolation, we are not aware of any study that examined two types of body responses concurrently. Here, we examined how the neurocognitive and cardiovascular systems interact in this singular context and whether these combined responses are influenced by gender. Ten women and nine men underwent three 5-minute centrifugation sessions (2.4g at the feet, 1.5g at the heart) in which participants rhythmically moved a hand-held object for 20 seconds. Grip force and hemodynamic responses were continuously measured during centrifugation and rest periods. Our results show that men optimize the modulation between grip force and the destabilizing load force, but not women. Exposure to artificial gravity induced higher heart rate and mean arterial pressure in both genders compared to baseline. However, during exposure, only women decreased heart rate across sessions. Interestingly, we found that Finishers (N=13, mostly men) and Non-Finishers (N=6, mostly women) exhibited divergent patterns of hemodynamic responses. We also suggest that the lack of grip force adaptation reported in women can be linked to challenged hemodynamic responses in that population. Finally, by deriving a simple model to predict failure to complete the experiment, we found that mean arterial pressure was the most relevant dimension, and not gender. As artificial gravity is being proposed as a countermeasure in long-term manned missions, our results are particularly important but also deserve follow-up studies.
Increased number and activity of a lateral subpopulation of hypothalamic orexin/hypocretin neurons underlies the expression of an addicted state in rats
Authors: James Morgan H , Stopper Colin M , Zimmer Benjamin A , Koll Nikki E , Bowrey Hannah E , Aston-Jones Gary
Published: June 2018

Background

The orexin system is important for reward-driven motivation but has not been implicated in the expression of a multi-phenotype addicted state.

Methods

Rats were assessed for economic demand for cocaine prior to and following 14d of short- (ShA), long- (LgA) or intermittent-access (IntA) to cocaine. Rats were also assessed for a number of other DSM- V-relevant addiction criteria following differential access conditions. Orexin system function was assessed by i) quantification of numbers and activity of orexin cells, ii) pharmacological blockade of the orexin-1 receptor, and iii) subregion-specific knockdown of orexin cell populations.

Results

IntA produced a cluster of addiction-like behaviors that closely recapitulate key diagnostic criteria for addiction to a greater extent than LgA or ShA. IntA was associated with plasticity in orexin cell function, including increased number and activity of orexin-expressing neurons within the lateral hypothalamic (LH) subregion. This plasticity persisted during protracted withdrawal from cocaine for at least 6 months and was associated with enhanced incubation of craving. Selective knockdown of LH orexin neurons reversed the addicted state, and orexin-1 receptor signaling played a larger role in drug seeking after IntA.

Conclusions

These data provide the first evidence that LH orexin system function extends beyond general reward seeking to play a critical role in the expression of a multi-phenotype addicted-like state. Thus, the orexin/hypocretin system is a potential novel target for pharmacotherapies designed to treat cocaine addiction. In addition, these data point to the IntA model as a preferred approach to modeling addictionlike behavior in rats.
Exosomes are key regulators of non-cell autonomous communication in senescence
Authors: Borghesan Michela , Fafián-Labora Juan , Carpintero-Fernández Paula , Ximenez-Embun Pilar , Peinado Hector , Muñoz Javier , O’Loghlen Ana
Published: June 2018

Senescence is a cellular phenotype characterized by an irreversible cell cycle arrest and the secretion of inflammatory proteins, denominated senescence-associated secretory phenotype (SASP). The SASP is important in influencing the behavior of neighboring cells and altering the microenvironment; yet, until now this role has been mainly attributed to soluble factors. Here, we report that extracellular vesicles also alter the environment by transmitting the senescent phenotype to other cells via exosomes (extracellular vesicles of endocytic origin). A combination of functional assays, Cre-/oxP reporter systems, proteomic analysis and RNAi screens confirm that exosomes form part of the senescent secretome and mediate paracrine senescence via the activation of a non-canonical interferon (IFN) pathway. Altogether, we speculate that exosomes could be drivers of tissue degeneration both locally and systemically during aging and age- related disease.
Gut bacterial tyrosine decarboxylases restrict the bioavailability of levodopa, the primary treatment in Parkinson’s disease
Authors: van Kessel Sebastiaan P. , Frye Alexandra K. , El-Gendy Ahmed O. , Castejon Maria , Keshavarzian Ali , van Dijk Gertjan , Aidy Sahar El
Published: June 2018

