bluuebunny/crossref_metadata_2025 huggingface dataset:
The Recapitation ofApatosaurus
Authors: Berman David S , McIntosh John S.
Published: June 2019

In 1915 the Carnegie Museum of Natural History's magnificent skeleton of the sauropod dinosaurApatosaurus louisae, discovered in 1909 at what is now Dinosaur National Monument in northeastern Utah, took its place alongside the equally impressive skeleton ofDiplodocus carnegiiin the Hall of Dinosaurs. At that time and for the next 17 years, however, it stood conspicuously headless. It was not until December of 1932 that the skeleton was completed, and then with the wrong head—aCamarasaurusskull. How this came about and how the error was corrected requires the untangling of a long series of events that began with the first discoveries and descriptions of the giant sauropod dinosaurs of North America over a century ago.
Missing Links in the History of Life
Authors: Marshall Charles R.
Published: June 2019

Ever since Darwin proposed his theory of evolution (or more correctly, theories; see Mayr, 1991) it has been assumed that intermediates now extinct once existed between living species. For some, the hunt for these so-called missing links in the fossil record became an obsession, a search for evidence thought needed to establish the veracity of evolutionary theory. Few modern paleontologists, however, search explicitly for ancestors in the fossil record because we now know that fossils can be used to chart the order of evolution regardless of whether they are directly ancestral either to extinct organisms or those living today.
Directed Network of Substorms Using SuperMAG Ground‐Based Magnetometer Data
Authors: Orr L. , Chapman S. C. , Gjerloev J. W.
Published: June 2019

We quantify the spatiotemporal evolution of the substorm ionospheric current system utilizing the SuperMAG 100+ magnetometers. We construct dynamical directed networks from this data for the first time. If the canonical cross‐correlation between vector magnetic field perturbations observed at two magnetometer stations exceeds a threshold, they form a network connection. The time lag at which canonical cross‐correlation is maximal determines the direction of propagation or expansion of the structure captured by the network connection. If spatial correlation reflects ionospheric current patterns, network properties can test different models for the evolving substorm current system. We select 86 isolated substorms based on nightside ground station coverage. We find, and obtain the timings for, a consistent picture in which the classic substorm current wedge forms. A current system is seen premidnight following the substorm current wedge westward expansion. Later, there is a weaker signal of eastward expansion. Finally, there is evidence of substorm‐enhanced convection.
MMS Measurements of the Vlasov Equation: Probing the Electron Pressure Divergence Within Thin Current Sheets
Authors: Shuster J. R. , Gershman D. J. , Chen L.‐J. , Wang S. , Bessho N. , Dorelli J. C. , da Silva D. E. , Giles B. L. , Paterson W. R. , Denton R. E. , Schwartz S. J. , Norgren C. , Wilder F. D. , Cassak P. A. , Swisdak M. , Uritsky V. , Schiff C. , Rager A. C. , Smith S. , Avanov L. A. , Viñas A. F.
Published: June 2019

We investigate the kinetic structure of electron‐scale current sheets found in the vicinity of the magnetopause and embedded in the magnetosheath within the reconnection exhaust. A new technique for computing terms of the Vlasov equation using Magnetospheric Multiscale (MMS) measurements is presented and applied to study phase space density gradients and the kinetic origins of the electron pressure divergence found within these current sheets. Crescent‐shaped structures in ∇⊥2fe give rise to bipolar and quadrupolar signatures in v·∇fe measured near the maximum ∇·Pe inside the current layers. The current density perpendicular to the magnetic field is strong (J⊥∼2 μA/m2), and the thickness of the current layers ranges from 3 to 5 electron inertial lengths. The electron flows supporting the current layers mainly result from the combination of E×B and diamagnetic drifts. We find nonzero J·E′ within the current sheets even though they are observed apart from typical diffusion region signatures.
Investigation of VLF Transmitter Signals in the Ionosphere by ZH‐1 Observations and Full‐Wave Simulation
Authors: Zhao Shufan , Zhou Chen , Shen Xuhui , Zhima Zeren
Published: June 2019

In this study, we investigate the very low frequency (VLF) signals in the ionosphere propagating from ground‐based transmitters by using the data from the newly launched China Seismo‐Electromagnetic Satellite (CSES), which is also called ZH‐1. The simultaneous ionospheric perturbations and electron precipitations induced by the NWC transmitter are also analyzed, and the possible mechanisms are discussed. The ZH‐1 and DEMETER observations of VLF transmitters are compared morphologically, which are generally consistent with the full‐wave simulations. The results show that the electromagnetic waves excited by the VLF transmitters penetrate into the ionosphere and propagate in the magnetosphere to its conjugate hemisphere as a ducted or nonducted whistler. When the VLF transmitter is located at L < 1.5, the wave propagates more easily as a nonducted whistler. When the wave propagates as a ducted whistler, the point of maximum observed transmitter‐induced electric field in the conjugate hemisphere will move poleward in the northern hemisphere and equatorward in the southern hemisphere. The results also show that the data stability of electromagnetic field recorded by ZH‐1 satellite is almost the same as DEMETER satellite, and there is a good correlation between the ZH‐1 observation and simulated results. These conclusions demonstrate that the nightside VLF band electromagnetic observation of ZH‐1 satellite is stable and reliable.
Advancing the Evidence for Integrated Pediatric Primary Care Psychology: A Call to Action
Authors: Lines Meghan McAuliffe
Published: June 2019

