bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond the Binary: Towards a Third Sex Category in Germany?
Authors: Dunne Peter , Mulder Jule
Published: March 2019

This Case Note discusses the recent judgment of the German Constitutional Court (1 BvR 2019/16) requiring either the legal recognition of sex categories beyond male or female, or the aboltion of sex registration requirements. The Note considers the Court's decision within the broader constitutional case law on gender identity, and explores both the progressive potential, and the future—perhaps unforeseen—consequences, of the ruling. The Case Note proceeds in three sections. Section A introduces the facts of the constitutional challenge, and sets out both the submissions of the complainant, as well as the reasoning of the Constitutional Court. In Section B, the Case Note explores the domestic law novelty of the decision, placing particular emphasis on the application of a constitutional equality framework to persons who experience intersex variance. Finally, in Section C, the Case Note contextualizes the judgment, situating the reasoning of the Constitutional Court within wider movements for transgender—otherwise known as trans—and intersex rights.
“Gender Quotas” in French and Italian Public Law: A Tale of Two Overlapping and Then Diverging Trajectories
Authors: Möschel Mathias
Published: March 2019

This Article compares the French and Italian experiences with gender quotas—understood as mechanisms intended to increase women's participation in public life, including but not limited to, the reservation of seats in certain positions and the modulation of electoral lists— in public entities such as legislative and executive bodies (including political parties), the judiciary, and public universities. The comparison between France and Italy demonstrates that even between two countries whose constitutional history and trajectory with regard to gender quotas has been portrayed as being essentially identical, a closer analysis of the recent developments in both countries’ constitutional and administrative case law shows a slightly more nuanced picture. Using Rodolfo Sacco's approach of legal formants, this Article argues that the difference stems mainly from the different attitude and interpretation of equality by the judicial formant.
Observing the Local Emergence of the Southern Ocean Residual‐Mean Circulation
Authors: Sévellec F. , Naveira Garabato A. C. , Vic C. , Ducousso N.
Published: March 2019

The role of mesoscale turbulence in maintaining the mean buoyancy structure and overturning circulation of the Southern Ocean is investigated through a 2‐year‐long, single‐mooring record of measurements in Drake Passage. The buoyancy budget of the area is successively assessed within the Eulerian and the Temporal‐Residual‐Mean frameworks. We find that a regime change occurs on time scales of 1 to 100 days, characteristic of mesoscale dynamics, whereby the eddy‐induced turbulent horizontal advection balances the vertical buoyancy advection by the mean flow. We use these diagnostics to reconstruct the region's overturning circulation, which is found to entail an equatorward downwelling of Antarctic Intermediate and Bottom Waters and a poleward upwelling of Circumpolar Deep Water. The estimated eddy‐induced flow can be accurately parameterized via the Gent‐McWilliams closure by adopting a diffusivity of ∼2,000 m2 s−1 with a middepth increase to 2,500 m2 s−1 at 2,100 m, immediately underneath the maximum interior stratification.
Along‐Strike Variations in Structure of the Continent‐Ocean Transition at the Northeastern Nova Scotia Margin From Wide‐Angle Seismic Observations
Authors: Lau K. W. Helen , Nedimović Mladen R. , Louden Keith E.
Published: March 2019

Our 2‐D‐layered velocity model along strike northeastern Nova Scotian margin, constrained by wide‐angle seismic Profile OCTOPUS and coincident 9‐km streamer Profile GXT‐5100, displays highly variable basement structures interpreted to define four distinct zones within the continent‐ocean transition: Zone I, with thin (1–2 km) and laterally uniform upper crust (5.2–5.5 km/s) and high‐velocity lower crust (6.5–7.7 km/s); Zone II, with velocities of 5.5–7.5 km/s and a high vertical velocity gradient (∼1.1/s) characteristic of exhumed serpentinized (up to 90%) mantle (ESM) above ∼3.5‐km‐thick slightly (<30%) serpentinized mantle layer of reduced mantle velocities (7.5–8.0 km/s); Zone III, with 1‐ to 2‐km‐thick upper crust and velocity of ∼5.2 km/s above a ∼6‐km‐thick, moderately (<60%) serpentinized mantle layer (velocity ∼6.4–7.9 km/s); and Zone IV, with lower crust (∼0.7–3.0 km thick and with velocity of 6.1–6.6 km/s) between upper crust (velocity ∼5.0–5.4 km/s) and a slightly serpentinized mantle layer (<40%; velocity ∼7.3–8.0 km/s). These continent‐ocean transition structures represent embryonic oceanic or rifted continental crust, and ESM. By combining our results with those from two dip‐oriented crossing profiles, we map a regional track of non‐ESM landward of Profile OCTOPUS with mostly uniform along‐dip width, but a limited extent and variable width section of ESM seaward. Our results indicate that there can be a remarkable amount of short‐wavelength (e.g., 50 km) lateral structural variability within individual rifted margin segments but that mapping it requires a grid of modern wide‐angle profiles.
AGRP neurons modulate fasting-induced anxiolytic effects
Authors: Li Changhong , Hou Yanjun , Zhang Jia , Sui Guangzhi , Du Xueliang , Licinio Julio , Wong Ma-Li , Yang Yunlei
Published: March 2019

