bluuebunny/crossref_metadata_2025 huggingface dataset:
Prey size selection in invasive (Hemigrapsus sanguineus and H. takanoi) compared with native (Carcinus maenas) marine crabs
Authors: Bouwmeester Mark M. , Waser Andreas M. , van der Meer Jaap , Thieltges David W.
Published: November 2019

Introductions of predators can have strong effects on native ecosystems and knowledge of the prey size selection of invasive predators is pivotal to understand their impact on native prey and intraguild competitors. Here, we investigated the prey size selection of two invasive crabs (Hemigrapsus sanguineus and Hemigrapsus takanoi) recently invading European coasts and compared them with native shore crabs (Carcinus maenas) which are known to feed on similar prey species. In laboratory experiments, we offered different size classes of native blue mussels (Mytilus edulis) to different size classes of the crab species in an effort to identify the respective prey size preferences and potential overlap in prey size range of native and invasive crabs. In all three species, the preferred prey size increased with crab size reflecting general predator–prey size relationships. Prey size preference did not differ among the crab species, i.e. crabs showed similar mussel size preference in relation to carapace width. Given that additional morphological measurements showed that both of the invasive crab species have much larger claws relative to their body size compared with the native species, this finding was surprising and may relate to differential claw morphologies or structural strength. These results suggest that the invasive crabs exert predation pressure on the same size classes of native mussels as the native crabs, with potential effects on mussel population dynamics due to the high densities of the invaders. In addition, the overlap in prey size range is likely to result in resource competition between invasive and native crabs.
Ice drift during the 1897 Andrée balloon expedition
Authors: Lantz Björn
Published: November 2019

The indirect cause of death of the three members of the Andrée balloon expedition on White Island in early October 1897 was the ice drift during their attempted retreat after the forced landing at 82°56′N 29°52′E. They initially tried to reach Cape Flora to the southeast of their current position in the Arctic pack ice even though they could deduce from prior explorers’ experience that the expected long-term direction of the ice drift in the area would be to the southwest. However, when they finally turned towards the Seven Islands in the southwest, the ice unexpectedly began to drift in a southeasterly direction. In this paper, trigonometrical methods are used to derive more precise measures of the ice drift the expedition members actually experienced, based on their own position fixes and their own descriptions of their marches. The results confirm that they were exposed to a southwesterly ice drift, on average, during the weeks they were trying to head southeast, and to a southeasterly ice drift, on average, during the weeks they were trying to head southwest. Hence, the disastrous ending of the expedition was, at least to some extent, a result of bad luck.
There is little evidence that the Industrial Revolution was caused by a preference shift
Authors: Hirshleifer David , Teoh Siew Hong
Published: November 2019

The idea, based on Life History Theory, that the Industrial Revolution was a positive feedback process wherein prosperity induced prosperity-promoting preference shifts is just an intriguing speculation. The evidence does not distinguish this explanation from simple alternatives. For example, increased prosperity may have freed up time for individuals to engage in innovative activity and increased the benefits from doing so.
What came first, the chicken or the egg?
Authors: Artige Lionel , Lubart Todd , van Neuss Leif
Published: November 2019

Current empirical evidence does not seem to confirm that an improvement in living conditions is the cause of the shift in the human mindset toward innovation and long-term risky investment. However, it may well be one of the conditions for greater tolerance of income inequality in exchange for a steady increase in average income.
Life History Theory and economic modernity
Authors: Hewson Martin
Published: November 2019

Baumard's new explanation of the Industrial Revolution shows that Life History Theory holds great potential. Here, I suggest two related hypotheses for examination. One is that there are long-term roots of slow life traits and preferences. The other is that Life History Theory can explain other aspects of economic modernity such as the Scientific Revolution and bureaucratic states. If so, then Life History Theory offers a way to reconcile several bodies of evidence and lines of explanation into a coherent general account of economic modernity.
EEG-Based Analysis of Air Traffic Conflict: Investigating Controllers’ Situation Awareness, Stress Level and Brain Activity during Conflict Resolution
Authors: Trapsilawati Fitri , Herliansyah Muhammad Kusumawan , Nugraheni Agustyandini Sekar Asih Nur Sari , Fatikasari Mifta Priani , Tissamodie Gharsina
Published: November 2019

The effects of air traffic conflict geometry have been well investigated in prior studies, particularly in the context of the pilot, though little in the context of the air traffic control officer (ATCO). No study to date has investigated the effects of conflict geometry on human factors variables of ATCOs through objective and physiological approaches. This study examines the effects of conflict geometries on ATCO situation awareness, stress level and brain activity during conflict resolution. Fifteen participants were instructed to resolve six different conflict geometries: crossing level, crossing non-level, converging level, converging non-level, overtaking level, and overtaking non-level. The results indicate that converging and crossing conflicts led to lower situation awareness (SA), higher stress level, and higher theta activation at the temporal and parietal lobes. Level conflict led to lower SA. The findings offer two implications, providing insights for the formal guidelines in ATC conflict resolution training and provision of inputs for the conflict resolution aid development.
Banning of herbicides and the impact on agriculture: the case of glyphosate in Sri Lanka
Authors: Marambe Buddhi , Herath Swarna
Published: November 2019

