bluuebunny/crossref_metadata_2025 huggingface dataset:
Prophylactic pacemaker placement at first signs of conduction disease in Kearns–Sayre syndrome
Authors: Trivedi Mira , Goldstein Amy , Arora Gaurav
Published: October 2018

Cardiac conduction disease affects patients with Kearns–Sayre syndrome. We report a young asymptomatic patient with Kearns–Sayre syndrome with abnormal conduction on electrocardiogram and Holter monitor, although not advanced atrioventricular block. She underwent prophylactic pacemaker placement, and rapidly developed complete atrioventricular block, which resulted in 100% ventricular pacing. It may be reasonable to consider prophylactic pacemaker implantation in patients with Kearns–Sayre syndrome with evidence of cardiac conduction disease even without overt atrioventricular block given its unpredictable progression to complete atrioventricular block.
CME: Mepolizumab, ein weiterer Baustein der individualisierten Therapie des schweren Asthma bronchiale
Authors: Platzer Sigrid , Fehr Thomas , Latshang Tsogyal
Published: October 2018

Zusammenfassung. Die herausfordernde Therapie eines schweren, unkontrollierbaren Asthma bronchiale hat primär eine ausreichende Symptomkontrolle und die Minimierung der Exazerbationsrate zum Ziel. Ist die Symptomkontrolle trotz ausgebauter medikamentöser Therapie nur sehr schwer zu erreichen, kann anstatt der nebenwirkungsreichen Kortikosteroidtherapie die Indikation für Biologika gestellt werden. Ziel dieses Artikels ist es, diese verschiedenen Asthma-Therapiepfade aufzuzeigen, Diagnosekriterien, aber auch praktische Erfahrungen durch deren Anwendung bei Patienten zu beschreiben.
Akute Effekte von TH4- Brustwirbelsäulenmobilisations­techniken auf das sympathische Nervensystem – eine Cross-over-Machbarkeitsstudie
Authors: Tal Amir , Taeymans Jan , Karstens Sven , Clijsen Ron , Clarys Peter , Rogan Slavko
Published: October 2018

Zusammenfassung. Empirische Erkenntnisse über Effekte auf das sympathische Nervensystem bei Brustwirbelsäulenmobilisationen auf Höhe TH4 sind bis heute kaum vorhanden. Das primäre Ziel dieser Machbarkeitsstudie war, Adhärenzrate, Sicherheit und Untersuchungsverfahren und -durchführung zu evaluieren. Sekundär wurde der akute Effekt auf das sympathische Nervensystem der Mobilisationen nach anterior bzw. posterior an sechs gesunden Probanden an zwei aufeinanderfolgenden Tagen analysiert und interpretiert. Die Machbarkeit dieser Studie konnte gezeigt werden. Die Mobilisationen verursachten keine Beschwerden. Eine Tendenz zur Reduzierung der Herzfrequenz konnte für eine Brustwirbelsäulenmobilisation mit Schub nach anterior nachgewiesen werden.
An Event on Simultaneous Amplification of Exohiss and Chorus Waves Associated With Electron Density Enhancements
Authors: Zhu Hui , Shprits Yuri Y. , Chen Lunjin , Liu Xu , Kellerman Adam C.
Published: October 2018

Whistler mode exohiss are the structureless hiss waves observed outside the plasmapause with featured equatorward Poynting flux. An event of the amplification of exohiss as well as chorus waves was recorded by Van Allen Probes during the recovery phase of a weak geomagnetic storm. Amplitudes of both types of the waves showed a significant increase at the regions of electron density enhancements. It is found that the electrons resonant with exohiss and chorus showed moderate pitch angle anisotropies. The ratio of the number of electrons resonating with exohiss to total electron number presented in‐phase correlation with density variations, which suggests that exohiss can be amplified due to electron density enhancement in terms of cyclotron instability. The calculation of linear growth rates further supports above conclusion. We suggest that exohiss waves have potential to become more significant due to the background plasma fluctuation.
A Hybrid ETAS‐Coulomb Approach to Forecast Spatiotemporal Aftershock Rates
Authors: Reverso T. , Steacy S. , Marsan D.
Published: October 2018

Aftershock sequences are an ideal testing ground for operational earthquake forecasting models as they contain relatively large numbers of earthquakes clustered in time and space. To date, most successful forecast models have been statistical, building on empirical observations of aftershock decay with time and earthquake size frequency distributions. Another approach is to include Coulomb stress changes from the mainshock which influence the spatial location of the aftershocks although these models have generally not performed as well as the statistical ones. Here we develop a new hybrid Epidemic‐Type Aftershock Sequence (ETAS)/Coulomb model which attempts to overcome the limitations of its predecessors by redistributing forecast rate from negatively to positively stressed regions based on observations in the model learning period of the percentage of events occurring in those positively stressed regions. We test this model against the 1992 Landers aftershock sequence using three different ETAS kernels and five different models for slip in the Landers earthquake. We also consider two variations of rate redistribution, one based on a fixed value and the other variable depending on the percentage of aftershocks observed in positively stressed Coulomb regions during the learning period. We find that the latter model performs at least as well as ETAS on its own in all tests and better than ETAS in 14 of 15 tests in which we forecast successive 24‐hr periods. Our results suggest that including Coulomb stress changes can improve operational earthquake forecasting models.
A Variational Approach to Data Assimilation in the Solar Wind
Authors: Lang Matthew , Owens Mathew J.
Published: October 2018