Recent studies indicate that activation of hypothalamic Agouti-related protein (Agrp) neurons can increase forage-related/repetitive behavior and decrease anxiety levels. However, the impact of physiological hunger states and food deprivation on anxiety-related behaviors have not been clarified. In the present study, we evaluated changes in anxiety levels induced by physiological hunger states and food deprivation, and identified the neuron population involved. Ad libitum fed and fasted mice were tested in the open field and elevated plus-maze behavioral tests. The DREADD approach was applied to selectively inhibit and stimulate neurons expressing Agrp in hypothalamic arcuate nucleus in Agrp-Cre transgenic mice. We found that anxiety levels were significantly reduced in the late light period when mice have increased need for food and increased Agrp neurons firing, in contrast to the levels in the early light period. Consistently, we also found that anxiety was potently reduced in 24-h fasted mice, relative to 12-h fasted mice or fed ad libitum. Mechanistically, we found that chemogenetic activation of Agrp neurons reduced anxiety in fed mice, and inactivation of Agrp neurons reduced fasting-induced anxiolytic effects. Our results suggest that anxiety levels may vary physiologically with the increasing need for food, and are influenced by acute fasting in a time-dependent manner. Agrp neurons contribute to fasting-induced anxiolytic effects, supporting the notion that Agrp neuron may serve as an entry point for the treatment of energy states-related anxiety disorders.
Motor cortex excitability and inhibitory imbalance in autism spectrum disorder assessed with transcranial magnetic stimulation: a systematic review
Authors: Masuda Fumi , Nakajima Shinichiro , Miyazaki Takahiro , Yoshida Kazunari , Tsugawa Sakiko , Wada Masataka , Ogyu Kamiyu , Croarkin Paul E. , Blumberger Daniel M. , Daskalakis Zafiris J. , Mimura Masaru , Noda Yoshihiro
Published: March 2019

Cortical excitation/inhibition (E/I) imbalances contribute to various clinical symptoms observed in autism spectrum disorder (ASD). However, the detailed pathophysiologic underpinning of E/I imbalance remains uncertain. Transcranial magnetic stimulation (TMS) motor-evoked potentials (MEP) are a non-invasive tool for examining cortical inhibition in ASD. Here, we conducted a systematic review on TMS neurophysiology in motor cortex (M1) such as MEPs and short-interval intracortical inhibition (SICI) between individuals with ASD and controls. Out of 538 initial records, we identified six articles. Five studies measured MEP, where four studies measured SICI. There were no differences in MEP amplitudes between the two groups, whereas SICI was likely to be reduced in individuals with ASD compared with controls. Notably, SICI largely reflects GABA(A) receptor-mediated function. Conversely, other magnetic resonance spectroscopy and postmortem methodologies assess GABA levels. The present review demonstrated that there may be neurophysiological deficits in GABA receptor-mediated function in ASD. In conclusion, reduced GABAergic function in the neural circuits could underlie the E/I imbalance in ASD, which may be related to the pathophysiology of clinical symptoms of ASD. Therefore, a novel treatment that targets the neural circuits related to GABA(A) receptor-mediated function in regions involved in the pathophysiology of ASD may be promising.
Atomic electrostatic maps of 1D channels in 2D semiconductors using 4D scanning transmission electron microscopy
Authors: Fang Shiang , Wen Yi , Allen Christopher S. , Ophus Colin , Han Grace G. D. , Kirkland Angus I. , Kaxiras Efthimios , Warner Jamie H.
Published: March 2019

Defects in materials give rise to fluctuations in electrostatic fields that reflect the local charge density, but imaging this with single atom sensitivity is challenging. However, if possible, this provides information about the energetics of adatom binding, localized conduction channels, molecular functionality and their relationship to individual bonds. Here, ultrastable electron-optics are combined with a high-speed 2D electron detector to map electrostatic fields around individual atoms in 2D monolayers using 4D scanning transmission electron microscopy. Simultaneous imaging of the electric field, phase, annular dark field and the total charge in 2D MoS2 and WS2 is demonstrated for pristine areas and regions with 1D wires. The in-gap states in sulphur line vacancies cause 1D electron-rich channels that are mapped experimentally and confirmed using density functional theory calculations. We show how electrostatic fields are sensitive in defective areas to changes of atomic bonding and structural determination beyond conventional imaging.
Evidence for model-based encoding of Pavlovian contingencies in the human brain
Authors: Pauli Wolfgang M. , Gentile Giovanni , Collette Sven , Tyszka Julian M. , O’Doherty John P.
Published: March 2019

Prominent accounts of Pavlovian conditioning successfully approximate the frequency and intensity of conditioned responses under the assumption that learning is exclusively model-free; that animals do not develop a cognitive map of events. However, these model-free approximations fall short of comprehensively capturing learning and behavior in Pavlovian conditioning. We therefore performed multivoxel pattern analysis of high-resolution functional MRI data in human participants to test for the encoding of stimulus-stimulus associations that could support model-based computations during Pavlovian conditioning. We found that dissociable sub-regions of the striatum encode predictions of stimulus-stimulus associations and predictive value, in a manner that is directly related to learning performance. Activity patterns in the orbitofrontal cortex were also found to be related to stimulus-stimulus as well as value encoding. These results suggest that the brain encodes model-based representations during Pavlovian conditioning, and that these representations are utilized in the service of behavior.
Gas identification with graphene plasmons
Authors: Hu Hai , Yang Xiaoxia , Guo Xiangdong , Khaliji Kaveh , Biswas Sudipta Romen , García de Abajo F. Javier , Low Tony , Sun Zhipei , Dai Qing
Published: March 2019