Objective: There has been recognition of the importance of integrating psychology services into the pediatric medical home to meet the developmental and behavioral needs of patients for the past 50 years. Momentum for integrated primary care has grown substantially over the past decade, related to an evolving health care landscape, including the passing of the Affordable Care Act, increased focus on patient-centered medical home models, and a shift in payment structures from fee-for-service to value-based care models. Method: There is a need to continue to develop the evidence base for pediatric integrated primary care to support clinical care models, roles in teaching and training, and advocacy efforts. Results: In this introduction, we present background and current state of integrated primary care with reference to several articles to follow in this issue. Conclusions: The paper concludes with a call for papers for an upcoming special issue of Clinical Practice in Pediatric Psychology focused on contributing to the literature base on integrated pediatric primary care.

Implications for Impact Statement

This introduction presents information on the history and current state of pediatric primary care psychology. This paper describes the existing literature, including contributions in the current issue, and the gaps in the literature. The paper includes a call for proposals for an upcoming special issue. This information is critical to guide pediatric primary care psychologists in their research and clinical practice.
Stain control with two experimental dentin hypersensitivity toothpastes containing spherical silica: a randomised, early-phase development study
Authors: Mason Stephen , Young Sarah , Araga Mako , Butler Andrew , Lucas Robert , Milleman Jeffery L. , Milleman Kimberly R.
Published: June 2019

Aims

To determine in human participants whether toothpastes containing small quantities of a novel spherical silica, added to provide enhanced cleaning properties, could achieve similar or greater extrinsic dental stain removal compared to toothpastes containing standard dental abrasive silica concentrations.

Materials and methods

One hundred and twenty-three adults with extrinsic dental stain were randomised to one of four parallel groups for 8 weeks’ twice-daily brushing with an experimental toothpaste containing either 0.5% or 1% spherical silica (with relative dentin abrasivity [RDA] of ~38 and ~58, respectively), or marketed toothpastes containing either 6% (RDA ~ 36) or 16% (RDA ~ 166) standard abrasive silica. The objective was to evaluate the ranking order in extrinsic dental stain removal at Week 8, as measured by MacPherson modification of Lobene stain index Area × Intensity.

Results

Small treatment differences were observed between toothpaste formulations. The ranking order in extrinsic dental stain removal was: experimental 1% spherical silica toothpaste >16% standard abrasive silica toothpaste >6% standard abrasive silica toothpaste >experimental 0.5% spherical silica toothpaste. Toothpastes were generally well tolerated.

Conclusion

This early-phase development study suggests that toothpaste formulations with low concentrations of a novel spherical silica abrasive with high-cleaning capability are generally well tolerated and appropriate for further development.
Extremely high conductivity observed in the triple point topological metal MoP
Authors: Kumar Nitesh , Sun Yan , Nicklas Michael , Watzman Sarah J. , Young Olga , Leermakers Inge , Hornung Jacob , Klotz Johannes , Gooth Johannes , Manna Kaustuv , Süß Vicky , Guin Satya N. , Förster Tobias , Schmidt Marcus , Muechler Lukas , Yan Binghai , Werner Peter , Schnelle Walter , Zeitler Uli , Wosnitza Jochen , Parkin Stuart S. P. , Felser Claudia , Shekhar Chandra
Published: June 2019

Weyl and Dirac fermions have created much attention in condensed matter physics and materials science. Recently, several additional distinct types of fermions have been predicted. Here, we report ultra-high electrical conductivity in MoP at low temperature, which has recently been established as a triple point fermion material. We show that the electrical resistivity is 6 nΩ cm at 2 K with a large mean free path of 11 microns. de Haas-van Alphen oscillations reveal spin splitting of the Fermi surfaces. In contrast to noble metals with similar conductivity and number of carriers, the magnetoresistance in MoP does not saturate up to 9 T at 2 K. Interestingly, the momentum relaxing time of the electrons is found to be more than 15 times larger than the quantum coherence time. This difference between the scattering scales shows that momentum conserving scattering dominates in MoP at low temperatures.
Cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents
Authors: Wang Ziwen , Chen Zelin , Jiang Zhongyong , Luo Peng , Liu Lang , Huang Yu , Wang Huilan , Wang Yu , Long Lei , Tan Xu , Liu Dengqun , Jin Taotao , Wang Yawei , Wang Yang , Liao Fengying , Zhang Chi , Chen Long , Gan Yibo , Liu Yunsheng , Yang Fan , Huang Chunji , Miao Hongming , Chen Jieping , Cheng Tianmin , Fu Xiaobing , Shi Chunmeng
Published: June 2019

The pathological mechanisms of radiation ulcer remain unsolved and there is currently no effective medicine. Here, we demonstrate that persistent DNA damage foci and cell senescence are involved in radiation ulcer development. Further more, we identify cordycepin, a natural nucleoside analogue, as a potent drug to block radiation ulcer (skin, intestine, tongue) in rats/mice by preventing cell senescence through the increase of NRF2 nuclear expression (the assay used is mainly on skin). Finally, cordycepin is also revealed to activate AMPK by binding with the α1 and γ1 subunit near the autoinhibitory domain of AMPK, then promotes p62-dependent autophagic degradation of Keap1, to induce NRF2 dissociate from Keap1 and translocate to the nucleus. Taken together, our findings identify cordycepin prevents radiation ulcer by inhibiting cell senescence via NRF2 and AMPK in rodents, and activation of AMPK or NRF2 may thus represent therapeutic targets for preventing cell senescence and radiation ulcer.
MRI-guided robotic arm drives optogenetic fMRI with concurrent Ca2+ recording
Authors: Chen Yi , Pais-Roldan Patricia , Chen Xuming , Frosz Michael H. , Yu Xin
Published: June 2019