Variational data assimilation (DA) has enabled huge improvements in the skill of operational weather forecasting. In this study, we use a simple solar‐wind propagation model to develop the first solar‐wind variational DA scheme. This scheme enables solar‐wind observations far from the Sun, such as at 1 AU, to update and improve the inner‐boundary conditions of the solar wind model (at 30 solar radii). In this way, observational information can be used to improve estimates of the near‐Earth solar wind, even when the observations are not directly downstream of the Earth. Using controlled experiments with synthetic observations, we demonstrate this method's potential to improve solar wind forecasts, though the best results are achieved in conjunction with accurate initial estimates of the solar wind. The variational DA scheme is also applied to Solar‐Terrestrial Relations Observatory (STEREO) in situ observations using initial solar wind conditions supplied by a coronal model of the observed photospheric magnetic field. We consider the period October 2010 to October 2011, when the STEREO spacecraft were approximately 80∘ ahead/behind Earth in its orbit. For 12 of 13 Carrington Rotations, assimilation of STEREO data improves the near‐Earth solar wind estimate over the nonassimilated state, with a 18.4% reduction in the root mean square error. The largest gains are made by the DA during times when the steady‐state assumption of the coronal models breaks down. While applying this pure variational approach to complex solar‐wind models is technically challenging, we discuss hybrid DA approaches which are simpler to implement and may retain many of the advantages demonstrated here.
Space Weather Events, Hurricanes, and Earthquakes in Mexico in September 2017
Authors: Gonzalez‐Esparza J. A. , Sergeeva M. A. , Corona‐Romero P. , Mejia‐Ambriz J. C. , Gonzalez L. X. , De la Luz V. , Aguilar‐Rodriguez E. , Rodriguez M. , Romero‐Hernández E.
Published: October 2018

In the interval of 4–10 September 2017, the Sun presented multiple solar flares from active region AR 2673. There were also coronal mass ejections that interacted with the Earth's magnetosphere. This solar activity produced several space weather events. These events were observed with ground‐based instruments of the Mexican Space Weather Service. The Mexican Array RadioTelescope detected highly perturbed solar transits associated with Type I radio emissions from active regions. The Compact Astronomical Low‐frequency, Low‐cost Instrument for Spectroscopy in Transportable Observatories‐Mexican Array RadioTelescope station detected several radio bursts including a Type III associated with the X8.2 flare on 10 September. The magnetometer detected variations reaching a regional K index of 8.3 during the geomagnetic storm. The ionosphere over Mexico was disturbed by different space weather phenomena with the dominant effects of the geomagnetic storm. We used total electron content data to study latitudinal and longitudinal ionospheric effects in this interval. The cosmic rays monitor detected a Forbush decrease associated also with the geomagnetic storm. This low‐latitude instrumental network in Mexico allowed estimating the regional response to space weather events. Coincidentally with the space weather events referred above, there were also two other types of natural hazards affecting the country at that moment, the hurricane Katia category 2 in the Gulf of Mexico, and two major earthquakes (7 and 19 September 2018). The conjunction of these natural phenomena were close to creating a worst‐case scenario in terms of civil protection reaction.
Clinical Features Associated with Survival Outcome in African-American Patients with Hepatocellular Carcinoma
Authors: Estevez Jacqueline , Yang Ju Dong , Leong Jennifer , Nguyen Pauline , Giama Nasra H. , Zhang Ning , Ali Hamdi A. , Lee Mei-Hsuan , Cheung Ramsey , Roberts Lewis , Schwartz Myron , Nguyen Mindie H.
Published: October 2018

BACKGROUND:

African-Americans (AA) have a higher incidence of hepatocellular carcinoma (HCC) and lower survival. We characterized survival rates and clinical features associated with survival in AA vs. Caucasians with HCC over the past two decades.

METHODS:

HCC patients from three US medical centers were matched by year of diagnosis (1991–2016): AA (n = 578)/Caucasian (n = 578) and placed in one of two groups—HCC diagnosed prior to 2010 or 2010 and after. Data were obtained from chart review and the National Death Index. Multivariate and survival analysis controlling for key predictors were conducted.

RESULTS:

Prior to 2010, there was no difference in survival between Caucasians and AA (p = 0.61). After 2010, AA patients had poorer survival compared to Caucasians (35% vs. 44%, respectively, p = 0.044). Over time, survival improved for Caucasians (32% before 2010 vs. 44% after 2010, p = 0.003), but not AA (36% vs. 35%, p = 0.50). AA on presentation (in the after 2010 cohort) were more likely to have BCLC (Barcelona Clinic Liver Cancer) stage C (24% vs. 15%, p = 0.010) and less likely to receive treatment (85% vs. 93%, p = 0.002) compared to matched Caucasians. BCLC beyond stage A (aHR: 1.75, 95% CI: 1.26–2.43, p = 0.001) and child’s class C (aHR 2.05, 95% CI: 1.23–3.41, p = 0.006) were the strongest predictors of mortality, while race was not.

CONCLUSIONS:

African-Americans presented with more advanced HCC and had poorer survival compared to Caucasians after 2010. Tumor stage was an independent predictor of mortality, but ethnicity was not. Further efforts are needed to improve early HCC diagnosis for AA.
Safety and Tolerability of Accelerated Infliximab Infusions in Patients With Inflammatory Bowel Disease
Authors: Ma Danning , Wong Wendy , Aviado Jeremie , Rodriguez Cesar , Wu Helen
Published: October 2018

INTRODUCTION:

Infliximab for inflammatory bowel disease (IBD) is FDA-approved to be administered 2 h or more. We adopted a new protocol to infuse infliximab over 1 h and in this study, we aimed to determine the safety of a 1-h infusion.

METHODS:

This retrospective cohort included adult IBD patients who received infliximab between June and December 2017 and compared reaction rates of 1-h maintenance infusions to that of 2-h maintenance infusions.