Identification of gas molecules plays a key role a wide range of applications extending from healthcare to security. However, the most widely used gas nano-sensors are based on electrical approaches or refractive index sensing, which typically are unable to identify molecular species. Here, we report label-free identification of gas molecules SO2, NO2, N2O, and NO by detecting their rotational-vibrational modes using graphene plasmon. The detected signal corresponds to a gas molecule layer adsorbed on the graphene surface with a concentration of 800 zeptomole per μm2, which is made possible by the strong field confinement of graphene plasmons and high physisorption of gas molecules on the graphene nanoribbons. We further demonstrate a fast response time (<1 min) of our devices, which enables real-time monitoring of gaseous chemical reactions. The demonstration and understanding of gas molecule identification using graphene plasmonic nanostructures open the door to various emerging applications, including in-breath diagnostics and monitoring of volatile organic compounds.
A Ca2+-regulated deAMPylation switch in human and bacterial FIC proteins
Authors: Veyron Simon , Oliva Giulia , Rolando Monica , Buchrieser Carmen , Peyroche Gérald , Cherfils Jacqueline
Published: March 2019

FIC proteins regulate molecular processes from bacteria to humans by catalyzing post-translational modifications (PTM), the most frequent being the addition of AMP or AMPylation. In many AMPylating FIC proteins, a structurally conserved glutamate represses AMPylation and, in mammalian FICD, also supports deAMPylation of BiP/GRP78, a key chaperone of the unfolded protein response. Currently, a direct signal regulating these FIC proteins has not been identified. Here, we use X-ray crystallography and in vitro PTM assays to address this question. We discover that Enterococcus faecalis FIC (EfFIC) catalyzes both AMPylation and deAMPylation and that the glutamate implements a multi-position metal switch whereby Mg2+ and Ca2+ control AMPylation and deAMPylation differentially without a conformational change. Remarkably, Ca2+ concentration also tunes deAMPylation of BiP by human FICD. Our results suggest that the conserved glutamate is a signature of AMPylation/deAMPylation FIC bifunctionality and identify metal ions as diffusible signals that regulate such FIC proteins directly.
Inner lumen proteins stabilize doublet microtubules in cilia and flagella
Authors: Owa Mikito , Uchihashi Takayuki , Yanagisawa Haru-aki , Yamano Takashi , Iguchi Hiro , Fukuzawa Hideya , Wakabayashi Ken-ichi , Ando Toshio , Kikkawa Masahide
Published: March 2019

Motile cilia are microtubule-based organelles that play important roles in most eukaryotes. Although axonemal microtubules are sufficiently stable to withstand their beating motion, it remains unknown how they are stabilized while serving as tracks for axonemal dyneins. To address this question, we have identified two uncharacterized proteins, FAP45 and FAP52, as microtubule inner proteins (MIPs) in Chlamydomonas. These proteins are conserved among eukaryotes with motile cilia. Using cryo-electron tomography (cryo-ET) and high-speed atomic force microscopy (HS-AFM), we show that lack of these proteins leads to a loss of inner protrusions in B-tubules and less stable microtubules. These protrusions are located near the inner junctions of doublet microtubules and lack of both FAP52 and a known inner junction protein FAP20 results in detachment of the B-tubule from the A-tubule, as well as flagellar shortening. These results demonstrate that FAP45 and FAP52 bind to the inside of microtubules and stabilize ciliary axonemes.
Heterologous biosynthesis and characterization of a glycocin from a thermophilic bacterium
Authors: Kaunietis Arnoldas , Buivydas Andrius , Čitavičius Donaldas J. , Kuipers Oscar P.
Published: March 2019

The genome of the thermophilic bacterium, Aeribacillus pallidus 8, encodes the bacteriocin pallidocin. It belongs to the small class of glycocins and is posttranslationally modified, containing an S-linked glucose on a specific Cys residue. In this study, the pallidocin biosynthetic machinery is cloned and expressed in Escherichia coli to achieve its full biosynthesis and modification. It targets other thermophilic bacteria with potent activity, demonstrated by a low minimum inhibitory concentration (MIC) value. Moreover, the characterized biosynthetic machinery is employed to produce two other glycopeptides Hyp1 and Hyp2. Pallidocin and Hyp1 exhibit antibacterial activity against closely related thermophilic bacteria and some Bacillus sp. strains. Thus, heterologous expression of a glycocin biosynthetic gene cluster including an S-glycosyltransferase provides a good tool for production of hypothetical glycocins encoded by various bacterial genomes and allows rapid in vivo screening.
Vaccination to prevent T cell subversion can protect against persistent hepacivirus infection
Authors: Hartlage Alex S. , Murthy Satyapramod , Kumar Arvind , Trivedi Sheetal , Dravid Piyush , Sharma Himanshu , Walker Christopher M. , Kapoor Amit
Published: March 2019