Optical fiber-mediated optogenetic activation and neuronal Ca2+ recording in combination with fMRI provide a multi-modal fMRI platform. Here, we developed an MRI-guided robotic arm (MgRA) as a flexible positioning system with high precision to real-time assist optical fiber brain intervention for multi-modal animal fMRI. Besides the ex vivo precision evaluation, we present the highly reliable brain activity patterns in the projected basal forebrain regions upon MgRA-driven optogenetic stimulation in the lateral hypothalamus. Also, we show the step-wise optical fiber targeting thalamic nuclei and map the region-specific functional connectivity with whole-brain fMRI accompanied by simultaneous calcium recordings to specify its circuit-specificity. The MgRA also guides the real-time microinjection to specific deep brain nuclei, which is demonstrated by an Mn-enhanced MRI method. The MgRA represents a clear advantage over the standard stereotaxic-based fiber implantation and opens a broad avenue to investigate the circuit-specific functional brain mapping with the multi-modal fMRI platform.
Feather moult and bird appearance are correlated with global warming over the last 200 years
Authors: Kiat Y. , Vortman Y. , Sapir N.
Published: June 2019

Global warming alters various avian phenological processes, including advanced reproduction and migration schedules. In birds, individual appearance is largely determined by plumage, influencing, for example, bird attractiveness, social status and camouflage. Juveniles of most passerine species replace their nest-grown plumage during the first months of life, a process that is called post-juvenile feather moult. Using data from ten natural history collections, we show that the extent of the post-juvenile moult has increased significantly over the last 212 years (1805–2016), a trend that is positively correlated with the temperature of the environment. Therefore, it seems that birds replaced more feathers under warmer conditions, causing juveniles to appear more similar to adult birds. Moreover, in several species, we describe a male–female switch in the extent of moult, with females currently replacing more feathers than males compared to the past. These results demonstrate different biological responses to climate warming by different phenotypes.
Sfrp3 modulates stromal–epithelial crosstalk during mammary gland development by regulating Wnt levels
Authors: Bernascone Ilenia , González Tamara , Barea Maria D. , Carabaña Claudia , Hachimi Mariam , Bosch-Fortea Minerva , Santamaria Silvia , Martin Raquel , Tarnick Julia , Garcia-Sanz Jose A. , Martín-Belmonte Fernando
Published: June 2019

Mammary stroma is essential for epithelial morphogenesis and development. Indeed, postnatal mammary gland (MG) development is controlled locally by the repetitive and bi-directional cross-talk between the epithelial and the stromal compartment. However, the signalling pathways involved in stromal–epithelial communication are not entirely understood. Here, we identify Sfrp3 as a mediator of the stromal–epithelial communication that is required for normal mouse MG development. Using Drosophila wing imaginal disc, we demonstrate that Sfrp3 functions as an extracellular transporter of Wnts that facilitates their diffusion, and thus, their levels in the boundaries of different compartments. Indeed, loss of Sfrp3 in mice leads to an increase of ductal invasion and branching mirroring an early pregnancy state. Finally, we observe that loss of Sfrp3 predisposes for invasive breast cancer. Altogether, our study shows that Sfrp3 controls MG morphogenesis by modulating the stromal-epithelial cross-talk during pubertal development.
Modeling the electrical resistivity of polymer composites with segregated structures
Authors: Park Sung-Hoon , Hwang Jinyoung , Park Gyeong-Su , Ha Ji-Hwan , Zhang Minsu , Kim Dongearn , Yun Dong-Jin , Lee Sangeui , Lee Sang Hyun
Published: June 2019

Hybrid carbon nanotube composites with two different types of fillers have attracted considerable attention for various advantages. The incorporation of micro-scale secondary fillers creates an excluded volume that leads to the increase in the electrical conductivity. By contrast, nano-scale secondary fillers shows a conflicting behavior of the decreased electrical conductivity with micro-scale secondary fillers. Although several attempts have been made in theoretical modeling of secondary-filler composites, the knowledge about how the electrical conductivity depends on the dimension of secondary fillers was not fully understood. This work aims at comprehensive understanding of the size effect of secondary particulate fillers on the electrical conductivity, via the combination of Voronoi geometry induced from Swiss cheese models and the underlying percolation theory. This indicates a transition in the impact of the excluded volume, i.e., the adjustment of the electrical conductivity was measured in cooperation with loading of second fillers with different sizes.
IκBζ facilitates protective immunity against Salmonella infection via Th1 differentiation and IgG production
Authors: Ahn Jae-Hee , Cho Jaewon , Kwon Bo-Eun , Lee Geun-Shik , Yoon Sung-il , Kang Seung Goo , Kim Pyeung-Hyeun , Kweon Mi-Na , Yang Hyungjun , Vallance Bruce A. , Kim Young-In , Chang Sun-Young , Ko Hyun-Jeong
Published: June 2019