Glyphosate, a widely used preplant herbicide in annual and perennial crops, was introduced to Sri Lanka in 1977. Its use has expanded since 2008 with the phase-out and ban in 2014 of paraquat. In December 2014, glyphosate use in Sri Lanka was regionally restricted. Crop protection and production in the country was severely affected in 2016 and 2017 due to the irrational decisions of the government of Sri Lanka (GoSL). Increased crop production costs due to the absence of effective and economically viable weed control techniques, low crop yields, loss of foreign exchange, and enhanced use of smuggled glyphosate products are the consequences of the glyphosate ban. The ban was imposed without a scientific basis because of sociopolitical pressure. A series of dialogues with the GoSL helped rescind the ban in 2018 for a period of 36 mo, but its use is limited to tea [Camellia sinensis (L.) Kuntz.] and rubber [Hevia brasiliensis (Willd. ex A. Juss.) Müll. Arg.]. In August 2019, the Cabinet of Ministers of the GoSL also decided to allow use of glyphosate to devitalize propagules in the floriculture industry (export oriented) and destroy coconut (Cocos nucifera L.) trees infected by Weligama coconut leaf wilt disease and sugarcane (Saccharum officinarum L.) infected by white leaf disease. However, glyphosate products with the co-formulant polyethoxylated tallow amine are still not permitted in Sri Lanka.
Variations in Martian Lithospheric Strength Based on Gravity/Topography Analysis
Authors: Ding Min , Lin Jian , Gu Chen , Huang Qinghua , Zuber Maria T.
Published: November 2019

We applied localized gravity/topography admittance and correlation analysis, as well as the Markov chain Monte Carlo method, to invert for loading and flexural parameters of 21 subregions on Mars with five distinct tectonic types. The loading styles of the five tectonic types are distinct: The surface and subsurface loading in the polar and plain regions can be assumed to be largely uncorrelated, in contrast to the correlated loading associated with the volcanic montes and Valles Marineris. For the impact basins, we consider the initial topographic depression and mantle plug before postimpact surface loading. Our analyses yield four main results: (1) The inverted effective lithospheric thickness (Te) is highly dependent on assumptions of loading type. (2) There is a trend of increasing Te from the Noachian southern highlands (20–60 km) to the Hesperian northern lowlands (>90 km) and from the Hesperian Elysium Mons (<55 km) to the Hesperian/Amazonian Olympus Mons (>105 km). These Te estimates are consistent with the thermal states at the time of loading, corresponding to a global secular cooling history with decreasing heat flux. (3) Our analyses suggest high‐density basaltic surface loading at the volcanic montes and Isidis basin, in contrast to the low‐density sedimentary surface loading at the Utopia and Argyre basins. (4) We find some degree of correlation between the surface and subsurface loading for the northern polar cap and the northern plains, likely due to earlier, larger polar deposits and ancient buried features, respectively.
High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels
Authors: Chang Jane Pei-Chen , Su Kuan-Pin , Mondelli Valeria , Satyanarayanan Senthil Kumaran , Yang Hui-Ting , Chiang Yi-Ju , Chen Hui-Ting , Pariante Carmine M.
Published: November 2019

No studies have examined the relationship between endogenous polyunsaturated fatty acids (PUFAs) levels and treatment response to PUFAs. We conducted a 12-week, double-blind, placebo-controlled trial comparing the effects of high-dose eicosapentaenoic acid (EPA, 1.2 g) and placebo on cognitive function (continuous performance test) in n = 92 youth (age 6–18-years-old) with Attention Deficit Hyperactivity Disorder (ADHD). Blood erythrocytes PUFAs were measured before and after treatment, to examine the effects of baseline endogenous EPA levels on treatment response and the effects of EPA treatment on PUFAs levels. Secondary measures included other ADHD symptoms, emotional symptoms, and levels of plasma high-sensitivity c-reactive protein (hs-CRP) and brain-derived neurotrophic factor (BDNF). Overall, EPA group improved more than placebo group on focused attention (variability, Effect size (ES) = 0.38, p = 0.041); moreover, within youth with the lowest baseline endogenous EPA levels, EPA group improved more than placebo group in another measure of focused attention (hit reaction time, HRT, ES = 0.89, p = 0.015) and in vigilance (HRT interstimulus interval changes, HRTISIC, ES = 0.83, p = 0.036). Interestingly, EPA group improved less than placebo group in impulsivity (commission errors), both overall and in youth with the highest baseline EPA levels, who also showed less improvement in other ADHD and emotional symptoms. EPA increased blood erythrocytes EPA by 1.6-fold but not DHA levels, and did not affect hs-CRP and BDNF plasma levels. In conclusion, EPA treatment improves cognitive symptoms in ADHD youth, especially if they have a low baseline endogenous EPA level, while youth with high EPA levels may be negatively affected by this treatment.
Hyperexcitability and impaired intracortical inhibition in patients with fragile-X syndrome
Authors: Morin-Parent Florence , Champigny Camille , Lacroix Angelina , Corbin François , Lepage Jean-François
Published: November 2019