Efforts to develop an effective vaccine against the hepatitis C virus (HCV; human hepacivirus) have been stymied by a lack of small animal models. Here, we describe an experimental rat model of chronic HCV-related hepacivirus infection and its response to T cell immunization. Immune-competent rats challenged with a rodent hepacivirus (RHV) develop chronic viremia characterized by expansion of non-functional CD8+ T cells. Single-dose vaccination with a recombinant adenovirus vector expressing hepacivirus non-structural proteins induces effective immunity in majority of rats. Resolution of infection coincides with a vigorous recall of intrahepatic cellular responses. Host selection of viral CD8 escape variants can subvert vaccine-conferred immunity. Transient depletion of CD8+ cells from vaccinated rats prolongs infection, while CD4+ cell depletion results in chronic viremia. These results provide direct evidence that co-operation between CD4+ and CD8+ T cells is important for hepacivirus immunity, and that subversion of responses can be prevented by prophylactic vaccination.
Publisher Correction: Structural insights into chaperone addiction of toxin-antitoxin systems
Authors: Guillet Valérie , Bordes Patricia , Bon Cécile , Marcoux Julien , Gervais Virginie , Sala Ambre Julie , Dos Reis Suzana , Slama Nawel , Mares-Mejía Israel , Cirinesi Anne-Marie , Maveyraud Laurent , Genevaux Pierre , Mourey Lionel
Published: March 2019

The original version of this Article contained errors in Figures 1 and 4. In Fig. 1b, the Mtb-SecBTA sequence was displayed incorrectly. In the inset panel within Fig. 4c, the y-axis of the graph incorrectly read (Q.Rg)2 × I(Q)//(0), and should have read (Q.Rg)2 × I(Q)/I(0). These errors have been corrected in both the PDF and HTML versions of the Article.
Emergence of self-affine surfaces during adhesive wear
Authors: Milanese Enrico , Brink Tobias , Aghababaei Ramin , Molinari Jean-François
Published: March 2019

Friction and wear depend critically on surface roughness and its evolution with time. An accurate control of roughness is essential to the performance and durability of virtually all engineering applications. At geological scales, roughness along tectonic faults is intimately linked to stick-slip behaviour as experienced during earthquakes. While numerous experiments on natural, fractured, and frictional sliding surfaces have shown that roughness has self-affine fractal properties, much less is known about the mechanisms controlling the origins and the evolution of roughness. Here, by performing long-timescale molecular dynamics simulations and tracking the roughness evolution in time, we reveal that the emergence of self-affine surfaces is governed by the interplay between the ductile and brittle mechanisms of adhesive wear in three-body contact, and is independent of the initial state.
Voluntary exercise in mice fed an obesogenic diet alters the hepatic immune phenotype and improves metabolic parameters – an animal model of life style intervention in NAFLD
Authors: Gehrke Nadine , Biedenbach Jana , Huber Yvonne , Straub Beate K. , Galle Peter R. , Simon Perikles , Schattenberg Jörn M.
Published: March 2019

Reproducible animal models to recapitulate the pathophysiology of non-alcoholic fatty liver disease (NAFLD) are urgently required to improve the understanding of the mechanisms of liver injury and to explore novel therapeutic options. Current guidelines recommend life-style interventions as first-line therapy for NAFLD and these types of intervention are considered standard-of-care. The current study establishes a reproducible mouse model of a life-style intervention in NAFLD using voluntary wheel running (VWR). Male C57BL/6J mice were fed a high-fat, high-carbohydrate diet (HFD) to induce NAFLD or a corresponding control diet for 12 weeks. Starting at week 9 of the obesogenic NAFLD diet, mice were randomized to either free access to a running wheel or being single caged resembling a sedentary (SED) life-style. VWR induced a transient weight reduction in HFD-fed mice up until week 10. In contrast to the SED mice, VWR mice exhibited normal ALT at the end of the intervention, while the metabolic alterations including elevated fasting glucose, insulin, triglyceride, and total cholesterol levels remained almost unchanged. Additionally, VWR prevented HFD-induced hepatic steatosis by alterations in key liver metabolic processes including the induction of fatty acid β-oxidation and lipogenesis inhibition following increased AMP-activated protein kinase (AMPK)-α activity. Phosphorylation of the serine kinase Akt in hepatic tissue was enhanced following VWR. Furthermore, VWR mice were protected from HFD-induced expression of pro-inflammatory cytokines, chemokines and liver macrophage infiltration. The SED/HFD group exhibited increasing activity of hepatic nuclear factor (NF)-κB p65, which was absent following exercise in the VWR/HFD group. In summary, in an obesogenic mouse model of NAFLD physical exercise improves fatty acid and glucose homeostasis and protects from macrophage-associated hepatic inflammation.
Deep-tissue optical imaging of near cellular-sized features
Authors: Dang Xiangnan , Bardhan Neelkanth M. , Qi Jifa , Gu Li , Eze Ngozi A. , Lin Ching-Wei , Kataria Swati , Hammond Paula T. , Belcher Angela M.
Published: March 2019

Detection of biological features at the cellular level with sufficient sensitivity in complex tissue remains a major challenge. To appreciate this challenge, this would require finding tens to hundreds of cells (a 0.1 mm tumor has ~125 cells), out of ~37 trillion cells in the human body. Near-infrared optical imaging holds promise for high-resolution, deep-tissue imaging, but is limited by autofluorescence and scattering. To date, the maximum reported depth using second-window near-infrared (NIR-II: 1000–1700 nm) fluorophores is 3.2 cm through tissue. Here, we design an NIR-II imaging system, “Detection of Optically Luminescent Probes using Hyperspectral and diffuse Imaging in Near-infrared” (DOLPHIN), that resolves these challenges. DOLPHIN achieves the following: (i) resolution of probes through up to 8 cm of tissue phantom; (ii) identification of spectral and scattering signatures of tissues without apriori knowledge of background or autofluorescence; and (iii) 3D reconstruction of live whole animals. Notably, we demonstrate noninvasive real-time tracking of a 0.1 mm-sized fluorophore through the gastrointestinal tract of a living mouse, which is beyond the detection limit of current imaging modalities.
Cross-disease analysis of Alzheimer’s disease and type-2 Diabetes highlights the role of autophagy in the pathophysiology of two highly comorbid diseases
Authors: Caberlotto Laura , Nguyen T.-Phuong , Lauria Mario , Priami Corrado , Rimondini Roberto , Maioli Silvia , Cedazo-Minguez Angel , Sita Giulia , Morroni Fabiana , Corsi Mauro , Carboni Lucia
Published: March 2019