Human gut bacteria play a critical role in the regulation of immune and metabolic systems, as well as in the function of the nervous system. The microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we identify and characterize gut-associated bacteria in their ability to decarboxylate L-DOPA (also known as Levodopa or L-3,4-dihydroxyphenylalanine) to dopamine via the tyrosine decarboxylases, which are mainly present in the class Bacilli. Although the bacterial tyrosine decarboxylases have a higher affinity for tyrosine compared to L-DOPA, this does not affect their ability to decarboxylate L-DOPA, nor does any inhibitor of the human decarboxylase. This study indicates thatin situbioavailability of L-DOPA is compromised by the gut bacterial tyrosine decarboxylase abundance in Parkinson’s patients. Finally, we show that the tyrosine decarboxylase abundance in the microbiota at the site of L-DOPA absorption, the proximal small intestine, significantly influences L-DOPA bioavailability in the plasma of rats. Our results highlight the role of microbial metabolism in drug bioavailability, and specifically, that small intestinal abundance of bacterial tyrosine decarboxylase can explain the highly variable L-DOPA dosage regimens required in the treatment of individual Parkinson’s patients.

Highlights

Small intestinal bacteria is able to convert L-DOPA to dopamine

L-DOPA metabolism by gut bacteria reduce the bioavailability of L-DOPA in the body, thus is a significant explanatory factor of the highly variable L-DOPA dosage regimens required in the treatment of individual Parkinson’s patients.

Inhibitors of the human DOPA decarboxylase are not potent inhibitors for bacterial tyrosine decarboxylases
Resolving challenges in quantitative modeling of microbial community dynamics
Authors: Hart Samuel F. M. , Mi Hanbing , Green Robin , Xie Li , Bello Pineda Jose Mario , Momeni Babak , Shou Wenying
Published: June 2018

Microbial communities can perform biochemical activities that monocultures cannot. Controlling communities requires an understanding of community dynamics. Here, we mathematically predict the growth rate of an engineered community consisting of twoS. cerevisiaestrains, each releasing a metabolite required and consumed by the partner. Initial model parameters were based on strain phenotypes measured in batch mono-cultures with zero or excess metabolite, and failed to quantitatively predict experimental results. To resolve model-experiment discrepancy, we chemically identified the correct exchanged metabolites, but this did not improve model performance. We then re-measured strain phenotypes in chemostats mimicking the metabolite-limited community environments, while mitigating or incorporating effects of rapid evolution. Almost all phenotypes we measured varied significantly with the metabolite environment. Once we used parameters measured in community-like chemostat environments, prediction agreed with experimental results. In summary, using a simplified community, we uncovered, and devised means to resolve, modeling challenges that are likely general.
Exploring the limits of network topology estimation using diffusion-based tractography and tracer studies in the macaque cortex
Authors: Shen Kelly , Goulas Alexandros , Grayson David , Eusebio John , Gati Joseph S. , Menon Ravi S. , McIntosh Anthony R. , Everling Stefan
Published: June 2018