Inhibitor of kappa B (IκB)-ζ transcription is rapidly induced by stimulation with TLR ligands and IL-1. Despite high IκBζ expression in inflammation sites, the association of IκBζ with host defence via systemic immune responses against bacterial infection remains unclear. Oral immunisation with a recombinant attenuated Salmonella vaccine (RASV) strain did not protect IκBζ-deficient mice against a lethal Salmonella challenge. IκBζ-deficient mice failed to produce Salmonella LPS-specific IgG, especially IgG2a, although inflammatory cytokine production and immune cell infiltration into the liver increased after oral RASV administration. Moreover, IκBζ-deficient mice exhibited enhanced splenic germinal centre reactions followed by increased total IgG production, despite IκBζ-deficient B cells having an intrinsic antibody class switching defect. IκBζ-deficient CD4+ T cells poorly differentiated into Th1 cells. IFN-γ production by CD4+ T cells from IκBζ-deficient mice immunised with RASV significantly decreased after restimulation with heat-killed RASV in vitro, suggesting that IκBζ-deficient mice failed to mount protective immune responses against Salmonella infection because of insufficient Th1 and IgG production. Therefore, IκBζ is crucial in protecting against Salmonella infection by inducing Th1 differentiation followed by IgG production.
An integration-to-bound model of decision-making that accounts for the spectral properties of neural data
Authors: Guevara Erra Ramón , Arbotto Marco , Schurger Aaron
Published: June 2019

Integration-to-bound models are among the most widely used models of perceptual decision-making due to their simplicity and power in accounting for behavioral and neurophysiological data. They involve temporal integration over an input signal (“evidence”) plus Gaussian white noise. However, brain data shows that noise in the brain is long-term correlated, with a spectral density of the form 1/fα (with typically 1 < α < 2), also known as pink noise or ‘1/f’ noise. Surprisingly, the adequacy of the spectral properties of drift-diffusion models to electrophysiological data has received little attention in the literature. Here we propose a model of accumulation of evidence for decision-making that takes into consideration the spectral properties of brain signals. We develop a generalization of the leaky stochastic accumulator model using a Langevin equation whose non-linear noise term allows for varying levels of autocorrelation in the time course of the decision variable. We derive this equation directly from magnetoencephalographic data recorded while subjects performed a spontaneous movement-initiation task. We then propose a nonlinear model of accumulation of evidence that accounts for the ‘1/f’ spectral properties of brain signals, and the observed variability in the power spectral properties of brain signals. Furthermore, our model outperforms the standard drift-diffusion model at approximating the empirical waiting time distribution.
Randomly weighted receptor inputs can explain the large diversity of colour-coding neurons in the bee visual system
Authors: Vasas Vera , Peng Fei , MaBouDi HaDi , Chittka Lars
Published: June 2019

True colour vision requires comparing the responses of different spectral classes of photoreceptors. In insects, there is a wealth of data available on the physiology of photoreceptors and on colour-dependent behaviour, but less is known about the neural mechanisms that link the two. The available information in bees indicates a diversity of colour opponent neurons in the visual optic ganglia that significantly exceeds that known in humans and other primates. Here, we present a simple mathematical model for colour processing in the optic lobes of bees to explore how this diversity might arise. We found that the model can reproduce the physiological spectral tuning curves of the 22 neurons that have been described so far. Moreover, the distribution of the presynaptic weights in the model suggests that colour-coding neurons are likely to be wired up to the receptor inputs randomly. The perceptual distances in our random synaptic weight model are in agreement with behavioural observations. Our results support the idea that the insect nervous system might adopt partially random wiring of neurons for colour processing.
A unified complex index to characterize two types of ENSO simultaneously
Authors: Zhang Zhiyuan , Ren Baohua , Zheng Jianqiu
Published: June 2019

It is widely considered the El Nino-South Oscillation (ENSO) has several different types which can be simply classified as eastern Pacific (EP) type and central Pacific (CP) type. However, indices proposed so far can only characterize one single type of ENSO. In this paper, we develop a unified index which can characterize two types of ENSO simultaneously. The new index named as unified complex ENSO index (UCEI) is defined in the complex plane whose real part is NINO3 + NINO4 and imagine part is NINO3-NINO4. The modulus (r) and quadrants (θ) represent the ENSO strength and the ENSO types, respectively. Apart from the EP and CP types, the UCEI could further distinguish the MIX type of ENSO. Besides, the UCEI can capture the type-transforming processes within one ENSO event. Applying UCEI on historical events from 1950 to 2017 demonstrates the new index could be a very useful tool for the research of different types of ENSO.
Promoter activity of ORF-less gene cassettes isolated from the oral metagenome
Authors: Tansirichaiya Supathep , Mullany Peter , Roberts Adam P.
Published: June 2019

