bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin B6 Deficiency in Patients With Parkinson Disease Treated With Levodopa/Carbidopa
Authors: Rojo-Sebastián Ana , González-Robles Cristina , García de Yébenes Justo 
Published: September 2020

Objective
The aim of the study was to investigate the role of L-DOPA/carbidopa (CD) therapy on vitamin B6 levels in patients with Parkinson disease (PD).

Methods
This is a cross-sectional retrospective study of vitamin B6 plasma levels in 24 patients with PD treated with L-DOPA/CD for 3 or more years, orally or intraduodenally. Vitamin B6 levels in plasma were measured by ELISA.

Results
All patients treated with intraduodenal L-DOPA/CD (6 of 6) and 13 of 18 patients receiving L-DOPA/CD orally had low plasma levels of vitamin B6. Eight of the 19 patients with low vitamin B6 levels had symptoms of hypovitaminosis B6. Patients with low vitamin B6 had been treated with larger doses of L-DOPA/CD, although the differences did not have statistical significance. Patients treated with intraduodenal L-DOPA/CD have vitamin B6 levels significantly lower than those treated with oral L-DOPA/CD. The variables that most correlated with vitamin B6 levels were the cumulative annual doses of CD (r = −0.36) and L-DOPA (r = −0.33) during the year preceding the study and the time to develop dyskinesias or fluctuations (r = +0.43).

Conclusions
Vitamin B6 could play an important role in PD and its levels seem to be influenced by L-DOPA/CD. Plasma vitamin B6 levels should be monitored in patients receiving high L-DOPA/CD doses, especially those treated with intraduodenal infusion.
In the Kingdom of Triphasic Waves, White Matter Is the Eminence Grise
Authors: Kotchetkov Ivan S. , Freund Brin , Husari Khalil , Kaplan Peter W. 
Published: September 2020

Purpose:
Triphasic waves (TWs) have been associated with multiple conditions and adverse outcomes. This study explores the role of white matter disease (WMD) in the generation of TWs when other common causes associated with these discharges are absent.

Methods:
This is a retrospective case series performed at Johns Hopkins Bayview Medical Center from January 2016 to May 2018, which screened for patients with severe WMD, who had TWs on EEG without the presence of commonly cited provoking factors, including (1) hepatic disease; (2) severe uremia over baseline; (3) the drugs cefepime, ifosfamide, lithium, and baclofen; or (4) global hypoxic–ischemic injury. A control population with no WMD or abnormal electrographic findings outside of theta–delta slowing was also identified.

Results:
Eleven patients were identified. The most common comorbid condition was infection, occurring in 82% of patients. Infections were urinary tract infection (36%), respiratory (27%), and central nervous system (18%). Metabolic abnormalities included glucose aberrations (36%), calcium derangements (18%), and hypernatremia (9%). Structural abnormalities included acute stroke (9%) and chronic central nervous system abscess (9%). All except one patient had one or more structural, metabolic, or infectious abnormalities in addition to WMD. Comorbidities were not statistically different in the control population.

Conclusions:
This is the first series to demonstrate convincingly the presence of TWs in patients with WMD in the absence of commonly cited risk factors. The authors hypothesize that less recognized risk factors of WMD and mild metabolic or infectious abnormalities may be drivers of TWs. With a growing elderly population, the presence of WMD will increase, and treating physicians need to look beyond the common causes of TWs.
Evaluation of a novel 5 day accelerated 1 Hz repetitive transcranial magnetic stimulation protocol in major depression
Authors: Miron Jean-Philippe , Hyde Molly , Fox Linsay , Sheen Jack , Voetterl Helena , Mansouri Farrokh , Zhou Ryan , Dees Sinjin , Mir-Moghtadaei Arsalan , Blumberger Daniel M. , Daskalakis Zafiris J. , Vila-Rodriguez Fidel , Downar Jonathan 
Published: September 2020