Reconstructing the anatomical pathways of the brain to study the human connectome has become an important endeavour for understanding brain function and dynamics. Reconstruction of the cortico-cortical connectivity matrix in vivo often relies on noninvasive diffusion-weighted imaging (DWI) techniques but the extent to which they can accurately represent the topological characteristics of structural connectomes remains unknown. We explored this question by constructing connectomes using DWI data collected from macaque monkeys in vivo and with data from published invasive tracer studies. We found the strength of fiber tracts was well estimated from DWI and topological properties like degree and modularity were captured by tractography-based connectomes. Rich-club/core-periphery type architecture could also be detected but the classification of hubs using betweenness centrality, participation coefficient and core-periphery identification techniques was inaccurate. Our findings indicate that certain aspects of cortical topology can be faithfully represented in noninvasively-obtained connectomes while other network analytic measures warrant cautionary interpretations.
Retrospective whole-genome sequencing analysis distinguished PFGE and drug resistance matched retail meat and clinical Salmonella isolates
Authors: Keefer Andrea B. , Xiaoli Lingzi , M’ikanatha Nkuchia M. , Yao Kuan , Hoffmann Maria , Dudley Edward G.
Published: June 2018

Non-typhoidal Salmonella are a leading cause of outbreak and sporadic-associated foodborne illnesses in the U.S. These infections have been associated with a range of foods, including retail meats. Traditionally, pulsed-field gel electrophoresis (PFGE) and antibiotic susceptibility testing (AST) have been used to facilitate public health investigations of Salmonella infections. However, whole-genome sequencing (WGS) has emerged as an alternative tool that can be routinely implemented. To assess its potential in enhancing integrated surveillance in Pennsylvania, WGS was used to directly compare the genetic characteristics of 7 retail meat and 43 clinical historic Salmonella isolates, subdivided into three subsets based on PFGE and AST results, to retrospectively resolve their genetic relatedness and identify antimicrobial resistance (AMR) determinants. Single nucleotide polymorphism (SNP) analyses revealed the retail meat isolates within S. Heidelberg, S. Typhimurium var. O5- subset 1, and S. Typhimurium var. O5- subset 2 were separated from each primary PFGE pattern-matched clinical isolate by 6-12, 41-96, and 21-81 SNPs, respectively. Fifteen resistance genes were identified across all isolates, including fosA7, a gene only recently found in a limited number of Salmonella and a ≥ 95% phenotype to genotype correlation was observed for all tested antimicrobials. Moreover, AMR was primarily plasmid-mediated in S. Heidelberg and S. Typhimurium var. O5- subset 2; whereas, AMR was chromosomally-carried in S. Typhimurium var. O5- subset 1. Similar plasmids were identified in both the retail meat and clinical isolates. Collectively, these data highlight the utility of WGS in retrospective analyses and enhancing integrated surveillance of Salmonella from multiple sources.
Household cockroaches carry CTX-M-15, OXA-48 and NDM-1, and share beta-lactam resistance determinants with humans
Authors: Obeng-Nkrumah Noah , Labi Appiah-Korang , Blankson Harriet , Awuah-Mensah Georgina , Oduro-Mensah Daniel , Anum Judelove , Teye James , Kwashie Solomon Dzidzornu , Bako Evariste , Ayeh-Kumi Patrick Ferdinand , Asmah Richard
Published: June 2018

Aim

Household insect pests, including cockroaches, have gained consideration as potential vectors for multidrug resistant pathogens of public health concern. This study was designed to investigate whether household cockroaches share beta-lactam resistance determinants with human inhabitants.

Methods

From February through July 2016, 400 cockroaches were systematically collected from 100 households. Whole insect homogenates and faecal samples from inhabitants of all included households were cultured for cephalosporin-resistant enterobacteria (CRe). The CRe were examined for AmpC, ESBL, and carbapenemase genes; antibiotic susceptibility patterns; and conjugative transfer of antibiotic resistance mechanisms. Clonal relationships between isolates were determined by multi-locus sequence typing (MLST).