Integrons are genetic elements consisting of a functional platform for recombination and expression of gene cassettes (GCs). GCs usually carry promoter-less open reading frames (ORFs), encoding proteins with various functions including antibiotic resistance. The transcription of GCs relies mainly on a cassette promoter (PC), located upstream of an array of GCs. Some integron GCs, called ORF-less GCs, contain no identifiable ORF with a small number shown to be involved in antisense mRNA mediated gene regulation. In this study, the promoter activity of ORF-less GCs, previously recovered from the oral metagenome, was verified by cloning them upstream of a gusA reporter, proving they can function as a promoter, presumably allowing bacteria to adapt to multiple stresses within the complex physico-chemical environment of the human oral cavity. A bi-directional promoter detection system was also developed allowing direct identification of clones with promoter-containing GCs on agar plates. Novel promoter-containing GCs were identified from the human oral metagenomic DNA using this construct, called pBiDiPD. This is the first demonstration and detection of promoter activity of ORF-less GCs from Treponema bacteria and the development of an agar plate-based detection system will enable similar studies in other environments.
Soft and flexible piezoelectric smart patch for vascular graft monitoring based on Aluminum Nitride thin film
Authors: Natta L. , Mastronardi V. M. , Guido F. , Algieri L. , Puce S. , Pisano F. , Rizzi F. , Pulli R. , Qualtieri A. , De Vittorio M.
Published: June 2019

Vascular grafts are artificial conduits properly designed to substitute a diseased blood vessel. However prosthetic fail can occur without premonitory symptoms. Continuous monitoring of the system can provide useful information not only to extend the graft’s life but also to optimize the patient’s therapy. In this respect, various techniques have been used, but all of them affect the mechanical properties of the artificial vessel. To overcome these drawbacks, an ultrathin and flexible smart patch based on piezoelectric Aluminum Nitride (AlN) integrated on the extraluminal surface of the prosthesis is presented. The sensor can be conformally wrapped around the external surface of the prosthesis. Its design, mechanical properties and dimensions are properly characterized and optimized in order to maximize performances and to avoid any interference with the graft structure during its activity. The sensorized graft is tested in vitro using a pulsatile recirculating flow system that mimics the physiological and pathological blood flow conditions. In this way, the ability of the device to measure real-time variations of the hemodynamics parameters has been tested. The obtained high sensitivity of 0.012 V Pa−1 m−2, joint to the inherent biocompatibility and non-toxicity of the used materials, demonstrates that the device can successfully monitor the prosthesis functioning under different conditions, opening new perspectives for real-time vascular graft surveillance.
Sentinel lymph node biopsy in cN0 neck management of parotid cancer
Authors: Pan Wenting , Ba Kai , Niu Xingyu , Liu Fei , Fang Qigen
Published: June 2019

Our goals was to evaluate how sentinel lymph node biopsy (SLNB) benefit neck management in patients with parotid cancer. Patients diagnosed with cN0 parotid cancer by preoperative fine needle puncture were prospectively enrolled. The neck status was evaluated by SLNB. If node metastasis was proved by SLNB, a neck dissection of level I–V a was performed, or a wait-and-see policy was conducted for the patient. All related information was extracted and analyzed. Positive SLNB result occurred in 33 (16.7%) patients, and level II metastasis was noted in 100% of the patients. Isolated level III metastasis was noted in 3 (9.1%) patients. During our follow-up with mean time of 49.5 months, 20 patients developed regional recurrence, in which 6 patients had neck dissection as part of their initial management. All the recurrent neck disease was successfully salvaged. Therefore, SLNB was a reliable procedure for neck management in parotid cancer.
How haptophytes microalgae mitigate vitamin B12 limitation
Authors: Nef Charlotte , Jung Sébastien , Mairet Francis , Kaas Raymond , Grizeau Dominique , Garnier Matthieu
Published: June 2019

Vitamin B12(cobalamin) can control phytoplankton development and community composition, with around half of microalgal species requiring this vitamin for growth. B12dependency is determined by the absence of cobalamin-independent methionine synthase and is unrelated across lineages. Despite their important role in carbon and sulphur biogeochemistry, little is known about haptophytes utilization of vitamin B12and their ability to cope with its limitation. Here we report the first evaluation of B12auxotrophy among this lineage based on molecular data of 19 species from 9 families. We assume that all species encode only a B12-dependent methionine synthase, suggesting ubiquitous B12auxotrophy in this phylum. We further address the effect of different B12limitations on the molecular physiology of the model haptophyteTisochrysis lutea. By coupling growth assays in batch and chemostat to cobalamin quantification and expression analyses, we propose that haptophytes use three strategies to cope with B12limitation. Haptophytes may assimilate dissolved methionine, finely regulate genes involved in methionine cycle and B12transport and/or limit B12transport to the mitochondrion. Taken together, these results provide better understanding of B12metabolism in haptophytes and represent valuable data for deciphering how B12-producing bacteria shape the structure and dynamics of this important phytoplankton community.
Enhanced avidity from a multivalent fluorescent antimicrobial peptide enables pathogen detection in a human lung model
Authors: Akram Ahsan R. , Avlonitis Nicolaos , Scholefield Emma , Vendrell Marc , McDonald Neil , Aslam Tashfeen , Craven Thomas H. , Gray Calum , Collie David S. , Fisher Andrew J. , Corris Paul A. , Walsh Timothy , Haslett Christopher , Bradley Mark , Dhaliwal Kevin
Published: June 2019