RESULTS:

A total of 551 infusions were administered to 179 patients. The infusion groups demonstrated no significant differences in reaction rates.

CONCLUSIONS:

Infliximab infusion over 1 h is well-tolerated.
Transgenic overexpression of furin increases epileptic susceptibility
Authors: Yang Yi , He Miaoqing , Tian Xin , Guo Yi , Liu Feng , Li Yun , Zhang Haiqing , Lu Xi , Xu Demei , Zhou Ruijiao , Ma Yuanlin , Wang Wei , Chen Guojun , Hu Yida , Wang Xuefeng
Published: October 2018

The proprotein convertase Furin plays crucial roles in the pathology of many diseases. However, the specific role of furin in epilepsy remains unclear. In our study, furin protein was increased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. The furin transgenic (TG) mice showed increased susceptibility to epilepsy and heightened epileptic activity compared with wild-type (WT) mice. Conversely, lentivirus-mediated knockdown of furin restrained epileptic activity. Using whole-cell patch clamp, furin knockdown and overexpression influenced neuronal inhibitory by regulating postsynaptic gamma-aminobutyric acid A receptor (GABAAR)-mediated synaptic transmission. Importantly, furin influenced the expression of GABAAR β2/3 membrane and total protein in epileptic mice by changing transcription level of GABAAR β2/3, not the protein degradation. These results reveal that furin may regulate GABAAR-mediated inhibitory synaptic transmission by altering the transcription of GABAAR β2/3 subunits in epilepsy; this finding could provide new insight into epilepsy prevention and treatment.
Aberrant activation of non-coding RNA targets of transcriptional elongation complexes contributes to TDP-43 toxicity
Authors: Chung Chia-Yu , Berson Amit , Kennerdell Jason R. , Sartoris Ashley , Unger Travis , Porta Sílvia , Kim Hyung-Jun , Smith Edwin R. , Shilatifard Ali , Van Deerlin Vivianna , Lee Virginia M.-Y. , Chen-Plotkin Alice , Bonini Nancy M.
Published: October 2018

TDP-43 is the major disease protein associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-TDP). Here we identify the transcriptional elongation factor Ell—a shared component of little elongation complex (LEC) and super elongation complex (SEC)—as a strong modifier of TDP-43-mediated neurodegeneration. Our data indicate select targets of LEC and SEC become upregulated in the fly ALS/FTLD-TDP model. Among them, U12 snRNA and a stress-induced long non-coding RNA Hsrω, functionally contribute to TDP-43-mediated degeneration. We extend the findings of Hsrω, which we identify as a chromosomal target of TDP-43, to show that the human orthologue Sat III is elevated in a human cellular disease model and FTLD-TDP patient tissue. We further demonstrate an interaction between TDP-43 and human ELL2 by co-immunoprecipitation from human cells. These findings reveal important roles of Ell-complexes LEC and SEC in TDP-43-associated toxicity, providing potential therapeutic insight for TDP-43-associated neurodegeneration.
Discovery of RNA-binding proteins and characterization of their dynamic responses by enhanced RNA interactome capture
Authors: Perez-Perri Joel I. , Rogell Birgit , Schwarzl Thomas , Stein Frank , Zhou Yang , Rettel Mandy , Brosig Annika , Hentze Matthias W.
Published: October 2018

Following the realization that eukaryotic RNA-binding proteomes are substantially larger than anticipated, we must now understand their detailed composition and dynamics. Methods such as RNA interactome capture (RIC) have begun to address this need. However, limitations of RIC have been reported. Here we describe enhanced RNA interactome capture (eRIC), a method based on the use of an LNA-modified capture probe, which yields numerous advantages including greater specificity and increased signal-to-noise ratios compared to existing methods. In Jurkat cells, eRIC reduces the rRNA and DNA contamination by >10-fold compared to RIC and increases the detection of RNA-binding proteins. Due to its low background, eRIC also empowers comparative analyses of changes of RNA-bound proteomes missed by RIC. For example, in cells treated with dimethyloxalylglycine, which inhibits RNA demethylases, eRIC identifies m6A-responsive RNA-binding proteins that escape RIC. eRIC will facilitate the unbiased characterization of RBP dynamics in response to biological and pharmacological cues.
Diffusion-limited reactions in dynamic heterogeneous media
Authors: Lanoiselée Yann , Moutal Nicolas , Grebenkov Denis S.
Published: October 2018

Most biochemical reactions in living cells rely on diffusive search for target molecules or regions in a heterogeneous overcrowded cytoplasmic medium. Rapid rearrangements of the medium constantly change the effective diffusivity felt locally by a diffusing particle and thus impact the distribution of the first-passage time to a reaction event. Here, we investigate the effect of these dynamic spatiotemporal heterogeneities onto diffusion-limited reactions. We describe a general mathematical framework to translate many results for ordinary homogeneous Brownian motion to heterogeneous diffusion. In particular, we derive the probability density of the first-passage time to a reaction event and show how the dynamic disorder broadens the distribution and increases the likelihood of both short and long trajectories to reactive targets. While the disorder slows down reaction kinetics on average, its dynamic character is beneficial for a faster search and realization of an individual reaction event triggered by a single molecule.
Dynamic coordination of two-metal-ions orchestrates λ-exonuclease catalysis
Authors: Hwang Wonseok , Yoo Jungmin , Lee Yuno , Park Suyeon , Hoang Phuong Lien , Cho HyeokJin , Yu Jeongmin , Hoa Vo Thi Minh , Shin Minsang , Jin Mi Sun , Park Daeho , Hyeon Changbong , Lee Gwangrog
Published: October 2018