Fragile-X syndrome (FXS) is characterized by neurological and psychiatric problems symptomatic of cortical hyperexcitability. Recent animal studies identified deficient γ-aminobutyricacid (GABA) inhibition as a key mechanism for hyperexcitability in FXS, but the GABA system remains largely unexplored in humans with the disorder. The primary objective of this study was to assess GABA-mediated inhibition and its relationship with hyperexcitability in patients with FXS. Transcranial magnetic stimulation (TMS) was used to assess cortical and corticospinal inhibitory and excitatory mechanisms in 18 patients with a molecular diagnosis of FXS and 18 healthy controls. GABA-mediated inhibition was measured with short-interval intracortical inhibition (GABAA), long-interval intracortical inhibition (GABAB), and the corticospinal silent period (GABAA+B). Net intracortical facilitation involving glutamate was assessed with intracortical facilitation, and corticospinal excitability was measured with the resting motor threshold. Results showed that FXS patients had significantly reduced short-interval intracortical inhibition, increased long-interval intracortical inhibition, and increased intracortical facilitation compared to healthy controls. In the FXS group, reduced short-interval intracortical inhibition was associated with heightened intracortical facilitation. Taken together, these results suggest that reduced GABAA inhibition is a plausible mechanism underlying cortical hyperexcitability in patients with FXS. These findings closely match those observed in animal models, supporting the translational validity of these markers for clinical research.
Effects of cannabidivarin (CBDV) on brain excitation and inhibition systems in adults with and without Autism Spectrum Disorder (ASD): a single dose trial during magnetic resonance spectroscopy
Authors: Pretzsch Charlotte M , Voinescu Bogdan , Lythgoe David , Horder Jamie , Mendez Maria Andreina , Wichers Robert , Ajram Laura , Ivin Glynis , Heasman Martin , Edden Richard A. E. , Williams Steven , Murphy Declan G. M. , Daly Eileen , McAlonan Gráinne M.
Published: November 2019

Autism spectrum disorder (ASD) is a high cost neurodevelopmental condition; and there are currently no effective pharmacological treatments for its core symptoms. This has led some families and researchers to trial alternative remedies – including the non-intoxicating Cannabis sativa-derived compound cannabidivarin (CBDV). However, how CBDV affects the human brain is unknown. Previous (pre)clinical evidence suggests that CBDV may modulate brain excitatory-inhibitory systems, which are implicated in ASD. Hence, our main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites – markers of the brain’s primary excitatory and inhibitory system - in both the ‘typical’ and autistic brain. Our subsidiary aim was to determine whether, within ASD, brain responsivity to CBDV challenge is related to baseline biological phenotype. We tested this using a repeated-measures, double-blind, randomized-order, cross-over design. We used magnetic resonance spectroscopy (MRS) to compare glutamate (Glx = glutamate + glutamine) and GABA + (GABA + macromolecules) levels following placebo (baseline) and 600 mg CBDV in 34 healthy men with (n = 17) and without (n = 17) ASD. Data acquisition from regions previously reliably linked to ASD (dorsomedial prefrontal cortex, DMPFC; left basal ganglia, BG) commenced 2 h (peak plasma levels) after placebo/CBDV administration. Where CBDV significantly shifted metabolite levels, we examined the relationship of this change with baseline metabolite levels. Test sessions were at least 13 days apart to ensure CBDV wash-out. CBDV significantly increased Glx in the BG of both groups. However, this impact was not uniform across individuals. In the ASD group, and not in the typically developing controls, the ‘shift’ in Glx correlated negatively with baseline Glx concentration. In contrast, CBDV had no significant impact on Glx in the DMPFC, or on GABA+ in either voxel in either group. Our findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the BG but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry. Future studies should examine the effect of CBDV on behaviour and if the response to an acute dose of CBDV could predict a potential clinical treatment response in ASD.
Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases
Authors: Mundo Lucia , Ambrosio Maria Raffaella , Raimondi Francesco , Del Porro Leonardo , Guazzo Raffaella , Mancini Virginia , Granai Massimo , Jim Rocca Bruno , Lopez Cristina , Bens Susanne , Onyango Noel , Nyagol Joshua , Abinya Nicholas , Navari Mohsen , Ndede Isaac , Patel Kirkita , Paolo Piccaluga Pier , Bob Roshanak , de Santi Maria Margherita , Russell Robert B. , Lazzi Stefano , Siebert Reiner , Stein Harald , Leoncini Lorenzo
Published: November 2019

MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.
Transcriptome analysis reveals significant differences between primary plasma cell leukemia and multiple myeloma even when sharing a similar genetic background
Authors: Rojas Elizabeta A. , Corchete Luis A. , Mateos María Victoria , García-Sanz Ramón , Misiewicz-Krzeminska Irena , Gutiérrez Norma C.
Published: November 2019