Rapid in situ detection of pathogens coupled with high resolution imaging in the distal human lung has the potential to provide new insights and diagnostic utility in patients in whom pneumonia is suspected. We have previously described an antimicrobial peptide (AMP) Ubiquicidin (fragment UBI29–41) labelled with an environmentally sensitive fluorophore that optically detected bacteria in vitro but not ex vivo. Here, we describe further chemical development of this compound and demonstrate that altering the secondary structure of the AMP to generate a tri-branched dendrimeric scaffold provides enhanced signal in vitro and ex vivo and consequently allows the rapid detection of pathogens in situ in an explanted human lung. This compound (NBD-UBIdend) demonstrates bacterial labelling specificity for a broad panel of pathogenic bacteria and Aspergillus fumigatus. NBD-UBIdend demonstrated high signal-to-noise fluorescence amplification upon target engagement, did not label host mammalian cells and was non-toxic and chemically robust within the inflamed biological environment. Intrapulmonary delivery of NBD-UBIdend, coupled with optical endomicroscopy demonstrated real-time, in situ detection of bacteria in explanted whole human Cystic Fibrosis lungs.
Histamine modulates hippocampal inflammation and neurogenesis in adult mice
Authors: Saraiva Cláudia , Barata-Antunes Sandra , Santos Tiago , Ferreiro Elisabete , Cristóvão Ana Clara , Serra-Almeida Catarina , Ferreira Raquel , Bernardino Liliana
Published: June 2019

Evidence points to a dual role of histamine in microglia-mediated neuroinflammation, a key pathological feature of several neurodegenerative pathologies. Moreover, histamine has been suggested as a modulator of adult neurogenesis. Herein, we evaluated the effect of histamine in hippocampal neuroinflammation and neurogenesis under physiological and inflammatory contexts. For that purpose, mice were intraperitoneally challenged with lipopolysaccharide (LPS) followed by an intrahippocampal injection of histamine. We showed that histamine per se triggered glial reactivity and induced mild long-term impairments in neurogenesis, reducing immature neurons dendritic volume and complexity. Nevertheless, in mice exposed to LPS (2 mg/Kg), histamine was able to counteract LPS-induced glial activation and release of pro-inflammatory molecules as well as neurogenesis impairment. Moreover, histamine prevented LPS-induced loss of immature neurons complexity as well as LPS-induced loss of both CREB and PSD-95 proteins (essential for proper neuronal activity). Altogether, our results highlight histamine as a potential therapeutic agent to treat neurological conditions associated with hippocampal neuroinflammation and neurodegeneration.
Volumetric optoacoustic tomography enables non-invasive in vivo characterization of impaired heart function in hypoxic conditions
Authors: Ivankovic Ivana , Deán-Ben Xose Luis , Lin Hsiao-Chun Amy , Zhang Zuwen , Trautz Benjamin , Petry Andreas , Görlach Agnes , Razansky Daniel
Published: June 2019

Exposure to chronic hypoxia results in pulmonary hypertension characterized by increased vascular resistance and pulmonary vascular remodeling, changes in functional parameters of the pulmonary vasculature, and right ventricular hypertrophy, which can eventually lead to right heart failure. The underlying mechanisms of hypoxia-induced pulmonary hypertension have still not been fully elucidated while no curative treatment is currently available. Commonly employed pre-clinical analytic methods are largely limited to invasive studies interfering with cardiac tissue or otherwise ex vivo functional studies and histopathology. In this work, we suggest volumetric optoacoustic tomography (VOT) for non-invasive assessment of heart function in response to chronic hypoxia. Mice exposed for 3 consecutive weeks to normoxia or chronic hypoxia were imaged in vivo with heart perfusion tracked by VOT using indocyanide green contrast agent at high temporal (100 Hz) and spatial (200 µm) resolutions in 3D. Unequivocal difference in the pulmonary transit time was revealed between the hypoxic and normoxic conditions concomitant with the presence of pulmonary vascular remodeling within hypoxic models. Furthermore, a beat-to-beat analysis of the volumetric image data enabled identifying and characterizing arrhythmic events in mice exposed to chronic hypoxia. The newly introduced non-invasive methodology for analysis of impaired pulmonary vasculature and heart function under chronic hypoxic exposure provides important inputs into development of early diagnosis and treatment strategies in pulmonary hypertension.
A semi-continuum model of saturation overshoot in one dimensional unsaturated porous media flow
Authors: Kmec Jakub , Fürst Tomáš , Vodák Rostislav , Šír Miloslav
Published: June 2019

A semi-continuum model for fluid flow in saturated-unsaturated porous medium in one spatial dimension is presented. The model is based on well-established physics, measurable parameters and material characteristics. The porous material is characterized by porosity, intrinsic permeability, main wetting and draining branches of the retention curve, and the saturation dependence of the relative permeability. The fluid is characterized by its density and dynamic viscosity. The only physics involved is the mass balance of fluid in porous media together with the Darcy-Buckingham Law for fluid flow in unsaturated porous media. The model is a cellular automaton based on the Macro Modified Invasion Percolation concept of dividing the porous medium into blocks which are not infinitesimal and are assumed to retain the characteristics of a porous medium. The cellular automaton repeats three successive rules: saturation update in each block, pressure update in each block, and flux update between neighboring blocks. The model tracks the evolution of the relative saturation, the fluid capillary pressure, and the fluid flux. The model is shown to reproduce qualitatively and quantitatively all features of one dimensional saturation overshoot behavior reported in the literature.
Cellular morphological changes detected by laser scanning in vivo confocal microscopy associated with clinical outcome in fungal keratitis
Authors: Chidambaram Jaya D. , Prajna Namperumalsamy V. , Palepu Srikanthi , Lanjewar Shruti , Shah Manisha , Elakkiya Shanmugam , Lalitha Prajna , Macleod David , Burton Matthew J.
Published: June 2019