Metal ions at the active site of an enzyme act as cofactors, and their dynamic fluctuations can potentially influence enzyme activity. Here, we use λ-exonuclease as a model enzyme with two Mg2+ binding sites and probe activity at various concentrations of magnesium by single-molecule-FRET. We find that while MgA2+ and MgB2+ have similar binding constants, the dissociation rate of MgA2+ is two order of magnitude lower than that of MgB2+ due to a kinetic-barrier-difference. At physiological Mg2+ concentration, the MgB2+ ion near the 5’-terminal side of the scissile phosphate dissociates each-round of degradation, facilitating a series of DNA cleavages via fast product-release concomitant with enzyme-translocation. At a low magnesium concentration, occasional dissociation and slow re-coordination of MgA2+ result in pauses during processive degradation. Our study highlights the importance of metal-ion-coordination dynamics in correlation with the enzymatic reaction-steps, and offers insights into the origin of dynamic heterogeneity in enzymatic catalysis.
High-performance and scalable on-chip digital Fourier transform spectroscopy
Authors: Kita Derek M. , Miranda Brando , Favela David , Bono David , Michon Jérôme , Lin Hongtao , Gu Tian , Hu Juejun
Published: October 2018

On-chip spectrometers have the potential to offer dramatic size, weight, and power advantages over conventional benchtop instruments for many applications such as spectroscopic sensing, optical network performance monitoring, hyperspectral imaging, and radio-frequency spectrum analysis. Existing on-chip spectrometer designs, however, are limited in spectral channel count and signal-to-noise ratio. Here we demonstrate a transformative on-chip digital Fourier transform spectrometer that acquires high-resolution spectra via time-domain modulation of a reconfigurable Mach-Zehnder interferometer. The device, fabricated and packaged using industry-standard silicon photonics technology, claims the multiplex advantage to dramatically boost the signal-to-noise ratio and unprecedented scalability capable of addressing exponentially increasing numbers of spectral channels. We further explore and implement machine learning regularization techniques to spectrum reconstruction. Using an ‘elastic-D1’ regularized regression method that we develop, we achieved significant noise suppression for both broad (>600 GHz) and narrow (<25 GHz) spectral features, as well as spectral resolution enhancement beyond the classical Rayleigh criterion.
Defective transcription elongation in a subset of cancers confers immunotherapy resistance
Authors: Modur Vishnu , Singh Navneet , Mohanty Vakul , Chung Eunah , Muhammad Belal , Choi Kwangmin , Chen Xiaoting , Chetal Kashish , Ratner Nancy , Salomonis Nathan , Weirauch Matthew T. , Waltz Susan , Huang Gang , Privette-Vinnedge Lisa , Park Joo-Seop , Janssen Edith M. , Komurov Kakajan
Published: October 2018

The nature and role of global transcriptional deregulations in cancers are not fully understood. We report that a large proportion of cancers have widespread defects in mRNA transcription elongation (TE). Cancers with TE defects (TEdeff) display spurious transcription and defective mRNA processing of genes characterized by long genomic length, poised promoters and inducible expression. Signaling pathways regulated by such genes, such as pro-inflammatory response pathways, are consistently suppressed in TEdeff tumors. Remarkably, TEdeff correlates with the poor response and outcome in immunotherapy, but not chemo- or targeted therapy, -treated renal cell carcinoma and metastatic melanoma patients. Forced pharmacologic or genetic induction of TEdeff in tumor cells impairs pro-inflammatory response signaling, and imposes resistance to the innate and adaptive anti-tumor immune responses and checkpoint inhibitor therapy in vivo. Therefore, defective TE is a previously unknown mechanism of tumor immune resistance, and should be assessed in cancer patients undergoing immunotherapy.
A microfabricated nerve-on-a-chip platform for rapid assessment of neural conduction in explanted peripheral nerve fibers
Authors: Gribi Sandra , du Bois de Dunilac Sophie , Ghezzi Diego , Lacour Stéphanie P.
Published: October 2018

Peripheral nerves are anisotropic and heterogeneous neural tissues. Their complex physiology restricts realistic in vitro models, and high resolution and selective probing of axonal activity. Here, we present a nerve-on-a-chip platform that enables rapid extracellular recording and axonal tracking of action potentials collected from tens of myelinated fibers. The platform consists of microfabricated stimulation and recording microchannel electrode arrays. First, we identify conduction velocities of action potentials traveling through the microchannel and propose a robust data-sorting algorithm using velocity selective recording. We optimize channel geometry and electrode spacing to enhance the algorithm reliability. Second, we demonstrate selective heat-induced neuro-inhibition of peripheral nerve activity upon local illumination of a conjugated polymer (P3HT) blended with a fullerene derivative (PCBM) coated on the floor of the microchannel. We demonstrate the nerve-on-a-chip platform is a versatile tool to optimize the design of implantable peripheral nerve interfaces and test selective neuromodulation techniques ex vivo.
Multipartite Entanglement at Finite Temperature
Authors: Gabbrielli Marco , Smerzi Augusto , Pezzè Luca
Published: October 2018

The interplay of quantum and thermal fluctuations in the vicinity of a quantum critical point characterizes the physics of strongly correlated systems. Here we investigate this interplay from a quantum information perspective presenting the universal phase diagram of the quantum Fisher information at a quantum phase transition. Different regions in the diagram are identified by characteristic scaling laws of the quantum Fisher information with respect to temperature. This feature has immediate consequences on the thermal robustness of quantum coherence and multipartite entanglement. We support the theoretical predictions with the analysis of paradigmatic spin systems showing symmetry-breaking quantum phase transitions and free-fermion models characterized by topological phases. In particular we show that topological systems are characterized by the survival of large multipartite entanglement, reaching the Heisenberg limit at finite temperature.
Spine-to-Dendrite Calcium Modeling Discloses Relevance for Precise Positioning of Ryanodine Receptor-Containing Spine Endoplasmic Reticulum
Authors: Breit Markus , Kessler Marcus , Stepniewski Martin , Vlachos Andreas , Queisser Gillian
Published: October 2018