Results

Twenty CRe were recovered from whole cockroach homogenates of 15 households. Five harbored ESBL genes (2 blaCTX-M-15/TEM-1; 1 blaCTX-M-15/TEM-4; 1 blaTEM-24; 1 blaSHV-4), and 3 carried carbapenemase genes (2 blaNDM-1 genes and 1 blaOXA-48 gene) all of which were transferrable by conjugation to E. coli J53 recipients. There was high clonal diversity with low inter-species similarity regardless of the beta-lactamase gene sequence. From 6 households, the pair of cockroach and human CRe shared the same antibiogram, ST and/or conjugable blaESBL gene sequence (house 34, E. coli ST9-blaTEM-4; house 37, E. coli ST44-blaCTX-15/TEM-4; house 41, E. coli ST443-blaCTX-15/TEM-1; house 49, K. pneumoniae ST231-blaSHV-13).

Conclusion

The findings highlight household cockroaches as reservoirs of CTX-M-15, OXA-48 and NDM-1 genes that share beta-lactam resistance determinants with humans.
Deletion of class II ARF causes essential tremors through Nav1.6 traffic impairment
Authors: Hosoi Nobutake , Shibasaki Koji , Hosono Mayu , Konno Ayumu , Shinoda Yo , Kiyonari Hiroshi , Inoue Kenichi , Aizawa Shinichi , Muramatsu Shinichi , Ishizaki Yasuki , Hirai Hirokazu , Furuichi Teiichi , Sadakata Tetsushi
Published: June 2018

ADP-ribosylation factors (ARFs) are a family of small monomeric GTPases consisting of three classes. In the present study, we generated class II ARF-deficient mice (ARF4+/−/ARF5−/−) and found that they exhibited severe movement-associated tremors. Treatment of the mice with propranolol and gabapentin, which alleviate symptoms in patients with essential tremors, similarly reduced the amplitude of the pathologic tremors. In vivo electrophysiological recordings of the ARF4+/−/ARF5−/− mice revealed that they exhibited reduced excitability of their cerebellar Purkinje cells. Immunohistochemical studies revealed that ARF4+/−/ARF5−/− mice exhibit a severe, selective reduction of Nav1.6 proteins that are important for maintaining repetitive action potential firing in the axon initial segments (AISs) of the Purkinje cells. This decrease in Nav1.6 protein expression and the consequent tremors were alleviated by Purkinje cell-specific expression of ARF5. These results indicate that class II ARF mediates the selective trafficking of Nav1.6 to the AISs in cerebellar Purkinje cells, and suggest that the essential tremors can be ascribed to the reduced intrinsic excitability of Purkinje cells, caused by the selective decrease of Nav1.6 proteins in the AISs.
The proto CpG island methylator phenotype of sessile serrated adenomas/polyps
Authors: Parker Hannah R. , Orjuela Stephany , Oliveira Andreia Martinho , Cereatti Fabrizio , Sauter Matthias , Heinrich Henriette , Tanzi Giulia , Weber Achim , Komminoth Paul , Vavricka Stephan , Albanese Luca , Buffoli Federico , Robinson Mark D. , Marra Giancarlo
Published: June 2018