Evidence is accumulating that the main chronic diseases of aging Alzheimer’s disease (AD) and type-2 diabetes mellitus (T2DM) share common pathophysiological mechanisms. This study aimed at applying systems biology approaches to increase the knowledge of the shared molecular pathways underpinnings of AD and T2DM. We analysed transcriptomic data of post-mortem AD and T2DM human brains to obtain disease signatures of AD and T2DM and combined them with protein-protein interaction information to construct two disease-specific networks. The overlapping AD/T2DM network proteins were then used to extract the most representative Gene Ontology biological process terms. The expression of genes identified as relevant was studied in two AD models, 3xTg-AD and ApoE3/ApoE4 targeted replacement mice. The present transcriptomic data analysis revealed a principal role for autophagy in the molecular basis of both AD and T2DM. Our experimental validation in mouse AD models confirmed the role of autophagy-related genes. Among modulated genes, Cyclin-Dependent Kinase Inhibitor 1B, Autophagy Related 16-Like 2, and insulin were highlighted. In conclusion, the present investigation revealed autophagy as the central dys-regulated pathway in highly co-morbid diseases such as AD and T2DM allowing the identification of specific genes potentially involved in disease pathophysiology which could become novel targets for therapeutic intervention.
Bcl-xL inhibition enhances Dinaciclib-induced cell death in soft-tissue sarcomas
Authors: Rello-Varona Santi , Fuentes-Guirado Miriam , López-Alemany Roser , Contreras-Pérez Aida , Mulet-Margalef Núria , García-Monclús Silvia , Tirado Oscar M. , García del Muro Xavier
Published: March 2019

Soft-tissue sarcomas (STS) are an uncommon and heterogeneous group of malignancies that result in high mortality. Metastatic STS have very bad prognosis due to the lack of effective treatments. Dinaciclib is a model drug for the family of CDK inhibitors. Its main targets are cell cycle regulator CDK1 and protein synthesis controller CDK9. We present data supporting Dinaciclib ability to inactivate in vitro different STS models at nanomolar concentrations. Moreover, the different rhythms of cell death induction allow us to further study into the mechanism of action of the drug. Cell death was found to respond to the mitochondrial pathway of apoptosis. Anti-apoptotic Bcl-xL was identified as the key regulator of this process. Already natural low levels of pro-apoptotic proteins BIM and PUMA in tolerant cell lines were insufficient to inhibit Bcl-xL as this anti-apoptotic protein showed a slow decay curve after Dinaciclib-induced protein synthesis disruption. Combination of Dinaciclib with BH3-mimetics led to quick and massive apoptosis induction in vitro, but in vivo assessment was prevented due to liver toxicity. Additionally, Bcl-xL inhibitor A-1331852 also synergized with conventional chemotherapy drugs as Gemcitabine. Thus, Bcl-xL targeted therapy arises as a major opportunity to the treatment of STS.
Provisional Tic Disorder is not so transient
Authors: Kim Soyoung , Greene Deanna J. , Bihun Emily C. , Koller Jonathan M. , Hampton Jacqueline M. , Acevedo Haley , Reiersen Angela M. , Schlaggar Bradley L. , Black Kevin J.
Published: March 2019

Motor and vocal tics are common in childhood. The received wisdom among clinicians is that for most children the tics are temporary, disappearing within a few months. However, that common clinical teaching is based largely on biased and incomplete data. The present study was designed to prospectively assess outcome of children with what the current nomenclature calls Provisional Tic Disorder. We identified 43 children with recent onset tics (mean 3.3 months since tic onset) and re-examined 39 of them on the 12-month anniversary of their first tic. Tic symptoms improved on a group level at the 12-month follow-up, and only two children had more than minimal impairment due to tics. Remarkably, however, tics were present in all children at follow-up, although in several cases tics were apparent only when the child was observed remotely by video. Our results suggest that remission of Provisional Tic Disorder is the exception rather than the rule. We also identified several clinical features present at the first examination that predict one-year outcome; these include baseline tic severity, subsyndromal autism spectrum symptoms, and the presence of an anxiety disorder.
Toxicity and neurophysiological impacts of plant essential oil components on bed bugs (Cimicidae: Hemiptera)
Authors: Gaire Sudip , Scharf Michael E. , Gondhalekar Ameya D.
Published: March 2019