The endoplasmic reticulum (ER) forms a complex endomembrane network that reaches into the cellular compartments of a neuron, including dendritic spines. Recent work discloses that the spine ER is a dynamic structure that enters and leaves spines. While evidence exists that ER Ca2+ release is involved in synaptic plasticity, the role of spine ER morphology remains unknown. Combining a new 3D spine generator with 3D Ca2+ modeling, we addressed the relevance of ER positioning on spine-to-dendrite Ca2+ signaling. Our simulations, which account for Ca2+ exchange on the plasma membrane and ER, show that spine ER needs to be present in distinct morphological conformations in order to overcome a barrier between the spine and dendritic shaft. We demonstrate that RyR-carrying spine ER promotes spine-to-dendrite Ca2+ signals in a position-dependent manner. Our simulations indicate that RyR-carrying ER can initiate time-delayed Ca2+ reverberation, depending on the precise position of the spine ER. Upon spine growth, structural reorganization of the ER restores spine-to-dendrite Ca2+ communication, while maintaining aspects of Ca2+ homeostasis in the spine head. Our work emphasizes the relevance of precise positioning of RyR-containing spine ER in regulating the strength and timing of spine Ca2+ signaling, which could play an important role in tuning spine-to-dendrite Ca2+ communication and homeostasis.
Intraventricular Vortex Interaction between Transmitral Flow and Paravalvular Leak
Authors: Morisawa Daisuke , Falahatpisheh Ahmad , Avenatti Eleonora , Little Stephen H. , Kheradvar Arash
Published: October 2018

Paravalvular leak (PVL) is a complication of transcatheter aortic valve replacement. Despite its marked clinical impact, no previous study has reported how PVL affects the intraventricular fluid dynamics. This study aims to delineate vortex interaction between PVL and transmitral flow and the influence of PVL orifice location on intraventricular fluid dynamics using Echocardiographic Particle Image Velocimetry. Three different conditions of no PVL, anterior PVL and posterior PVL were experimentally studied and clinically compared. Circulation, impulse, kinetic energy (KE) and change in KE (ΔKE) were calculated. As well, vortex formation analyses and streamline description were performed to study vortex interactions. The anterior PVL jet streamed into the LV and interfered with the transmitral flow. Posterior PVL jet formed a large clockwise vortex and collided with transmitral flow, which resulted in flow disturbance. Compared to no PVL condition, average circulation, impulse, KE and ΔKE increased in presence of PVL. In conclusion, we found that PVL jets lead to abnormal vortex formation that interfere with natural advancement of transmitral flow, and negatively affect the LV fluid dynamics parameters. PVL orifice location strongly affects the intraventricular vortex formation, and posterior PVL may have more negative effects compared to anterior PVL.
Sensory attenuation in Parkinson’s disease is related to disease severity and dopamine dose
Authors: Wolpe Noham , Zhang Jiaxiang , Nombela Cristina , Ingram James N. , Wolpert Daniel M. ,   Cam-CAN, Tyler Lorraine K. , Brayne Carol , Bullmore Edward T. , Calder Andrew C. , Cusack Rhodri , Dalgleish Tim , Duncan John , Matthews Fiona E. , Marslen-Wilson William D. , Shafto Meredith A. , Cheung Teresa , Geerligs Linda , McCarrey Anna , Mustafa Abdur , Price Darren , Samu David , Treder Matthias , Tsvetanov Kamen A. , van Belle Janna , Williams Nitin , Bates Lauren , Gadie Andrew , Gerbase Sofia , Georgieva Stanimira , Hanley Claire , Parkin Beth , Troy David , Auer Tibor , Correia Marta , Gao Lu , Green Emma , Henriques Rafael , Allen Jodie , Amery Gillian , Amunts Liana , Barcroft Anne , Castle Amanda , Dias Cheryl , Dowrick Jonathan , Fair Melissa , Fisher Hayley , Goulding Anna , Grewal Adarsh , Hale Geoff , Hilton Andrew , Johnson Frances , Johnston Patricia , Kavanagh-Williamson Thea , Kwasniewska Magdalena , McMinn Alison , Norman Kim , Penrose Jessica , Roby Fiona , Rowland Diane , Sargeant John , Squire Maggie , Stevens Beth , Stoddart Aldabra , Stone Cheryl , Thompson Tracy , Yazlik Ozlem , Dan Barnes  , Dixon Marie , Hillman Jaya , Mitchell Joanne , Villis Laura , Rowe James B.
Published: October 2018

Abnormal initiation and control of voluntary movements are among the principal manifestations of Parkinson’s disease (PD). However, the processes underlying these abnormalities and their potential remediation by dopamine treatment remain poorly understood. Normally, movements depend on the integration of sensory information with the predicted consequences of action. This integration leads to a suppression in the intensity of predicted sensations, reflected in a ‘sensory attenuation’. We examined this integration process and its relation to dopamine in PD, by measuring sensory attenuation. Patients with idiopathic PD (n = 18) and population-derived controls (n = 175) matched a set of target forces applied to their left index finger by a torque motor. To match the force, participants either pressed with their right index finger (‘Direct’ condition) or moved a knob that controlled a motor through a linear potentiometer (‘Slider’ condition). We found that despite changes in sensitivity to different forces, overall sensory attenuation did not differ between medicated PD patients and controls. Importantly, the degree of attenuation was negatively related to PD motor severity but positively related to individual patient dopamine dose, as measured by levodopa dose equivalent. The results suggest that dopamine could regulate the integration of sensorimotor prediction with sensory information to facilitate the control of voluntary movements.
c-Fos induces chondrogenic tumor formation in immortalized human mesenchymal progenitor cells
Authors: Abarrategi Ander , Gambera Stefano , Alfranca Arantzazu , Rodriguez-Milla Miguel A. , Perez-Tavarez Raquel , Rouault-Pierre Kevin , Waclawiczek Alexander , Chakravarty Probir , Mulero Francisca , Trigueros César , Navarro Samuel , Bonnet Dominique , García-Castro Javier
Published: October 2018