Sessile serrated adenomas/polyps (SSA/Ps) are the putative precursors of the ˜20% of colon cancers with the CpG island methylator phenotype (CIMP), but their molecular features are poorly understood. We used high-throughput analysis of DNA methylation and gene expression to investigate the epigenetic phenotype of SSA/Ps. Fresh-tissue samples of 17 SSA/Ps and (for comparison purposes) 15 conventional adenomas (cADNs)—each with a matched sample of normal mucosa— were prospectively collected during colonoscopy (total no. samples analyzed: 64). DNA and RNA were extracted from each sample. DNA was subjected to bisulfite next-generation sequencing to assess methylation levels at ˜2.7 million CpG sites located predominantly in gene regulatory regions and spanning 80.5Mb (˜2.5% of the genome); RNA was sequenced to define the samples’ transcriptomes. An independent series of 61 archival lesions was used for targeted verification of DNA methylation findings. Compared with normal mucosa samples, SSA/Ps and cADNs exhibited markedly remodeled methylomes. In cADNs, hypomethylated regions were far more numerous (18,417 vs 4288 in SSA/Ps) and rarely affected CpG islands/shores. SSA/Ps seemed to have escaped this wave of demethylation. Cytosine hypermethylation in SSA/Ps was more pervasive (hypermethylated regions: 22,147 vs 15,965 in cADNs; hypermethylated genes: 4938 vs 3443 in cADNs) and more extensive (region for region), and it occurred mainly within CpG islands and shores. Given its resemblance to the CIMP typical of SSA/Ps’ putative descendant colon cancers, we refer to the SSA/P methylation phenotype as proto-CIMP. Verification studies of six hypermethylated regions (3 SSA/P-specific and 3 common) demonstrated the high potential of DNA methylation markers for predicting the diagnosis of SSA/Ps and cADNs. Surprisingly, proto-CIMP in SSA/Ps was associated with upregulated gene expression (n=618 genes vs 349 that were downregulated); downregulation was more common in cADNs (n=712 vs 516 upregulated genes). The epigenetic landscape of SSA/Ps differs markedly from that of cADNs. These differences are a potentially rich source of novel tissue-based and noninvasive biomarkers that can add precision to the clinical management of the two most frequent colon-cancer precursors.
Electron microscopy 3-dimensional segmentation and quantification of axonal dispersion and diameter distribution in mouse brain corpus callosum
Authors: Lee Hong-Hsi , Yaros Katarina , Veraart Jelle , Pathan Jasmine , Liang Feng-Xia , Kim Sungheon G. , Novikov Dmitry S. , Fieremans Els
Published: June 2018

To model the diffusion MRI signal in brain white matter, general assumptions have been made about the microstructural properties of axonal fiber bundles, such as the axonal shape and the fiber orientation dispersion. In particular, axons are modeled by perfectly circular cylinders with no diameter variation within each axon, and their directions obey a specific orientation distribution. However, these assumptions have not been validated by histology in 3-dimensional high-resolution neural tissue. Here, we reconstructed sequential scanning electron microscopy images in mouse brain corpus callosum, and introduced a semi-automatic random-walker (RaW) based algorithm to rapidly segment individual intra-axonal spaces and myelin sheaths of myelinated axons. Confirmed with a conventional machine-learning-based interactive segmentation method, our semi-automatic algorithm is reliable and less time-consuming. Based on the segmentation, we calculated histological estimates of size-related (e.g., inner axonal diameter, g-ratio) and orientation-related (e.g., Fiber orientation distribution and its rotational invariants, dispersion angle) quantities, and simulated how these quantities would be observed in actual diffusion MRI experiments by considering diffusion time-dependence. The reported dispersion angle is consistent with previous 2-dimensional histology studies and diffusion MRI measurements, though the reported diameter is larger than those in other mouse brain studies. Our results show that the orientation-related metrics have negligible diffusion time-dependence; however, inner axonal diameters demonstrate a non-trivial time-dependence at diffusion times typical for clinical and preclinical use. In other words, the fiber dispersion estimated by diffusion MRI modeling is relatively independent, while the "apparent" axonal size estimated by axonal diameter mapping potentially depends on experimental MRI settings.
RAMP1 in Kupffer cells is a critical regulator in immune-mediated hepatitis
Authors: Inoue Tomoyoshi , Ito Yoshiya , Nishizawa Nobuyuki , Eshima Koji , Kojo Ken , Otaka Fumisato , Betto Tomohiro , Yamane Sakiko , Tsujikawa Kazutake , Koizumi Wasaburo , Majima Masataka
Published: June 2018