BACKGROUNDRepetitive transcranial magnetic stimulation (rTMS) is an effective intervention in major depressive disorder (MDD) but requires daily travel to a treatment clinic over several weeks. Shorter rTMS courses retaining similar effectiveness would thus increase the practicality and scalability of the technique, and therefore its accessibility.OBJECTIVEWe assessed the feasibility of a novel 5 day accelerated 1 Hz rTMS protocol. We hypothesized that this novel rTMS protocol would be safe and well-tolerated while shortening the overall treatment course.METHODSWe conducted a prospective, single-arm, open-label feasibility study. Thirty (30) participants received a one-week (5 days) accelerated (8 sessions per day, 40 sessions total) course of 1 Hz rTMS (600 pulses per session, 50-minute intersession interval) over the right dorsolateral prefrontal cortex (R-DLPFC) using a figure-of-eight coil at 120% of the resting motor threshold (rMT). Depression severity was assessed on the Beck Depression Inventory-II (BDI-II) and 17-item Hamilton Rating Scale for Depression (HRSD-17).RESULTSResponse and remission rates 1 week after treatment were 33.3% and 13.3% respectively and increased to 43.3% and 30.0% at 4 weeks after treatment. No serious adverse events occurred. All participants reported manageable pain levels.CONCLUSION1 Hz rTMS administered 8 times daily for 5 days is safe and well-tolerated. Efficacy at the end of the course was similar to a standard daily course of 1 Hz rTMS, and there appears to be an additional delayed effect. Further validation in a randomized trial is required.ClinicalTrials.gov Identifier:NCT04376697
Ceftazidime Is a Potential Drug to Inhibit SARS-CoV-2 Infection In Vitro by Blocking Spike Protein-ACE2 Interaction
Authors: Lin ChangDong , Li Yue , Yuan MengYa , Huang MengWen , Liu Cui , Du Hui , Pan XingChao , Wen YaTing , Xu Xinyi , Xu Chenqi , Chen JianFeng 
Published: September 2020

SUMMARYCoronavirus Disease 2019 (COVID-19) spreads globally as a sever pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cell entry of SARS-CoV-2 mainly depends on binding of the viral spike (S) proteins to angiotensin converting enzyme 2 (ACE2) on host cells. Therefore, repurposing of known drugs to inhibit S protein-ACE2 interaction could be a quick way to develop effective therapy for COVID-19. Using a high-throughput screening system to investigate the interaction between spike receptor binding domain (S-RBD) and ACE2 extracellular domain, we screened 3581 FDA-approved drugs and natural small molecules and identified ceftazidime as a potent compound to inhibit S-RBD–ACE2 interaction by binding to S-RBD. In addition to significantly inhibit S-RBD binding to HPAEpiC cells, ceftazidime efficiently prevented SARS-CoV-2 pseudovirus to infect ACE2-expressing 293T cells. The inhibitory concentration (IC50) was 113.2 μM, which is far below the blood concentration (over 300 μM) of ceftazidime in patients when clinically treated with recommended dose. Notably, ceftazidime is a drug clinically used for the treatment of pneumonia with minimal side effects compared with other antiviral drugs. Thus, ceftazidime has both anti-bacterial and anti-SARS-CoV-2 effects, which should be the first-line antibiotics used for the clinical treatment of COVID-19.
In vitrotranscription using psychrophilic phage VSW-3 RNA polymerase
Authors: Xia Heng , Jiang Yixin , Cheng Rui , Yu Bingbing , Lu Xueling , Wu Hui , Zhu Bin 
Published: September 2020

ABSTRACTRNA research and applications were underpinned byin vitrotranscription (IVT), while the RNA impurity resulted from the enzymatic reagents severely impede downstream applications. To improve the stability and purity of synthesized RNA we had characterized a novel single-subunit RNA polymerase (RNAP) encoded by a psychrophilic phage VSW-3 from plateau lake to produce RNA at low temperature. The VSW-3 RNAP is capable of carrying outin vitroRNA synthesis at low temperature (4-25°C) to reduce RNA degradation and alleviate the need of costly RNase inhibitor. Compared to routinely used T7 RNAP, VSW-3 RNAP provides comparable yield of transcripts, but is insensitive to class II transcription terminators and synthesizes RNA without redundant 3’ -cis extension. More importantly, through dot-blot detection with the J2 monoclonal antibody, we found that the RNA products synthesized by VSW-3 RNAP contain much lower amount of or virtually no double-stranded RNA (dsRNA) by-products, which are significant in most T7 RNAP products and may cause severe cellular immune response. Combining these advantages, the VSW-3 RNAP is an advantageous enzyme for IVT, especially to produce RNA forin vivouse.
Optimizing automated detection of high frequency oscillations using visual markings does not improve SOZ localization
Authors: Mendoza Trisha , Trevino Casey L. , Shrey Daniel W. , Lin Jack J. , Sen-Gupta Indranil , Lopour Beth A. 
Published: September 2020