Mesenchymal progenitor cells (MPCs) have been hypothesized as cells of origin for sarcomas, and c-Fos transcription factor has been showed to act as an oncogene in bone tumors. In this study, we show c-Fos is present in most sarcomas with chondral phenotype, while multiple other genes are related to c-Fos expression pattern. To further define the role of c-Fos in sarcomagenesis, we expressed it in primary human MPCs (hMPCs), immortalized hMPCs and transformed murine MPCs (mMPCs). In immortalized hMPCs, c-Fos expression generated morphological changes, reduced mobility capacity and impaired adipogenic- and osteogenic-differentiation potentials. Remarkably, immortalized hMPCs or mMPCs expressing c-Fos generated tumors harboring a chondrogenic phenotype and morphology. Thus, here we show that c-Fos protein has a key role in sarcomas and that c-Fos expression in immortalized MPCs yields cell transformation and chondrogenic tumor formation.
Detecting long-lived autodependency changes in a multivariate system via change point detection and regime switching models
Authors: Cabrieto Jedelyn , Adolf Janne , Tuerlinckx Francis , Kuppens Peter , Ceulemans Eva
Published: October 2018

Long-lived simultaneous changes in the autodependency of dynamic system variables characterize crucial events as epileptic seizures and volcanic eruptions and are expected to precede psychiatric conditions. To understand and predict such phenomena, methods are needed that detect such changes in multivariate time series. We put forward two methods: First, we propose KCP-AR, a novel adaptation of the general-purpose KCP (Kernel Change Point) method. Whereas KCP is implemented on the raw data and does not shed light on which parameter changed, KCP-AR is applied to the running autocorrelations, allowing to focus on changes in this parameter. Second, we revisit the regime switching AR(1) approach and propose to fit models wherein only the parameters capturing autodependency differ across the regimes. We perform a simulation study comparing both methods: KCP-AR outperforms regime switching AR(1) when variables are uncorrelated, while the latter is more reliable when multicolinearity is severe. Regime switching AR(1), however, may yield recurrent switches even when the change is long-lived. We discuss an application to psychopathology data where we investigate whether emotional inertia -the autodependency of affective states- changes before a relapse into depression.
Effect of therapy on Quantiferon-Plus response in patients with active and latent tuberculosis infection
Authors: Petruccioli Elisa , Chiacchio Teresa , Vanini Valentina , Cuzzi Gilda , Codecasa Luigi Ruffo , Ferrarese Maurizio , Schininà Vincenzo , Palmieri Fabrizio , Ippolito Giuseppe , Goletti Delia
Published: October 2018

Lack of biomarkers for treatment monitoring is listed among the main requirements for next generation assays, as identified globally among tuberculosis (TB) researchers. In this study, we evaluated in a low TB endemic country such as Italy, the effect of preventive therapy on the results obtained in the QuantiFERON TB Plus (QFT-Plus), in a cohort of subjects with latent TB infection (LTBI) and active TB. We found that TB therapy significantly decreased IFN-γ values and number of responders to TB1- and TB2- peptides stimulation in both LTBI and active TB patients. Stratifying LTBI subjects according to the type of preventive TB therapy used, we found that INH treatment but not INH and RIF significantly decreased IFN-γ production. Stratifying the active TB patients according the microbiological status, we found that TB therapy significantly decreased IFN-γ response to antigen present in QFT-Plus test in patients with clinical diagnosis compared to those with a microbiological diagnosis. In conclusions, we demonstrated that TB therapy decreases IFN-γ level in response to antigen present in QFT-Plus test in LTBI and active TB patients. Future studies are needed to better characterize Mtb-specifc response as a potential marker for monitoring TB therapy and preventive treatment effects.
Structural and functional insights into the interaction and targeting hub TMD0 of the polypeptide transporter TAPL
Authors: Bock Christoph , Löhr Frank , Tumulka Franz , Reichel Katrin , Würz Julia , Hummer Gerhard , Schäfer Lars , Tampé Robert , Joseph Benesh , Bernhard Frank , Dötsch Volker , Abele Rupert
Published: October 2018

The ATP-binding cassette transporter TAPL translocates polypeptides from the cytosol into the lysosomal lumen. TAPL can be divided into two functional units: coreTAPL, active in ATP-dependent peptide translocation, and the N-terminal membrane spanning domain, TMD0, responsible for cellular localization and interaction with the lysosomal associated membrane proteins LAMP-1 and LAMP-2. Although the structure and function of ABC transporters were intensively analyzed in the past, the knowledge about accessory membrane embedded domains is limited. Therefore, we expressed the TMD0 of TAPL via a cell-free expression system and confirmed its correct folding by NMR and interaction studies. In cell as well as cell-free expressed TMD0 forms oligomers, which were assigned as dimers by PELDOR spectroscopy and static light scattering. By NMR spectroscopy of uniformly and selectively isotope labeled TMD0 we performed a complete backbone and partial side chain assignment. Accordingly, TMD0 has a four transmembrane helix topology with a short helical segment in a lysosomal loop. The topology of TMD0 was confirmed by paramagnetic relaxation enhancement with paramagnetic stearic acid as well as by nuclear Overhauser effects with c6-DHPC and cross-peaks with water.
Retinal vascular changes and aqueous humor cytokines changes after aflibercept intravitreal injection in treatment-naïve myopic choroidal neovascularization
Authors: Di Antonio Luca , Toto Lisa , Mastropasqua Alessandra , Brescia Lorenza , Erroi Emanuele , Lamolinara Alessia , Di Nicola Marta , Mastropasqua Leonardo
Published: October 2018