The significanceF of the relationship between the nervous and immune systems with respect to disease course is increasingly apparent. Immune cells in the liver and spleen are responsible for the development of acute liver injury, yet the regulatory mechanisms of the interactions remain elusive. Calcitonin gene-related peptide (CGRP), which is released from the sensory nervous system, regulates innate immune activation via receptor activity-modifying protein 1 (RAMP1), a subunit of the CGRP receptor. Here, we show that RAMP1 in Kupffer cells (KCs) plays a critical role in the etiology of immune-mediated hepatitis. RAMP1-deficient mice with concanavalin A (ConA)-mediated hepatitis, characterized by severe liver injury accompanied by infiltration of immune cells and increased secretion of pro-inflammatory cytokines by KCs and splenic T cells, showed poor survival. Removing KCs ameliorated liver damage, while depleting T cells or splenectomy led to partial amelioration. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury. Co-culture of KCs with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 in KCs is a key regulator of immune responses.
Human Immunodeficiency Virus Status in Malnourished Children seen at Lagos
Authors: Temiye EO , Adeniyi OF , Fajolu IB , Ogbenna AA , Ladapo TA , Esezobor CI , Akinsulie AO , Mabogunje CA
Published: June 2018

Introduction

Human immunodeficiency virus and protein energy malnutrition are still prevalent in Nigeria and the occurrence of the two conditions together confers a poor prognosis. The aim of this study was to determine the current categories of malnutrition amongst under 5 children in Lagos, document their HIV status and determine any peculiarities in the clinical features, haematological and some biochemical profile in these children.

Methods

The study was a prospective crossectional study conducted at the Paediatric department of the Lagos University Teaching Hospital and the Massey Street Children’s Hospital over a 6 month period. All the subjects had anthropometry, HIV testing, full blood count and serum proteins done. The factors associated with HIV status were determined with the logistic regression analysis.

Results

Two hundred and fourteen (214) malnourished children ≤5 years were recruited into the study and 25(11.7%) were HIV positive. One hundred and five (49.1%) of the participants had moderate malnutrition while 25.2% had severe forms of malnutrition. Fever, cough and diarrhea were the commonest symptoms. Severe wasting, oral thrush, dermatoses and splenomegaly were seen more commonly in the HIV positive subjects. The haematological indices were comparable in the two groups, however, the total protein was significantly higher in the HIV positive subjects compared to the negative group (p=0.042). Multivariate analysis showed that the total protein (p=0.001) and platelet count (p=0.016) could significantly predict the occurrence of HIV in the malnourished children

Conclusion

The presence of severe wasting, oral thrush, diarrhea, splenomegaly, thrombocytopenia and high total proteins in malnourished children should heighten the suspicion of possible underlying associated HIV infection. This study reinforces the recommendation by the World Health Organisation (WHO) that all malnourished children should have mandatory HIV screening.
The C9orf72-interacting protein Smcr8 is a negative regulator of autoimmunity and lysosomal exocytosis
Authors: Zhang Yingying , Burberry Aaron , Wang Jin-Yuan , Sandoe Jackson , Ghosh Sulagna , Udeshi Namrata D. , Svinkina Tanya , Mordes Daniel A. , Mok Joanie , Charlton Maura , Li Quan-Zhen , Carr Steven A. , Eggan Kevin
Published: June 2018

While a mutation inC9ORF72is the most common genetic contributor to amyotrophic lateral sclerosis (ALS), much remains to be learned concerning the function of the protein normally encoded at this locus. To elaborate further on functions for C9ORF72, we used quantitative mass spectrometry-based proteomics to identify interacting proteins in motor neurons and found that its long isoform complexes with and stabilizes SMCR8, which further enables interaction with WDR41. To study the organismal and cellular functions for this tripartite complex, we generatedSmcr8loss-of-function mutant mice and found that they developed phenotypes also observed inC9orf72loss-of-function animals, including autoimmunity. Along with a loss of tolerance for many nervous system autoantigens, we found increased lysosomal exocytosis inSmcr8mutant macrophages. In addition to elevated surface Lamp1 (lysosome-associated membrane protein 1) expression, we also observed enhanced secretion of lysosomal components—phenotypes that we subsequently observed inC9orf72loss-of-function macrophages. Overall, our findings demonstrate that C9ORF72 and SMCR8 have interdependent functions in suppressing autoimmunity as well as negatively regulating lysosomal exocytosis—processes of potential importance to ALS.
Nollmotzite, Mg[UV(UVIO2)2O4F3]·4H2O, the first natural uranium oxide containing fluorine
Authors: Plášil Jakub , Kampf Anthony R. , Škoda Radek , Čejka Jiří
Published: June 2018