Primary plasma cell leukemia (pPCL) is a highly aggressive plasma cell dyscrasia characterised by short remissions and very poor survival. Although the 17p deletion is associated with poor outcome and extramedullary disease in MM, its presence does not confer the degree of aggressiveness observed in pPCL. The comprehensive exploration of isoform expression and RNA splicing events may provide novel information about biological differences between the two diseases. Transcriptomic studies were carried out in nine newly diagnosed pPCL and ten MM samples, all of which harbored the 17p deletion. Unsupervised cluster analysis clearly distinguished pPCL from MM samples. In total 3584 genes and 20033 isoforms were found to be deregulated between pPCL and MM. There were 2727 significantly deregulated isoforms of non-differentially expressed genes. Strangely enough, significant differences were observed in the expression of spliceosomal machinery components between pPCL and MM, in respect of the gene, isoform and the alternative splicing events expression. In summary, transcriptome analysis revealed significant differences in the relative abundance of isoforms between pPCL and MM, even when they both had the 17p deletion. The mRNA processing pathway including RNA splicing machinery emerged as one of the most remarkable mechanisms underlying the biological differences between the two entities.
Airway epithelial regeneration requires autophagy and glucose metabolism
Authors: Li Kuan , Li Minmin , Li Wenli , Yu Hongzhi , Sun Xin , Zhang Qiuyang , Li Yu , Li Xue , Li Yue , Abel E. Dale , Wu Qi , Chen Huaiyong
Published: November 2019

Efficient repair of injured epithelium by airway progenitor cells could prevent acute inflammation from progressing into chronic phase in lung. Here, we used small molecules, genetic loss-of-function, organoid cultures, and in vivo lung-injury models to show that autophagy is essential for maintaining the pool of airway stem-like vClub cells by promoting their proliferation during ovalbumin-induced acute inflammation. Mechanistically, impaired autophagy disrupted glucose uptake in vClub progenitor cells, and either reduced accessibility to glucose or partial inhibition of glycolysis promoted the proliferative capacity of vClub progenitor cells and their daughter Club cells. However, glucose deprivation or glycolysis blockade abrogated the proliferative capacity of airway vClub cells and Club cells but promoted ciliated and goblet cell differentiation. Deficiency of glucose transporter-1 suppressed the proliferative capacity of airway progenitor cells after ovalbumin challenge. These findings suggested that autophagy and glucose metabolism are essential for the maintenance of airway epithelium at steady state and during allergic inflammation.
Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins
Authors: Takeda Takashi , Komatsu Masayuki , Chiwaki Fumiko , Komatsuzaki Rie , Nakamura Kanako , Tsuji Kosuke , Kobayashi Yusuke , Tominaga Eiichiro , Ono Masaya , Banno Kouji , Aoki Daisuke , Sasaki Hiroki
Published: November 2019

Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal, IGF2R is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.
Distinct CD1d docking strategies exhibited by diverse Type II NKT cell receptors
Authors: Almeida Catarina F. , Sundararaj Srinivasan , Le Nours Jérôme , Praveena T. , Cao Benjamin , Burugupalli Satvika , Smith Dylan G. M. , Patel Onisha , Brigl Manfred , Pellicci Daniel G. , Williams Spencer J. , Uldrich Adam P. , Godfrey Dale I. , Rossjohn Jamie
Published: November 2019

Type I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. While we have an understanding of the antigen reactivity and function of type I NKT cells, our knowledge of type II NKT cells in health and disease remains unclear. Here we describe a population of type II NKT cells that recognise and respond to the microbial antigen, α-glucuronosyl-diacylglycerol (α-GlcADAG) presented by CD1d, but not the prototypical type I NKT cell agonist, α-galactosylceramide. Surprisingly, the crystal structure of a type II NKT TCR-CD1d-α-GlcADAG complex reveals a CD1d F’-pocket-docking mode that contrasts sharply with the previously determined A’-roof positioning of a sulfatide-reactive type II NKT TCR. Our data also suggest that diverse type II NKT TCRs directed against distinct microbial or mammalian lipid antigens adopt multiple recognition strategies on CD1d, thereby maximising the potential for type II NKT cells to detect different lipid antigens.
Integrin-linked kinase controls retinal angiogenesis and is linked to Wnt signaling and exudative vitreoretinopathy
Authors: Park Hongryeol , Yamamoto Hiroyuki , Mohn Lucas , Ambühl Lea , Kanai Kenichi , Schmidt Inga , Kim Kee-Pyo , Fraccaroli Alessia , Feil Silke , Junge Harald J. , Montanez Eloi , Berger Wolfgang , Adams Ralf H.
Published: November 2019