The aim of the study was to assess retinal vascular changes using optical coherence tomography angiography (OCTA) and aqueous humour changes of vascular endothelial growth factor (VEGF) and placental growth factor (PIGF) levels in treatment-naïve myopic choroidal neovascularization (mCNV) after aflibercept intravitreal injection. To explore the correlation between clinical and laboratory parameters. Fifteen eyes of 15 patients with treatment-naïve mCNV underwent 2 intravitreal injections of aflibercept. Main outcome measures were best corrected visual acuity (BCVA), central retinal thickness (CRT) and external limiting membrane (ELM) visualization at OCT, lesion area and leakage at fluorescein angiography (FA), OCTA flow area and selected area at baseline and after the injections. Analysis of VEGF and PlGF in the aqueous humor was performed before each injection in cases and prior to cataract surgery on 10 patients as included as controls. Median BCVA increased from 0.6 to 0.3 logMAR (p < 0.001); CRT decreased from 387.5 to 267 micron (p < 0.001); FA area from 0.8 to 0.5 mm2 and OCTA area from 0.9 to 0.5 mm2 (p = 0.005). PIGF values changed from 1.8 to 1.4 pg/ml (p = 0.019) and VEGF values from 3.4 to 0.5 pg/ml (p = 0.008). A significant correlation was found after treatment between PIGF levels and BCVA (rho = 0.006) and VEGF levels and BCVA (rho = 0.018); between PlGF and CRT (rho = 0.020), PlGF and ELM visualization (rho = 0.002) and PlGF and FA leakage (rho < 0.001). Our results showed a significant reduction of mCNV area after aflibercept in both FA and OCTA measurements; an improvement of BCVA, and a reduction of VEGF and PIGF levels related to inactivity of the disease.
Molecular mechanism of substrate selectivity of the arginine-agmatine Antiporter AdiC
Authors: Krammer Eva-Maria , Gibbons Andrew , Roos Goedele , Prévost Martine
Published: October 2018

The arginine-agmatine antiporter (AdiC) is a component of an acid resistance system developed by enteric bacteria to resist gastric acidity. In order to avoid neutral proton antiport, the monovalent form of arginine, about as abundant as its divalent form under acidic conditions, should be selectively bound by AdiC for transport into the cytosol. In this study, we shed light on the mechanism through which AdiC distinguishes Arg+ from Arg2+ of arginine by investigating the binding of both forms in addition to that of divalent agmatine, using a combination of molecular dynamics simulations with molecular and quantum mechanics calculations. We show that AdiC indeed preferentially binds Arg+. The weaker binding of divalent compounds results mostly from their greater tendency to remain hydrated than Arg+. Our data suggests that the binding of Arg+ promotes the deprotonation of Glu208, a gating residue, which in turn reinforces its interactions with AdiC, leading to longer residence times of Arg+ in the binding site. Although the total electric charge of the ligand appears to be the determinant factor in the discrimination process, two local interactions formed with Trp293, another gating residue of the binding site, also contribute to the selection mechanism: a cation-π interaction with the guanidinium group of Arg+ and an anion-π interaction involving Glu208.
Near theoretical ultra-high magnetic performance of rare-earth nanomagnets via the synergetic combination of calcium-reduction and chemoselective dissolution
Authors: Lee Jimin , Hwang Tae-Yeon , Cho Hong-Baek , Kim Jongryoul , Choa Yong-Ho
Published: October 2018

Rare earth permanent magnets with superior magnetic performance have been generally synthesized through many chemical methods incorporating calcium thermal reduction. However, a large challenge still exists with regard to the removal of remaining reductants, byproducts, and trace impurities generated during the purifying process, which serve as inhibiting intermediates, inducing productivity and purity losses, and a reduction in magnetic properties. Nevertheless, the importance of a post-calciothermic reduction process has never been seriously investigated. Here, we introduce a novel approach for the synthesis of a highly pure samarium-cobalt (Sm-Co) rare earth nanomagnet with near theoretical ultra-high magnetic performance via consecutive calcium-assisted reduction and chemoselective dissolution. The chemoselective dissolution effect of various solution mixtures was evaluated by the purity, surface microstructure, and magnetic characteristics of the Sm-Co. As a result, NH4Cl/methanol solution mixture was only capable of selectively rinsing out impurities without damaging Sm-Co. Furthermore, treatment with NH4Cl led to substantially improved magnetic properties over 95.5% of the Ms for bulk Sm-Co. The mechanisms with regard to the enhanced phase-purity and magnetic performance were fully elucidated based on analytical results and statistical thermodynamics parameters. We further demonstrated the potential application of chemoselective dissolution to other intermetallic magnets.
Off-axis rotor in Enterococcus hirae V-ATPase visualized by Zernike phase plate single-particle cryo-electron microscopy
Authors: Tsunoda Jun , Song Chihong , Imai Fabiana Lica , Takagi Junichi , Ueno Hiroshi , Murata Takeshi , Iino Ryota , Murata Kazuyoshi
Published: October 2018