HRT3 in vivo confocal microscopy (IVCM) images may indicate clinical outcome, but few studies have analysed this in fungal keratitis (FK). Adults with FK (diameter ≥3 mm) presenting to Aravind Eye Hospital, India from 2012-3 were enrolled prospectively. IVCM was performed at baseline, days 7, 14 and 21 post-enrolment (+/− 3 days where possible). Specific morphologies were identified in IVCM images by a grader masked to microbiology and clinical outcome (defined as good: healed/improving, or poor: enlarged ulcer, perforation or transplant/glue). Associations with final visit outcome assessed using logistic regression. 143 FK participants were enrolled; 87 had good outcome, 56 had poor outcome. Poor outcomes were associated with stellate interconnected cellular processes with no visible nuclei (OR 2.28, 95% CI: 1.03–5.06, p = 0.043) in baseline IVCM images, and fungal filaments (OR 6.48, 95% CI:2.50–16.78, p < 0.001) or honeycomb distribution of inflammatory cells (OR 5.24, 95% CI: 1.44–19.06, p = 0.012) in final visit images. Fungal filaments (OR 3.61, 95% CI:1.64–7.95, p = 0.001), stromal dendritiform cells (OR 2.88, 95% CI:1.17–7.11, p = 0.022), or stellate cellular processes with no visible nuclei (OR 2.09, 95% CI:1.14–3.82, p = 0.017) were associated with poor outcome if not in baseline but present in final visit images. IVCM can reveal morphological changes associated with clinical outcome.
Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing
Authors: Giau Vo Van , Bagyinszky Eva , Yang Young Soon , Youn Young Chul , An Seong Soo A. , Kim Sang Yun
Published: June 2019

Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia, but the cause of AD remained poorly understood. Many mutations in the amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been reported as the pathogenic causes of early-onset AD (EOAD), which accounts for up to 5% of all AD cases. In this study, we screened familiar/de novo EOAD (n = 67) samples by next-generation sequencing (NGS) of a 50-gene panel, which included causative and possible pathogenic variants linked to neurodegenerative disorders. Remarkably, three missense mutations in PSEN1 (T119I, G209A, and G417A) and one known variant in PSEN2 (H169N) were discovered in 6% of the cases. Additionally, 67 missense mutations in susceptibility genes for late-onset AD were identified, which may be involved in cholesterol transport, inflammatory response, and β-amyloid modulation. We identified 70 additional novel and missense variants in other genes, such as MAPT, GRN, CSF1R, and PRNP, related to neurodegenerative diseases, which may represent overlapping clinical and neuropathological features with AD. Extensive genetic screening of Korean patients with EOAD identified multiple rare variants with potential roles in AD pathogenesis. This study suggests that individuals diagnosed with AD should be screened for other neurodegenerative disease-associated genes. Our findings expand the classic set of genes involved in neurodegenerative pathogenesis, which should be screened for in clinical trials. Main limitation of this study was the absence of functional assessment for possibly and probably pathogenic variants. Additional issues were that we could not perform studies on copy number variants, and we could not verify the segregation of mutations.
Immunostaining in whole-mount lipid-cleared peripheral nerves and dorsal root ganglia after neuropathy in mice
Authors: Bernal L. , Cisneros E. , García-Magro N. , Roza C.
Published: June 2019

Immunohistochemical characterization of primary afferent fibers (intact or after nerve damage) is traditionally performed in thin sections from dorsal root ganglia (DRGs) or in teased fibers, as light scattering in whole-mounts compromises visualization. These procedures are time-consuming, require specific equipment and advanced experimental skills. Lipid-clearing techniques are increasing in popularity, but they have never been used for the peripheral nervous system. We established a modified, inexpensive clearing method based on lipid-removal protocols to make transparent peripheral nerve tissue (inCLARITY). We compared retrograde-labeling and free-floating immunostaining with cryo-sections. Confocal microscopy on whole-mount transparent DRGs showed neurons marked with retrograde tracers applied to experimental neuromas (Retrobeads, Fluoro-ruby, Fluoro-emerald, DiI, and Fluoro-gold). After immunostaining with calcitonin gene-related peptide (peptidergic) or isolectin IB4 (non-peptidergic), nociceptors were visualized. Immunostaining in transparent whole-mount nerves allows simultaneous evaluation of the axotomized branches containing the neuroma and neighboring intact branches as they can be mounted preserving their anatomical disposition and fiber integrity. The goal of our study was to optimize CLARITY for its application in peripheral nerve tissues. The protocol is compatible with the use of retrograde tracers and improves immunostaining outcomes when compared to classical cryo-sectioning, as lack of lipids maximizes antibody penetration within the tissue.
Development of a Novel Ex-vivo 3D Model to Screen Amoebicidal Activity on Infected Tissue
Authors: Guzmán-Delgado Nancy Elena , Carranza-Torres Irma Edith , García-Davis Sara , Rivera Gildardo , Morán-Martínez Javier , Betancourt-Martínez Nadia Denys , Groothuis G. M. M. , de Graaf I. A. M. , Carranza-Rosales Pilar
Published: June 2019