Familial exudative vitreoretinopathy (FEVR) is a human disease characterized by defective retinal angiogenesis and associated complications that can result in vision loss. Defective Wnt/β-catenin signaling is an established cause of FEVR, whereas other molecular alterations contributing to the disease remain insufficiently understood. Here, we show that integrin-linked kinase (ILK), a mediator of cell-matrix interactions, is indispensable for retinal angiogenesis. Inactivation of the murine Ilk gene in postnatal endothelial cells results in sprouting defects, reduced endothelial proliferation and disruption of the blood-retina barrier, resembling phenotypes seen in established mouse models of FEVR. Retinal vascularization defects are phenocopied by inducible inactivation of the gene for α-parvin (Parva), an interactor of ILK. Screening genomic DNA samples from exudative vitreoretinopathy patients identifies three distinct mutations in human ILK, which compromise the function of the gene product in vitro. Together, our data suggest that defective cell-matrix interactions are linked to Wnt signaling and FEVR.
Highly variable iron content modulates iceberg-ocean fertilisation and potential carbon export
Authors: Hopwood Mark J. , Carroll Dustin , Höfer Juan , Achterberg Eric P. , Meire Lorenz , Le Moigne Frédéric A. C. , Bach Lennart T. , Eich Charlotte , Sutherland David A. , González Humberto E.
Published: November 2019

Marine phytoplankton growth at high latitudes is extensively limited by iron availability. Icebergs are a vector transporting the bioessential micronutrient iron into polar oceans. Therefore, increasing iceberg fluxes due to global warming have the potential to increase marine productivity and carbon export, creating a negative climate feedback. However, the magnitude of the iceberg iron flux, the subsequent fertilization effect and the resultant carbon export have not been quantified. Using a global analysis of iceberg samples, we reveal that iceberg iron concentrations vary over 6 orders of magnitude. Our results demonstrate that, whilst icebergs are the largest source of iron to the polar oceans, the heterogeneous iron distribution within ice moderates iron delivery to offshore waters and likely also affects the subsequent ocean iron enrichment. Future marine productivity may therefore be not only sensitive to increasing total iceberg fluxes, but also to changing iceberg properties, internal sediment distribution and melt dynamics.
Structural determinants of microtubule minus end preference in CAMSAP CKK domains
Authors: Atherton Joseph , Luo Yanzhang , Xiang Shengqi , Yang Chao , Rai Ankit , Jiang Kai , Stangier Marcel , Vemu Annapurna , Cook Alexander D. , Wang Su , Roll-Mecak Antonina , Steinmetz Michel O. , Akhmanova Anna , Baldus Marc , Moores Carolyn A.
Published: November 2019

CAMSAP/Patronins regulate microtubule minus-end dynamics. Their end specificity is mediated by their CKK domains, which we proposed recognise specific tubulin conformations found at minus ends. To critically test this idea, we compared the human CAMSAP1 CKK domain (HsCKK) with a CKK domain from Naegleria gruberi (NgCKK), which lacks minus-end specificity. Here we report near-atomic cryo-electron microscopy structures of HsCKK- and NgCKK-microtubule complexes, which show that these CKK domains share the same protein fold, bind at the intradimer interprotofilament tubulin junction, but exhibit different footprints on microtubules. NMR experiments show that both HsCKK and NgCKK are remarkably rigid. However, whereas NgCKK binding does not alter the microtubule architecture, HsCKK remodels its microtubule interaction site and changes the underlying polymer structure because the tubulin lattice conformation is not optimal for its binding. Thus, in contrast to many MAPs, the HsCKK domain can differentiate subtly specific tubulin conformations to enable microtubule minus-end recognition.
Towards the application of Tc toxins as a universal protein translocation system
Authors: Roderer Daniel , Schubert Evelyn , Sitsel Oleg , Raunser Stefan
Published: November 2019

Tc toxins are bacterial protein complexes that inject cytotoxic enzymes into target cells using a syringe-like mechanism. Tc toxins are composed of a membrane translocator and a cocoon that encapsulates a toxic enzyme. The toxic enzyme varies between Tc toxins from different species and is not conserved. Here, we investigate whether the toxic enzyme can be replaced by other small proteins of different origin and properties, namely Cdc42, herpes simplex virus ICP47, Arabidopsis thaliana iLOV, Escherichia coli DHFR, Ras-binding domain of CRAF kinase, and TEV protease. Using a combination of electron microscopy, X-ray crystallography and in vitro translocation assays, we demonstrate that it is possible to turn Tc toxins into customizable molecular syringes for delivering proteins of interest across membranes. We also infer the guidelines that protein cargos must obey in terms of size, charge, and fold in order to apply Tc toxins as a universal protein translocation system.
Combined orbital tomography study of multi-configurational molecular adsorbate systems
Authors: Kliuiev Pavel , Zamborlini Giovanni , Jugovac Matteo , Gurdal Yeliz , Arx Karin von , Waltar Kay , Schnidrig Stephan , Alberto Roger , Iannuzzi Marcella , Feyer Vitaliy , Hengsberger Matthias , Osterwalder Jürg , Castiglioni Luca
Published: November 2019