EhV-ATPase is an ATP-driven Na+ pump in the eubacteria Enterococcus hirae (Eh). Here, we present the first entire structure of detergent-solubilized EhV-ATPase by single-particle cryo-electron microscopy (cryo-EM) using Zernike phase plate. The cryo-EM map dominantly showed one of three catalytic conformations in this rotary enzyme. To further stabilize the originally heterogeneous structure caused by the ATP hydrolysis states of the V1-ATPases, a peptide epitope tag system was adopted, in which the inserted peptide epitope sequence interfered with rotation of the central rotor by binding the Fab. As a result, the map unexpectedly showed another catalytic conformation of EhV-ATPase. Interestingly, these two conformations identified with and without Fab conversely coincided with those of the minor state 2 and the major state 1 of Thermus thermophilus V/A-ATPase, respectively. The most prominent feature in EhV-ATPase was the off-axis rotor, where the cytoplasmic V1 domain was connected to the transmembrane Vo domain through the off-axis central rotor. Furthermore, compared to the structure of ATP synthases, the larger size of the interface between the transmembrane a-subunit and c-ring of EhV-ATPase would be more advantageous for active ion pumping.
Cardiac regeneration following cryoinjury in the adult zebrafish targets a maturation-specific biomechanical remodeling program
Authors: Yu Joseph K. , Sarathchandra Padmini , Chester Adrian , Yacoub Magdi , Brand Thomas , Butcher Jonathan T.
Published: October 2018

Cardiac regeneration post-injury is a tantalizing feature of many lower vertebrates such as fishes and urodeles, but absent in adult humans. Restoration of pumping function is a key endpoint of cardiac regeneration, but very little is known about the biomechanical remodeling process. Here, we quantify and compare the evolution of cellular composition and mechanical stiffness of the zebrafish ventricular myocardium during maturation and following cryoinjury during regeneration to better understand the dynamics of biomechanical remodeling during these two processes. With increasing age, normal myocardial trabecular density and cardiomyocyte fraction increased, while non-myocyte cell fractions decreased. Cell density remained constant during maturation. Cardiomyocyte sarcomeres shortened to a minimum reached at 7.5 months of age, but lengthened with additional age. Concomitantly, ventricular wall stiffness increased up until 7.5 months before plateauing with additional age. Endothelial, myofibroblast/smooth muscle, and cardiomyocyte cell fractions were disrupted following cryoinjury, but were progressively restored to age-specific natural norms by 35 days post infarct (DPI). Infarcted myocardium stiffened immediately following cryoinjury and was a 100-fold greater than non-infarcted tissue by 3 DPI. By 14 DPI, stiffness of the infarcted myocardium had fallen below that of 0 DPI and had completely normalized by 35 DPI. Interestingly, cardiomyocyte sarcomere length increased until 14 DPI, but subsequently shortened to lengths below age-specific natural norms, indicating recovery from a volume overloaded condition. These observations are consistent with the view that regenerating myocardium requires biomechanical stimulation (e.g. strain) to rescue from a volume overloaded condition. Intriguingly, the biomechanical progression of the infarcted adult myocardial wall mirrors that of normal remodeling during aging. The biomechanical progression of the infarcted myocardium targets the values of age-specific norms despite a large divergence in initial conditions. These findings identify a novel biomechanical control of heart regeneration that may orchestrate cellular and tissue level remodeling responses.
Imaging acoustic sources through scattering media by using a correlation full-matrix filter
Authors: Rui Wei , Tao Chao , Liu Xiaojun
Published: October 2018

In the inhomogeneous medium, acoustic scattering is always a fundamental challenge for photoacoustic imaging. We implement a correlation full-matrix filter (CFMF) combing with a time reversal operator to improve the imaging quality of acoustic sources in complex media. The correlation full-matrix filtering process extracts the direct wave component from the detected signal and preserve all the useful information at the same time. A location factor is considered in the time reversal operator to compensate for the image distortion and false contrast caused by the limited-view detection. The numerical simulations demonstrate that the proposed approach can perform good imaging quality with the higher image signal-noise ratio and better resolution in an acoustic scattering environment. This scheme might be applied to improve the photoacoustic imaging for inhomogeneous biological tissues.
Locus Coeruleus as a vigilance centre for active inspiration and expiration in rats
Authors: Magalhães Karolyne S. , Spiller Pedro F. , da Silva Melina P. , Kuntze Luciana B. , Paton Julian F. R. , Machado Benedito H. , Moraes Davi J. A.
Published: October 2018

At rest, inspiration is an active process while expiration is passive. However, high chemical drive (hypercapnia or hypoxia) activates central and peripheral chemoreceptors triggering reflex increases in inspiration and active expiration. The Locus Coeruleus contains noradrenergic neurons (A6 neurons) that increase their firing frequency when exposed to hypercapnia and hypoxia. Using recently developed neuronal hyperpolarising technology in conscious rats, we tested the hypothesis that A6 neurons are a part of a vigilance centre for controlling breathing under high chemical drive and that this includes recruitment of active inspiration and expiration in readiness for flight or fight. Pharmacogenetic inhibition of A6 neurons was without effect on resting and on peripheral chemoreceptors-evoked inspiratory, expiratory and ventilatory responses. On the other hand, the number of sighs evoked by systemic hypoxia was reduced. In the absence of peripheral chemoreceptors, inhibition of A6 neurons during hypercapnia did not affect sighing, but reduced both the magnitude and incidence of active expiration, and the frequency and amplitude of inspiration. These changes reduced pulmonary ventilation. Our data indicated that A6 neurons exert a CO2-dependent modulation of expiratory drive. The data also demonstrate that A6 neurons contribute to the CO2-evoked increases in the inspiratory motor output and hypoxia-evoked sighing.