Amoebiasis is a parasitic disease that causes thousands of deaths every year, its adverse effects and resistance to conventional treatments have led to the search of new treatment options, as well as the development of novel screening methods. In this work, we implemented a 3D model of intestine and liver slices from hamsters that were infected ex vivo with virulent E. histolytica trophozoites. Results show preserved histology in both uninfected tissues as well as ulcerations, destruction of the epithelial cells, and inflammatory reaction in intestine slices and formation of micro abscesses, and the presence of amoebae in the sinusoidal spaces and in the interior of central veins in liver slices. The three chemically synthetized compounds T-001, T-011, and T-016, which act as amoebicides in vitro, were active in both infected tissues, as they decreased the number of trophozoites, and provoked death by disintegration of the amoeba, similar to metronidazole. However, compound T-011 induced signs of cytotoxicity to liver slices. Our results suggest that ex vivo cultures of precision-cut intestinal and liver slices represent a reliable 3D approach to evaluate novel amoebicidal compounds, and to simultaneously detect their toxicity, while reducing the number of experimental animals commonly required by other model systems.
Impacts of changes in vegetation on saturated hydraulic conductivity of soil in subtropical forests
Authors: Hao Mingzhuo , Zhang Jinchi , Meng Miaojing , Chen Han Y. H. , Guo Xiaoping , Liu Shenglong , Ye Lixin
Published: June 2019

Saturated hydraulic conductivity (Ks) is one of the most important soil properties that determines water flow behavior in terrestrial ecosystems. However, the Ks of forest soils is difficult to predict due to multiple interactions, such as anthropological and geomorphic processes. In this study, we examined the impacts of vegetation type on Ks and associated mechanisms. We found that Ks differed with vegetation type and soil depth, and the impact of vegetation type on Ks was dependent on soil depth. Ks did not differ among vegetation types at soil depths of 0–10 and 20–30 cm, but was significantly lower in managed forest types (mixed evergreen broad-leaved and coniferous forests, bamboo forests, and tea gardens) than native evergreen broadleaf forests at a depth of 10–20 cm. Boosted regression tree analysis indicated that total porosity, non-capillary porosity, and macro water-stable aggregates were the primary factors that influenced Ks. Our results suggested that vegetation type was a key factor that influences hydraulic properties in subtropical forest soils through the alteration of soil properties, such as porosity and macro water-stable aggregates.
Patients with III and IV category of the Bethesda System under levothyroxine non-suppressive therapy have a lower rate of thyroid malignancy
Authors: Kaliszewski Krzysztof , Diakowska Dorota , Wojtczak Beata , Sutkowski Krzysztof , Knychalski Bartłomiej , Forkasiewicz Zdzisław
Published: June 2019

Thyroid nodules (TNs) assigned to the Bethesda System categories III and IV include numerous clinical characteristics, which increase or decrease the risk of malignancy. However, there are very few data regarding the influence of TSH non-suppressive thyroid hormone therapy (NSTHT) on the risk of malignancy in patients in the aforementioned categories. We assessed the number of patients with thyroid nodules assigned to categories III and IV who take TSH NSTHT and if thyroid hormone therapy is associated with a rate of malignancy. We retrospectively analyzed the medical records of 4,716 individuals and selected 532 (11.28%) patients with Bethesda System category III and IV thyroid nodules. All participants underwent surgery, and histopathological verification was obtained in all cases. In all, 33.1% of individuals with category III and IV thyroid nodules took TSH NSTHT. In patients with category III nodules, application of NSTHT was associated with a lower rate of thyroid cancer (TC), though this observation was not significant (OR = 0.55, p = 0.381). In patients with category IV nodules, we demonstrated a significantly lower rate of TC when NSTHT was applied (OR = 0.44, p = 0.005). In conclusion, the prevalence of patients with Bethesda System category III and IV thyroid nodules who take NSTHT is high. TSH NSTHT significantly decreases a rate of malignancy in category IV, but not category III patients.
Optimal monitor positioning and camera rotation angle for mirror image: overcoming reverse alignment during laparoscopic colorectal surgery
Authors: Miura Susumu , Oshikiri Taro , Miura Yukiko , Takiguchi Gosuke , Takase Nobuhisa , Hasegawa Hiroshi , Yamamoto Masashi , Kanaji Shingo , Matsuda Yoshiko , Yamashita Kimihiro , Matsuda Takeru , Nakamura Tetsu , Suzuki Satoshi , Kakeji Yoshihiro
Published: June 2019

Mirror image is one of the most difficult situations that the assistant surgeon encounters in laparoscopic colorectal surgery. The aim of the present study was to investigate whether task performance with mirror images improves by changing the position of the monitor and the rotation angle of the camera. Twenty-four surgeons performed the task under different conditions: Coaxial image (C), Mirror image (M), Mirror image + Monitor on the left side of participants (M + Mon), Mirror image + Camera rotated 90 degrees to the right (M + Cam), and Mirror image + Monitor on the left side + Camera rotated to the right (M + Mon + Cam) in a training box. The outcome measure was the mean time for completing the task. The mean time for completing the task, in decreasing order, was M (111.4 ± 58.9 seconds) > M + Mon (70.5 ± 29.4 seconds) > M + Cam (47.1 ± 17.1 seconds) > M + Mon + Cam (33.4 ± 10.3 seconds) > C (20.5 ± 3.5 seconds). (multivariable analysis of variance (MANOVA), p = 7.9 × 10−7) Task performance with mirror images improved by changing the monitor positioning and camera rotation angle. This novel method is a simple way to overcome mirror image in laparoscopic colorectal surgery.