Molecular reactivity is determined by the energy levels and spatial extent of the frontier orbitals. Orbital tomography based on angle-resolved photoelectron spectroscopy is an elegant method to study the electronic structure of organic adsorbates, however, it is conventionally restricted to systems with one single rotational domain. In this work, we extend orbital tomography to systems with multiple rotational domains. We characterise the hydrogen evolution catalyst Co-pyrphyrin on an Ag(110) substrate and compare it with the empty pyrphyrin ligand. In combination with low-energy electron diffraction and DFT simulations, we fully determine adsorption geometry and both energetics and spatial distributions of the valence electronic states. We find two states close to the Fermi level in Co-pyrphyrin with Co $$3d$$
3
d
character that are not present in the empty ligand. In addition, we identify several energetically nearly equivalent adsorption geometries that are important for the understanding of the electronic structure. The ability to disentangle and fully elucidate multi-configurational systems renders orbital tomography much more useful to study realistic catalytic systems.
Author Correction: Possible role of L-form switching in recurrent urinary tract infection
Authors: Mickiewicz Katarzyna M. , Kawai Yoshikazu , Drage Lauren , Gomes Margarida C. , Davison Frances , Pickard Robert , Hall Judith , Mostowy Serge , Aldridge Phillip D. , Errington Jeff
Published: November 2019

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Competing rhythmic neural representations of orientations during concurrent attention to multiple orientation features
Authors: Mo Ce , Lu Junshi , Wu Bichan , Jia Jianrong , Luo Huan , Fang Fang
Published: November 2019

When a feature is attended, all locations containing this feature are enhanced throughout the visual field. However, how the brain concurrently attends to multiple features remains unknown and cannot be easily deduced from classical attention theories. Here, we recorded human magnetoencephalography signals when subjects concurrently attended to two spatially overlapping orientations. A time-resolved multivariate inverted encoding model was employed to track the ongoing temporal courses of the neural representations of the attended orientations. We show that the two orientation representations alternate with each other and undergo a theta-band (~4 Hz) rhythmic fluctuation over time. Similar temporal profiles are also revealed in the orientation discrimination performance. Computational modeling suggests a tuning competition process between the two neuronal populations that are selectively tuned to one of the attended orientations. Taken together, our findings reveal for the first time a rhythm-based, time-multiplexing neural machinery underlying concurrent multi-feature attention.
Influence of confinement on free radical chemistry in layered nanostructures
Authors: Ghandi Khashayar , Landry Cody , Du Tait , Lainé Maxime , Saul Andres , Le Caër Sophie
Published: November 2019

The purpose of the present work was to study how chemical reactions and the electronic structure of atoms are affected by confinement at the sub-nanometer scale. To reach this goal, we studied the H atom in talc, a layered clay mineral. Talc is a highly 2D-confining material with the width of its interlayer space close to angstrom. We investigated talc with a particle accelerator-based spectroscopic method that uses elementary particles. This technique generates an exotic atom, muonium (Mu), which can be considered as an isotope of the H atom. Moreover, the technique allows us to probe a single atom (H atom) at any time and explore the effects of the layered clay on a single ion (proton) or atom. The cation/electron recombination happens in two time windows: one faster than a nanosecond and the other one at longer than microseconds. This result suggests that two types of electron transfer processes take place in these clay minerals. Calculations demonstrated that the interlayer space acts as a catalytic surface and is the primary location of cation/electron recombination in talc. Moreover, the studies of the temperature dependence of Mu decay rates, due to the formation of the surrogate of H2, is suggestive of an “H2” formation reaction that is thermally activated above 25 K, but governed by quantum diffusion below 25 K. The experimental and computational studies of the hyperfine coupling constant of Mu suggest that it is formed in the interlayer space of talc and that its electronic structure is extremely changed due to confinement. All these results imply that the chemistry could be strongly affected by confinement in the interlayer space of clays.
Twist-to-bend ratio: an important selective factor for many rod-shaped biological structures
Authors: Wolff-Vorbeck Steve , Langer Max , Speck Olga , Speck Thomas , Dondl Patrick
Published: November 2019

Mechanical optimisation plays a key role in living beings either as an immediate response of individuals or as an evolutionary adaptation of populations to changing environmental conditions. Since biological structures are the result of multifunctional evolutionary constraints, the dimensionless twist-to-bend ratio is particularly meaningful because it provides information about the ratio of flexural rigidity to torsional rigidity determined by both material properties (bending and shear modulus) and morphometric parameters (axial and polar second moment of area). The determination of the mutual contributions of material properties and structural arrangements (geometry) or their ontogenetic alteration to the overall mechanical functionality of biological structures is difficult. Numerical methods in the form of gradient flows of phase field functionals offer a means of addressing this question and of analysing the influence of the cross-sectional shape of the main load-bearing structures on the mechanical functionality. Three phase field simulations were carried out showing good agreement with the cross-sections found in selected plants: (i) U-shaped cross-sections comparable with those of Musa sp. petioles, (ii) star-shaped cross-sections with deep grooves as can be found in the lianoid wood of Condylocarpon guianense stems, and (iii) flat elliptic cross-sections with one deep groove comparable with the cross-sections of the climbing ribbon-shaped stems of Bauhinia guianensis.
DeepIso: A Deep Learning Model for Peptide Feature Detection from LC-MS map
Authors: Zohora Fatema Tuz , Rahman M. Ziaur , Tran Ngoc Hieu , Xin Lei , Shan Baozhen , Li Ming
Published: November 2019