Bed bugs (Cimex lectulariusL.) are globally important human parasites. Integrated pest management (IPM) approaches, which include the use of essential oil-based insecticidal compounds, have been proposed for their control. This study aimed to define insecticidal activity and neurophysiological impacts of plant essential oil constituents. The topical and fumigant toxicity of 15 compounds was evaluated against adult male bed bugs. Neurological effects of the 6 most toxicologically active compounds were also determined. In both topical and fumigant bioassays, carvacrol and thymol were the most active compounds. The potency of bifenthrin (a pyrethroid insecticide) in topical bioassays was 72,000 times higher than carvacrol, while vapors of dichlorvos (an organophosphate insecticide) were 445 times more potent than thymol. Spontaneous electrical activity measurements of the bed bug nervous system demonstrated neuroinhibitory effects of carvacrol, thymol and eugenol, whereas linalool produced an excitatory effect. Although citronellic acid and (±)-camphor increased baseline activity of the nervous system their effects were not statistically significant. Bifenthrin also caused neuroexcitation, which is consistent with its known mode of action. These comparative toxicity and neurological impact findings provide new information for formulating effective essential oil-based insecticides for bed bug IPM and conducting mode-of-action studies on individual essential oil components.
Daiokanzoto (Da-Huang-Gan-Cao-Tang) is an effective laxative in gut microbiota associated with constipation
Authors: Takayama Kento , Takahara Chiho , Tabuchi Norihiko , Okamura Nobuyuki
Published: March 2019

Interindividual differences affect the purgative activities of sennoside A (SA) and Daiokanzoto (Da-Huang-Gan-Cao-Tang, DKT). In this study, we manipulated gut microbiota in mice to establish laxative responders and non-responders by feeding them a high-carbohydrate, a high-fat or a high-fibre diet. To assess the relationship between laxatives and gut microbiota, we monitored the gut microbiota before and after administering laxatives. Twenty mice per diet were divided into four groups of five mice to evaluate purgative activities of four laxative preparations, DKT, SA, SA plus rhein 8-O-β-D-glucopyranoside (SA + RG), and SA plus liquiritin (SA + LQ). Gut microbiota changes were monitored by next-generation sequencing of 16 S rRNA gene amplicons. In high-carbohydrate and high-fat diet-fed mice, DKT exerted a significantly higher purgative activity than SA alone, and RG contributed to this activity. DKT and SA + RG administration increased the Enterobacteriaceae content of gut microbiota, which was associated with an increased purgative activity. In contrast, DKT activity was significantly suppressed by high-fibre diet. Hence, diet-induced differences in gut microbiota determined the effect of DKT, which is interesting, considering that Oriental medicines are formulated for a specific functional state or “pattern”. These results demonstrated that the purgative activity of anthranoid laxatives is susceptible to diet-induced alterations in gut microbiota.
Solid-phase synthesis of molecularly imprinted polymer nanolabels: Affinity tools for cellular bioimaging of glycans
Authors: Medina Rangel Paulina X. , Laclef Sylvain , Xu Jingjing , Panagiotopoulou Maria , Kovensky José , Tse Sum Bui Bernadette , Haupt Karsten
Published: March 2019

Hyaluronic acid (HA) is a glycosaminoglycan that plays many roles in health and disease and is a key biomarker of certain cancers. Therefore, its detection at an early stage, by histochemical methods, is of importance. However, intracellular HA can be masked by other HA-binding macromolecules, rendering its visualization somehow problematic. We show that fluorescent molecularly imprinted polymer nanogels (MIP-NPs), can localize and detect intracellular HA. MIP-NPs were synthesized by solid-phase synthesis on glass beads (GBs). GBs were functionalized with terminal alkyne groups on which an azide derivative of the template molecule glucuronic acid was immobilized via click chemistry. Immobilization via the anomeric carbon left the template’s carboxyl moiety free to enable strong stoichiometric electrostatic interactions with a benzamidine-based functional monomer, to confer selective recognition to the MIP-NPs. Due to the two-point orientation of the template, the resulting MIP-NPs were endowed with improved binding site homogeneity and specificity, reminiscent of monoclonal antibodies. These synthetic antibodies were then applied for probing and staining HA, of which glucuronic acid is a substructure (epitope), on human epidermal cells. Their excellent sensitivity, small size and water compatibility, enabled the MIP-NPs to visualize HA, as evidenced by confocal fluorescence micrographs.
The prevalence of nonlinearity and detection of ecological breakpoints across a land use gradient in streams
Authors: D’Amario Sarah C. , Rearick Daniel C. , Fasching Christina , Kembel Steven W. , Porter-Goff Emily , Spooner Daniel E. , Williams Clayton J. , Wilson Henry F. , Xenopoulos Marguerite A.
Published: March 2019

Human activities can alter aquatic ecosystems through the input of nutrients and carbon, but there is increasing evidence that these pressures induce nonlinear ecological responses. Nonlinear relationships can contain breakpoints where there is an unexpected change in an ecological response to an environmental driver, which may result in ecological regime shifts. We investigated the occurrence of nonlinearity and breakpoints in relationships between total dissolved nitrogen (TDN), total dissolved phosphorus (TDP), and total dissolved carbon (DOC) concentrations and ecological responses in streams with varying land uses. We calculated breakpoints using piecewise regression, two dimensional Kolmogorov-Smirnov (2DKS), and significant zero crossings (SiZer) methods. We found nonlinearity was common, occurring in half of all analyses, with some evidence of multiple breakpoints. Linearity, by contrast, occurred in less than 14% of cases, on average. Breakpoints were related to land use gradients, with 34–43% agricultural cover associated with DOC and TDN breakpoints, and 15% wetland and 9.5% urban land associated with DOC and nutrient breakpoints, respectively. While these breakpoints are likely specific to our study area, our study contributes to the growing literature of the prevalence and location of ecological breakpoints in streams, providing watershed managers potential criteria for catchment land use thresholds.
Ultra-dense (~20 Tdot/in2) nanoparticle array from an ordered supramolecular dendrimer containing a metal precursor
Authors: Kwon Kiok , Suh Bong Lim , Park Kangho , Kim Jihan , Jung Hee-Tae
Published: March 2019