Nollmotzite (IMA2017-100), Mg[UV(UVIO2)2F3O4](H2O)4, is a new uranium oxide fluoride mineral found in the Clara mine, Black Forest Mountains, Germany. Electron microprobe analysis provided the empirical formula (Mg1.06Cu0.02)Σ1.08[UV(UVIO2)2O3.85F3.15][(H2O)3.69(OH)0.31]Σ4.00based on three U and 15 O + F atoms per formula unit. Nollmotzite is monoclinic, space groupCm, witha= 7.1015 (12) Å,b= 11.7489 (17) Å,c= 8.1954 (14) Å, β = 98.087 (14)°,V= 676.98 (19) Å3andZ= 2. The crystal structure [twinned by reticular merohedry; refined toR= 0.0369 with GoF = 1.09 for 1527 unique observed reflections,I> 3σ(I)] is based upon [UV(UVIO2)2F3O4]2–sheets of β-U3O8topology and contains an interlayer with MgF2(H2O)4octahedra. Adjacent sheets are linked through F–Mg–F bonds, as well asviahydrogen bonds. The presence of fluorine and pentavalent uranium in the structure of nollmotzite has potentially important implications for the safe disposal of nuclear waste.
Engineering glycoside hydrolase stability by the introduction of zinc binding
Authors: Ellinghaus Thomas L. , Pereira Jose H. , McAndrew Ryan P. , Welner Ditte H. , DeGiovanni Andy M. , Guenther Joel M. , Tran Huu M. , Feldman Taya , Simmons Blake A. , Sale Kenneth L. , Adams Paul D.
Published: June 2018

The development of robust enzymes, in particular cellulases, is a key step in the success of biological routes to `second-generation' biofuels. The typical sources of the enzymes used to degrade biomass include mesophilic and thermophilic organisms. The endoglucanase J30 from glycoside hydrolase family 9 was originally identified through metagenomic analyses of compost-derived bacterial consortia. These studies, which were tailored to favor growth on targeted feedstocks, have already been shown to identify cellulases with considerable thermal tolerance. The amino-acid sequence of J30 shows comparably low identity to those of previously analyzed enzymes. As an enzyme that combines a well measurable activity with a relatively low optimal temperature (50°C) and a modest thermal tolerance, it offers the potential for structural optimization aimed at increased stability. Here, the crystal structure of wild-type J30 is presented along with that of a designed triple-mutant variant with improved characteristics for industrial applications. Through the introduction of a structural Zn2+ site, the thermal tolerance was increased by more than 10°C and was paralleled by an increase in the catalytic optimum temperature by more than 5°C.
Crystal structure of the FAS1 domain of the hyaluronic acid receptor stabilin-2
Authors: Twarda-Clapa Aleksandra , Labuzek Beata , Krzemien Dobroslawa , Musielak Bogdan , Grudnik Przemyslaw , Dubin Grzegorz , Holak Tad A.
Published: June 2018

Recent research has identified a potential role of the hyaluronic acid receptor stabilin-2 (Stab2) in cancer metastasis. Stab2 belongs to a group of scavenger receptors and is responsible for the clearance of more than ten ligands, including hyaluronic acid (HA).In vivoexperiments on mice have shown that the absence of Stab2, or its blocking by an antibody, effectively opposes cancer metastasis, which is accompanied by an increase in the level of circulating HA. Knowledge of ligand recognition and signal transduction by Stab2 is limited and no three-dimensional structures of any protein fragments of this receptor have been solved to date. Here, a high-resolution X-ray structure of the seventh FAS1 domain of Stab2 is reported. This structure provides the first insight into the Stab2 structure.
Born globals and business incubators: a case analysis
Authors: Kuryan Nadzeya , Khan Mohammad Saud , Gustafsson Veronika
Published: June 2018

Purpose

This paper aims to analyze born globals and business incubators from an empirical standpoint. Particularly, the role of business incubators in the emergence and development of born global firms is focused, thereby outlining the significance of incubator influence on rapid internationalization.