Liquid chromatography with tandem mass spectrometry (LC-MS/MS) based quantitative proteomics provides the relative different protein abundance in healthy and disease-afflicted patients, which offers the information for molecular interactions, signaling pathways, and biomarker identification to serve the drug discovery and clinical research. Typical analysis workflow begins with the peptide feature detection and intensity calculation from LC-MS map. We are the first to propose a deep learning based model, DeepIso, that combines recent advances in Convolutional Neural Network (CNN) and Recurrent Neural Network (RNN) to detect peptide features of different charge states, as well as, estimate their intensity. Existing tools are designed with limited engineered features and domain-specific parameters, which are hardly updated despite a huge amount of new coming proteomic data. On the other hand, DeepIso consisting of two separate deep learning based modules, learns multiple levels of representation of high dimensional data itself through many layers of neurons, and adaptable to newly acquired data. The peptide feature list reported by our model matches with 97.43% of high quality MS/MS identifications in a benchmark dataset, which is higher than the matching produced by several widely used tools. Our results demonstrate that novel deep learning tools are desirable to advance the state-of-the-art in protein identification and quantification.
Aerosol gas exchange system (AGES) for nanoparticle sampling at elevated temperatures: Modeling and experimental characterization
Authors: Bainschab Markus , Martikainen Sampsa , Keskinen Jorma , Bergmann Alexander , Karjalainen Panu
Published: November 2019

An aerosol gas exchange system (AGES) for nanoparticle sampling at elevated temperatures was developed, modeled, and further characterized with laboratory tests with respect to gas exchange efficiency and particle losses. The model describing the gas exchange was first verified with oxygen and later studied with several inert gases having molecular masses between 18 and 135 u. The exchange rate of the lightest compounds exceeds 90% efficiency at the flow rates used. In order to reach similarly high removal efficiencies for larger molecules, the residence time in the AGES has to be increased. The removal of sticky gases was studied with gaseous sulfuric acid. Results agreed with the model where the boundary condition is zero concentration on the wall. The AGES exhibits very limited particle losses (<5%) for mono-disperse 6 nm particles. Furthermore, diffusional losses for particles down to 1.2 nm were measured utilizing polydisperse aerosol. The experimental findings are in good agreement with the model derived. As both, gas exchange rate and particle losses, rely on the physical effect of diffusion, an optimization for enhanced gas exchange efficiency will come at the cost of increased diffusional particle losses. The presented model can be used as a tool to redesign and optimize the AGES for a desired application. With an application targeted design, particle dilution can be avoided, which can lead to improved results in many fields of aerosol measurement.
The interplay between Mn and Fe in Deinococcus radiodurans triggers cellular protection during paraquat-induced oxidative stress
Authors: Santos Sandra P. , Yang Yang , Rosa Margarida T. G. , Rodrigues Mafalda A. A. , De La Tour Claire Bouthier , Sommer Suzanne , Teixeira Miguel , Carrondo Maria A. , Cloetens Peter , Abreu Isabel A. , Romão Célia V.
Published: November 2019

The bacterium Deinococcus radiodurans is highly resistant to several stress conditions, such as radiation. According to several reports, manganese plays a crucial role in stress protection, and a high Mn/Fe ratio is essential in this process. However, mobilization of manganese and iron, and the role of DNA-binding-proteins-under-starved-conditions during oxidative-stress remained open questions. We used synchrotron-based X-ray fluorescence imaging at nano-resolution to follow element-relocalization upon stress, and its dependency on the presence of Dps proteins, using dps knockout mutants. We show that manganese, calcium, and phosphorus are mobilized from rich-element regions that resemble electron-dense granules towards the cytosol and the cellular membrane, in a Dps-dependent way. Moreover, iron delocalizes from the septum region to the cytoplasm affecting cell division, specifically in the septum formation. These mechanisms are orchestrated by Dps1 and Dps2, which play a crucial role in metal homeostasis, and are associated with the D. radiodurans tolerance against reactive oxygen species.
De novo cancer incidence after kidney and liver transplantation: Results from a nationwide population based data
Authors: Park Boyoung , Yoon Junghyun , Choi Dongho , Kim Han Joon , Jung Yun Kyung , Kwon Oh Jung , Lee Kyeong Geun
Published: November 2019