The fabrication of an ultra-dense, highly periodic nanoparticle array from a soft template is one of the most important issues in the fields of material science and nanotechnology. To date, block copolymer (BCP) structures have been primarily used as templates for fabricating highly periodic nanoparticle arrays with high areal densities. Herein, we demonstrate for the first time the use of a supramolecular dendrimer assembly for the formation of a highly ordered nanoparticle array with a high areal density of ~20 Tdot/in2, four times larger than that of the currently reported BCP-based nanoparticle arrays. By the simple thermal annealing of a dendrimers containing a metal precursor between two flat, solid substrates, a hexagonal array of small gold nanoparticles (with a diameter of ~1.6 nm and center-to-center distance of ~5.3 nm), oriented normal to the bottom, was achieved. Density functional theory calculations demonstrated that the gold cation strongly bound to the head group of the dendrimer. This structure served as a building block for self-assembly into a stable cylindrical structure. We anticipate that this study will lead to the creation of a large family of supramolecular dendrimers that can be utilized as soft templates for creating periodic, ultra-dense nanoparticle arrays.
Previously published drug interaction models predict loss of response for transoesophageal echocardiography sedation well but not response to oesophageal instrumentation
Authors: Su Fu-Wei , Ting Chien-Kun , Liou Jing-Yang , Chen Yi-Chang , Tsou Mei-Yung , Wang Shen-Chih
Published: March 2019

Response surface models (RSMs) were used to predict effects of multiple drugs interactions. Our study was aimed to validate accuracy of the previous published volunteer models during transoesophageal echocardiography (TEE). This is a cross-sectional study with 20 patients scheduled for transesophageal echocardiography in Taipei Veterans General Hospital, Taiwan. Effect-site concentration pairs of alfentanil and propofol were recorded and converted to equivalent remifentanil and propofol effect-site concentrations. Observer’s Assessment of Alertness/Sedation (OAA/S) scores were assessed every 2 minutes. Using these data, previous published models of loss of response (LOR), intolerable ventilatory depression (IVD), and loss of response to esophageal instrumentation (LREI) were then estimated. Accuracy of prediction is assessed by calculating the difference between the true response and the model-predicted probability. Clinical events such as interruption of TEE were recorded. The average procedure time was 11 minutes. Accuracy for prediction of LOR and LREI is 63.6% and 38.5%, respectively. There were four patients experienced desaturation for less than 1 minute, which were not predicted by IVD model, and one interruption of TEE due to involuntary movement. The previous published drug-interaction RSMs predict LOR well but not LREI for TEE sedation. Further studies using response surface methodology are needed to improve quality for TEE sedation and clinical implementation.
Risk Factors and Outcomes of Choroidal Neovascularization Secondary to Central Serous Chorioretinopathy
Authors: Lee Ga-In , Kim A. Young , Kang Se Woong , Cho Soo Chang , Park Kyu Hyung , Kim Sang Jin , Kim Kyung Tae
Published: March 2019

We identified clinical characteristics and risk factors of choroidal neovascularization (CNV) in eyes with prior episode of central serous chorioretinopathy (CSC). This retrospective case-control study included those initially diagnosed with CSC and developed CNV secondarily (Group 1, n = 16), those diagnosed with CNV in eyes of previous putative CSC (Group 2, n = 14), and those initially diagnosed with CSC, and did not develop CNV secondarily, as a control group for Group 1 (Group 3, n = 250). Clinical characteristics including treatment outcomes were assessed. Demographics and multimodal imaging at the time of CSC diagnosis of secondary CNV were compared between the groups to identify risk factors. Duration from diagnosis of CSC to development of CNV in Group 1 was 40.2 ± 42.0 months. Classic CNV was noted in 23 (76.7%) eyes. After treatment with intravitreal antiangiogenics with average of 4.9 times, visual acuity improved in Group 1 and Group 2 (p = 0.002). Multivariate analysis revealed that systemic hypertension, pigmentary changes, and double layer sign were associated with development of CNV secondary to CSC (p < 0.05). Hypertension, pigmentary changes, and double layer sign were independent risk factors for CNV secondary to CSC. The CNV’s responded well to treatment, resulting in improved vision.
Key role of excess atomic volume in structural rearrangements at the front of moving partial dislocations in copper nanocrystals
Authors: Psakhie S. G. , Zolnikov K. P. , Kryzhevich D. S. , Korchuganov A. V.
Published: March 2019

Here we report on a molecular dynamics simulation of the atomic volume distribution in fcc copper with moving partial dislocations 1/6 〈112〉 {111}. The simulation shows that the leading and trailing partial dislocations surrounding a stacking fault move via local fcc→hcp and hcp→fcc transformations and that a fcc–hcp transition zone exists in which the atomic volume is larger than that in the perfect close-packed structure. The excess volume is five to seven percent, which compares with volume jumps on melting. The simulation results agree with experimental data showing that the nucleation of dislocations is preceded by the formation of regions with an excess atomic volume.
Modelling Duchenne muscular dystrophy in MYOD1-converted urine-derived cells treated with 3-deazaneplanocin A hydrochloride
Authors: Takizawa Hotake , Hara Yuko , Mizobe Yoshitaka , Ohno Taisuke , Suzuki Sadafumi , Inoue Ken , Takeshita Eri , Shimizu-Motohashi Yuko , Ishiyama Akihiko , Hoshino Mikio , Komaki Hirofumi , Takeda Shin’ichi , Aoki Yoshitsugu
Published: March 2019