Design/methodology/approach

Based on extant literature on born globals, business incubators and their interrelationship that nurtures internationalization, a theoretical model is developed and empirically tested to analyze potential born globals residing in business incubators.

Findings

Due to services provided, such as infrastructure, business support and networking, business incubators create a favorable environment for rapid internationalization of their tenants. However, the initiative to go international comes from the incubatees, and the motivating role of business incubators in this process is fairly insignificant.

Originality/value

The incubator-incubation phenomenon is notably under-researched, with most of the literature focusing on “incubator topics.” This relationship is extremely important to understand to choose appropriate political measures and orchestrate effective management of business incubators.
Coupling effects of the impact factors in micro-scale on the performance of aerostatic guideway
Authors: Chen Dongju , Dong Lihua , Pan Ri , Fan Jinwei , Cheng Qiang
Published: June 2018

Purpose

The purpose of this study is to investigate the coupling effects of the velocity slip, rarefaction effect and effective viscosity of the gas film on the performance of the aerostatic guideway in micro-scale and improve the analysis precision of the static performance of aerostatic guideway.

Design/methodology/approach

The corresponding model of the gas film flow with consideration of the velocity slip, rarefaction effect and effective viscosity of the gas film in micro-scale is proposed. By solving the corresponding model, the bearing capacity and the stiffness of the aerostatic guideway are obtained through the pressure distributions of the air cavity. Through comparing the bearing capacity and the stiffness in different situations, the couple effects of the three factors are analyzed. Finally, the experimental results about the stiffness are obtained and the contrast between the simulation stiffness and the tested stiffness is achieved.

Findings

Through comparing the coupling effects of the micro scale factors under different conditions on the performance of the aerostatic guideway, it was found that when comparing the effects of a single factor, the effect of the first-order slip is the largest. When two factors are randomly combined, velocity slip and viscosity of the gas film is the largest, but these coupling effects are less than the effect of considering three factors simultaneously.

Originality/value

It is essential to consider the first-order velocity slip, the flow factor Q and the effective viscosity when analyzing the static performance of the aerostatic guideway in micro-scale. This makes studying the performance of the aerostatic guideway in micro-scale feasible and improves the machine’s accuracy.
Quantifying the impact of Ramadan on global raw sugar prices
Authors: Hossain Kazi Abrar , Basher Syed Abul , Haque A.K. Enamul
Published: June 2018

Purpose

The purpose of this study is to quantify the impact of Ramadan on both the level and the growth of global raw sugar price.

Design/methodology/approach

The study uses a dummy and a fractional variable to capture Ramadan to overcome the asynchronicity of time between Ramadan fasting (which is based on the Islamic lunar calendar) and the movement in prices (which follows the Gregorian solar calendar). To capture the seasonality of sugar production, the data on sugar price span 34 years so that the Islamic calendar makes a complete cycle of the Gregorian calendar. The empirical model is estimated using both autoregressive integrated moving average model and unobserved components model.

Findings

The results show that monthly raw sugar prices in the global market increases by roughly 6.06 per cent (or $17.78 per metric ton) every year ahead of Ramadan.

Practical implications

The study illustrates the implications of the results for the consumption of imported sugar in Bangladesh.

Originality/value

The study uses a broader set of Ramadan indicators in its empirical models and checks the robustness of its baseline model using the unobserved components model. It also performs seasonal unit root tests on the global raw sugar prices.