The cancer risk among solid organ transplantation recipients in East-Asia has been insufficiently studied. This study estimated de novo cancer incidence in kidney and liver recipients 2008–2015, compared with the general population in Korea using nationwide data. This is a retrospective cohort study using nationwide health insurance claims data. The study population was comprised of cancer-free 10,085 kidney recipients and 3,822 liver recipients. Standardized incidence ratio (SIR) of cancer using indirect standardization was calculated. Compared with the general population, the cancer risk increased by 3.19-fold in male and 2.56-fold in female kidney recipients. By cancer type, a notably increased SIR was observed for Kaposi sarcoma, renal cancer, skin cancer, and non-Hodgkin’s lymphoma in male and for bladder cancer, renal cancer, and non-Hodgkin’s lymphoma in female kidney recipients. In liver recipients, the SIR of all cancers was 3.43 in males and 2.30 in females. In male liver recipients, the SIRs for Kaposi sarcoma, non-Hodgkin’s lymphoma, myeloid leukemia, and skin cancer and in female recipients those for non-Hodgkin’s lymphoma and liver cancer were prominent. A greatly higher SIRs for overall cancer and non-Hodgkin’s lymphoma in kidney and liver recipients aged 0–19 were observed, compared with recipients in other age group. The incidence of de novo cancer in kidney and liver recipients was higher than the general population and common types were different. Strategies of cancer prevention and screening after kidney and liver transplantation should be developed in response to the incidence of common types of de novo cancers.
Discovery of novel potential selective HDAC8 inhibitors by combine ligand-based, structure-based virtual screening and in-vitro biological evaluation
Authors: Debnath Sudhan , Debnath Tanusree , Bhaumik Samhita , Majumdar Swapan , Kalle Arunasree M. , Aparna Vema
Published: November 2019

Neuroblastoma is the most common extracranial solid tumor found in children and survival rate is extremely meager. HDAC8, a class I zinc-dependent enzyme, is a potential drug target for treatment of neuroblastoma and T cell lymphoma. Most of the HDAC8 inhibitors discovered till date contains a hydroxamic acid group which acts as a zinc binding group. The high binding affinity to the zinc and other ions results in adverse effects. Also, the non-selective inhibition of HDACs cause a variety of side effects. The objective of this is to identify structurally diverse, non-hydroxamate, novel, potential and selective HDAC8 inhibitors. A number of five featured pharmacophore hypotheses were generated using 32 known selective HDAC8 inhibitors. The hypotheses ADDRR.4 were selected for building 3D QSAR model. This model has an excellent correlation coefficient and good predictive ability, which was employed for virtual screening of Phase database containing 4.3 × 106 molecules. The resultant hits with fitness score >1.0 were optimized using in-silico ADMET (absorption, distribution, metabolism,  excretion, and toxicity) and XP glide docking studies. On the basis of pharmacophore matching, interacting amino acid residues, XP glide score, more affinity towards HDAC8 and less affinity towards other HDACs, and ADME results five hits- SD-01, SD-02, SD-03, SD-04 and SD-05 with new structural scaffolds,  non-hydroxamate were selected for in vitro activity study. SD-01 and SD-02 were found to be active in the nanomolar (nM) range. SD-01 had considerably good selectivity for HDAC8 over HDAC6 and SD-02 had marginal selectivity for HDAC6 over HDAC8. The compounds SD-01 and SD-02 were found to inhibit HDAC8 at concentrations (IC50) 9.0 nM and 2.7 nM, respectively.
Contribution of rare coding mutations in CD36 to type 2 diabetes and cardio-metabolic complications
Authors: Meyre David , Andress Edward J. , Sharma Tanmay , Snippe Marjolein , Asif Hamza , Maharaj Arjuna , Vatin Vincent , Gaget Stefan , Besnard Philippe , Choquet Hélène , Froguel Philippe , Linton Kenneth J.
Published: November 2019

We sequenced coding regions of the cluster of differentiation 36 (CD36) gene in 184 French individuals of European ancestry presenting simultaneously with type 2 diabetes (T2D), arterial hypertension, dyslipidemia, and coronary heart disease. We identified rare missense mutations (p.Pro191Leu/rs143150225 and p.Ala252Val/rs147624636) in two heterozygous cases. The two CD36 mutation carriers had no family history of T2D and no clustering of cardio-metabolic complications. While the p.Pro191Leu mutation was found in 84 heterozygous carriers from five ethnic groups from the genome aggregation database (global frequency: 0.0297%, N = 141,321), only one European carrier of the p.Ala252Val mutation was identified (global frequency: 0.00040%, N = 125,523). The Pro191 and Ala252 amino acids were not conserved (74.8% and 68.9% across 131 animal species, respectively). In vitro experiments showed that the two CD36 mutant proteins are expressed and trafficked to the plasma membrane where they bind modified low-density-lipoprotein (LDL) cholesterol as normal. However, molecular modelling of the recent CD36 crystal structure showed that Pro191 was located at the exit/entrance gate of the lipid binding chamber and Ala252 was in line with the chamber. Overall, our data do not support a major contribution of CD36 rare coding mutations to T2D and its cardio-metabolic complications in the French population.