AbstractObjectiveHigh frequency oscillations (HFOs) are a biomarker of the seizure onset zone (SOZ) and can be visually or automatically detected. In theory, one can optimize an automated algorithm’s parameters to maximize SOZ localization accuracy; however, there is no consensus on whether or how this should be done. Therefore, we optimized an automated detector using visually identified HFOs and evaluated the impact on SOZ localization accuracy.MethodsWe detected HFOs in intracranial EEG from 20 patients with refractory epilepsy from two centers using (1) unoptimized automated detection, (2) visual identification, and (3) automated detection optimized to match visually detected HFOs.ResultsSOZ localization accuracy based on HFO rate was not significantly different between the three methods. Across patients, visually optimized detector settings varied, and no single set of settings produced universally accurate SOZ localization. Exploratory analysis suggests that, for many patients, detection settings exist that would improve SOZ localization.ConclusionsSOZ localization accuracy was similar for all three methods, was not improved by visually optimizing detector settings, and may benefit from patient-specific parameter optimization.SignificanceVisual HFO marking is laborious, and optimizing automated detection using visual markings does not improve localization accuracy. New patient-specific detector optimization methods are needed.
Engineering, Generation and Preliminary Characterization of a Humanized Porcine Sickle Cell Disease Animal Model
Authors: Franks Tobias M. , Haugabook Sharie J. , Ottinger Elizabeth A. , Vermillion Meghan S. , Pawlik Kevin M. , Townes Tim M. , Rogers Christopher S. 
Published: September 2020

AbstractMouse models of sickle cell disease (SCD) that faithfully switch from fetal to adult hemoglobin (Hb) have been important research tools that accelerated advancement towards treatments and cures for SCD. Red blood cells (RBCs) in these animals sickledin vivo, occluded small vessels in many organs and resulted in severe anemia like in human patients. SCD mouse models have been valuable in advancing clinical translation of some therapeutics and providing a better understanding of the pathophysiology of SCD. However, mouse models vary greatly from humans in their anatomy and physiology and therefore have limited application for certain translational efforts to transition from the bench to bedside. These differences create the need for a higher order animal model to continue the advancement of efforts in not only understanding relevant underlying pathophysiology, but also the translational aspects necessary for the development of better therapeutics to treat or cure SCD. Here we describe the development of a humanized porcine sickle cell model that like the SCD mice, expresses human ɑ-, β− and γ-globin genes under the control of the respective endogenous porcine locus control regions (LCR). We also describe our initial characterization of the SCD pigs and plans to make this model available to the broader research community.
Frequency Spectra and the Color of Cellular Noise
Authors: Gupta Ankit , Khammash Mustafa 
Published: September 2020