Duchenne muscular dystrophy (DMD) is a severe muscle disorder characterised by mutations in the DMD gene. Recently, we have completed a phase I study in Japan based on systemic administration of the morpholino antisense that is amenable to exon-53 skipping, successfully. However, to achieve the effective treatment of DMD, in vitro assays on patient muscle cells to screen drugs and patient eligibility before clinical trials are indispensable. Here, we report a novel MYOD1-converted, urine-derived cells (UDCs) as a novel DMD muscle cell model. We discovered that 3-deazaneplanocin A hydrochloride, a histone methyltransferase inhibitor, could significantly promote MYOGENIN expression and myotube differentiation. We also demonstrated that our system, based on UDCs from DMD patients, could be used successfully to evaluate exon-skipping drugs targeting DMD exons including 44, 50, 51, and 55. This new autologous UDC-based disease modelling could lead to the application of precision medicine for various muscle diseases.
Higher ventricular rate during atrial fibrillation relates to increased cerebral hypoperfusions and hypertensive events
Authors: Saglietto Andrea , Scarsoglio Stefania , Ridolfi Luca , Gaita Fiorenzo , Anselmino Matteo
Published: March 2019

Atrial fibrillation (AF) is associated with cognitive impairment/dementia, independently of clinical cerebrovascular events (stroke/TIA). One of the plausible mechanisms is the occurrence of AF-induced transient critical hemodynamic events; however, it is presently unknown, if ventricular response rate during AF may impact on cerebral hemodynamics. AF was simulated at different ventricular rates (50, 70, 90, 110, 130 bpm) by two coupled lumped parameter validated models (systemic and cerebral circulation), and compared to corresponding control normal sinus rhythm simulations (NSR). Hemodynamic outcomes and occurrence of critical events (hypoperfusions and hypertensive events) were assessed along the internal carotid artery-middle cerebral artery pathway up to the capillary-venous bed. At the distal cerebral circle level (downstream middle cerebral artery), increasing ventricular rates lead to a reduced heart rate-related dampening of hemodynamic signals compared to NSR (p = 0.003 and 0.002 for flow rate and pressure, respectively). This response causes a significant progressive increase in critical events in the distal cerebral circle (p < 0.001) as ventricular rate increases during AF. On the other side, at the lowest ventricular response rates (HR 50 bpm), at the systemic-proximal cerebral circle level (up to middle cerebral artery) hypoperfusions (p < 0.001) occur more commonly, compared to faster AF simulations. This computational study suggests that higher ventricular rates relate to a progressive increase in critical cerebral hemodynamic events (hypoperfusions and hypertensive events) at the distal cerebral circle. Thus, a rate control strategy aiming to around 60 bpm could be beneficial in terms on cognitive outcomes in patients with permanent AF.
Fast spectrally encoded Mueller optical scanning microscopy
Authors: Rivet Sylvain , Dubreuil Matthieu , Bradu Adrian , Le Grand Yann
Published: March 2019

Mueller microscopes enable imaging of the optical anisotropic properties of biological or non-biological samples, in phase and amplitude, at sub-micrometre scale. However, the development of Mueller microscopes poses an instrumental challenge: the production of polarimetric parameters must be sufficiently quick to ensure fast imaging, so that the evolution of these parameters can be visualised in real-time, allowing the operator to adjust the microscope while constantly monitoring them. In this report, a full Mueller scanning microscope based on spectral encoding of polarization is presented. The spectrum, collected every 10 μs for each position of the optical beam on the specimen, incorporates all the information needed to produce the full Mueller matrix, which allows simultaneous display of all the polarimetric parameters, at the unequalled rate of 1.5 Hz (for an image of 256 × 256 pixels). The design of the optical blocks allows for the real-time display of linear birefringent images which serve as guidance for the operator. In addition, the instrument has the capability to easily switch its functionality from a Mueller to a Second Harmonic Generation (SHG) microscope, providing a pixel-to-pixel matching of the images produced by the two modalities. The device performance is illustrated by imaging various unstained biological specimens.
Development of an inducible lytic system for functional metagenomic screening
Authors: Cárcel-Márquez Jara , Flores Amando , Martín-Cabello Guadalupe , Santero Eduardo , Camacho Eva M.
Published: March 2019

Functional metagenomic is a powerful tool that allows the discovery of new enzymes with biotechnological potential. During functional screenings of enzymes, the ability of the substrate to enter the surrogate host or the ability of this bacterium to export heterologous extracellular enzymes may hamper the technique. Here we have used an inducible autolysis system that lyses bacteria thus releasing its content in both, liquid and solid cultures, in response to anhydrotetracycline. The lytic cluster is tightly regulated to prevent impaired bacterial growth in absence of the inducer and produced very efficient though not complete bacterial lysis upon induction, which allowed the recovery of live bacteria. The system can be used in combination with specialised fosmids and E. coli strains that maximize transcription of metagenomic DNA. Our results show that colony-lysis on plates allows detection of an endogenous intracellular amylase activity naturally present in E. coli and clearly increased detection of clones coding for cellulase activities in a metagenomic screening, while allowing recovery of survivor positive clones from the lysed colonies in all cases. Therefore, this tool represents an important step towards the effective access to the extraordinary potential of the uncultivated bacteria genetic resources.