AbstractThe invention of the Fourier integral in the 19th century laid the foundation for modern spectral analysis methods. By decomposing a (time) signal into its essential frequency components, these methods uncovered deep insights into the signal and its generating process, precipitating tremendous inventions and discoveries in many fields of engineering, technology, and physical science. In systems and synthetic biology, however, the impact of frequency methods has been far more limited despite their huge promise. This is in large part due to the difficulties encountered in connecting the underlying stochastic reaction network in the living cell, whose dynamics is typically modelled as a continuous-time Markov chain (CTMC), to the frequency content of the observed, distinctively noisy single-cell trajectories. Here we draw on stochastic process theory to develop a spectral theory and computational methodologies tailored specifically to the computation and analysis of frequency spectra of noisy cellular networks. Specifically, we develop a generic method to obtain accurate Padé approximations of the spectrum from a handful of trajectory simulations. Furthermore, for linear networks, we present a novel decomposition result that expresses the frequency spectrum in terms of its sources. Our results provide new conceptual and practical methods for the analysis and design of noisy cellular networks based on their output frequency spectra. We illustrate this through diverse case studies in which we show that the single-cell frequency spectrum facilitates topology discrimination, synthetic oscillator optimization, cybergenetic controller design, systematic investigation of stochastic entrainment, and even parameter inference from single-cell trajectory data.
The Anti-histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits SARS-CoV-2 Infection in Reconstituted Human Nasal Tissue In Vitro
Authors: Konrat Robert , Papp Henrietta , Szijártó Valéria , Gesell Tanja , Nagy Gábor , Madai Mónika , Zeghbib Safia , Kuczmog Anett , Lanszki Zsófia , Helyes Zsuzsanna , Kemenesi Gábor , Jakab Ferenc , Nagy Eszter 
Published: September 2020

ABSTRACTBackgroundThe COVID-19 pandemic is an enormous threat for healthcare systems and economies worldwide that urgently demands effective preventive and therapeutic strategies. Unlike the development of vaccines and new drugs specifically targeting SARS-CoV-2, repurposing of approved or clinically tested drugs can provide an immediate solution.MethodsWe applied a novel computational approach to search among approved and clinically tested drugs from the DrugBank database. Candidates were selected based on Shannon entropy homology and predefined activity profiles of three small molecules with proven anti-SARS-CoV activity and a published data set. Antiviral activity of a predicted drug, azelastine, was testedin vitroin SARS-CoV-2 infection assays with Vero E6 monkey kidney epithelial cells and reconstituted human nasal tissue. The effect on viral replication was assessed by quantification of viral genomes by droplet digital PCR.FindingsThe computational approach with four independent queries identified major drug families, most often and in overlapping fashion anti-infective, anti-inflammatory, anti-hypertensive, anti-histamine and neuroactive drugs. Azelastine, an histamine 1 receptor-blocker, was predicted in multiple screens, and based on its attractive safety profile and availability in nasal formulation, was selected for experimental testing. Azelastine significantly reduced cytopathic effect and SARS-CoV-2 infection of Vero E6 cells with an EC50of ∼6 μM both in a preventive and treatment setting. Furthermore, azelastine in a commercially available nasal spray tested at 5-fold dilution was highly potent in inhibiting viral propagation in SARS-CoV-2 infected reconstituted human nasal tissue.InterpretationsAzelastine, an anti-histamine, available in nasal sprays developed against allergic rhinitis may be considered as a topical prevention or treatment of nasal colonization with SARS-CoV-2. As such, it could be useful in reducing viral spread and prophylaxis of COVID-19. Ultimately, its potential benefit should be proven in clinical studies.Fundingprovided by the Hungarian government to the National Laboratory of Virology and by CEBINA GmbH.
Wasp controls oriented migration of endothelial cells to achieve functional vascular patterning
Authors: Rosa André , Giese Wolfgang , Meier Katja , Alt Silvanus , Klaus-Bergmann Alexandra , Edgar Lowell , Bartels Eireen , Collins Russell , Szymborska-Mell Anna , Coxam Baptiste , Bernabeu Miguel O. , Gerhardt Holger 
Published: September 2020

AbstractEndothelial cell migration and proliferation are essential for the establishment of a hierarchical organization of blood vessels and optimal distribution of blood. However, how these cellular processes are coordinated remains unknown. Here, using the zebrafish trunk vasculature we show that in future veins endothelial cells proliferate more than in future arteries and migrate preferentially towards neighboring arteries. In future arteries endothelial cells show a biphasic migration profile. During sprouting cells move away from the dorsal aorta, during remodelling cells stop or move towards the feeding aorta. The final morphology of blood vessels is thus established by local proliferation and oriented cell migration to and from neighboring vessels. Additionally, we identify WASp to be essential for this differential migration. Loss of WASp leads to irregular distribution of endothelial cells, substantially enlarged veins and persistent arteriovenous shunting. Mechanistically, we report that WASp drives the assembly of junctional associated actin filaments and is required for junctional expression of PECAM-1. Together, our data identify that functional vascular patterning in the zebrafish trunk utilizes differential cell movement regulated by junctional actin, and that interruption of differential migration may represent a pathomechanism in vascular malformations.
Understanding the photophysics and structural organization of photosynthetic proteins using model lipid membranes assembled from natural plant thylakoids
Authors: Meredith Sophie A. , Yoneda Takuro , Hancock Ashley M. , Connell Simon D. , Evans Stephen D. , Morigaki Kenichi , Adams Peter G. 
Published: September 2020

AbstractThe light-harvesting (LH) biomembranes from photosynthetic organisms perform solar energy absorption and transfer with high efficiency. There is great interest in the nanoscale biophysics of photosynthesis, however, natural membranes are complex and highly curved so can be challenging to study. Here we present model photosynthetic “hybrid membranes” assembled from a combination of natural LH membranes and synthetic lipids deposited into a patterned polymerized lipid template on glass. This arrangement offers many advantages over previous model systems including: a sufficiently complex mixture of natural proteins to mimic the biological processes, a modular self-assembly mechanism, and a stabilizing template promoting the formation of supported lipid bilayers from complex natural membranes with high protein content (that would not otherwise form). These hybrid membranes can be used as a platform to delineate the complex relationship between LH energy pathways and membrane organization. Atomic force microscopy and fluorescence lifetime microscopy revealed that hybrid membranes have an elongated fluorescence lifetime (∼4 ns) compared to native membranes (∼0.5 ns), a direct consequence of reduced protein density and an uncoupling of protein-protein interactions. We observed the real time self-assembly and migration of LH proteins from natural membrane extracts into the hybrid membranes and monitored the photophysical state of the membranes at each stage. Finally, experiments utilizing our hybrid membranes suggest that assays currently used in the photosynthesis community to test the electron transfer activity of Photosystem II may have non-specific interactions with other proteins, implying that new methods are needed for reliable quantification of electron transfers in photosynthesis.
Gpr125 identifies myoepithelial progenitors at tips of lacrimal ducts and is essential for tear film
Authors: Spina Elena , Handlin Rebecca , Simundza Julia , Incassati Angela , Faiq Muneeb , Sainulabdeen Anoop , Chan Kevin C , Cowin Pamela 
Published: September 2020

AbstractGpr125, encoded byAdgra3, is an orphan adhesion G-protein coupled receptor (aGPCR) implicated in modulating Wnt signaling and planar polarity. Here we establish both physiological and pathological roles for Gpr125. We show that mice lacking Gpr125 or its signaling domains display an ocular phenotype with many hallmarks of human dry eye syndrome. These include squinting, abnormal lacrimation, mucus accumulation, swollen eyelids and inflammatory infiltration of lacrimal and meibomian glands. Utilizing a Gpr125-β-gal reporter and scRNAseq, we identify Gpr125 expression in a discrete population of cells located at the tips of migrating embryonic lacrimal ducts. By lineage tracing we show these cells function as progenitors of the adult lacrimal myoepithelium. Beyond defining an essential role for Gpr125 in tear film and identifying its utility as a marker of lacrimal progenitors, this study implicates Gpr125 in the etiology of blepharitis and dry eye syndrome, and defines novel animal models of these common maladies.
Heterogeneity in collective endothelial cell behavior is a driver of arterio-venous remodeling
Authors: Jiang Keyi , Pichol-Thievend Cathy , Neufeld Zoltan , Francois Mathias 
Published: September 2020

AbstractDuring vascular development, arteries and veins form in a stepwise process that combines vasculogenesis and sprouting angiogenesis. Despite extensive data on the mechanisms governing blood vessel assembly at the single cell level, little is known about how cell populations migrate in a finely tuned and coordinated manner, and distribute precisely between arteries and veins. Here, we use an endothelial-specific zebrafish reporter,arteriobow, to label small cohorts of arterial cells and trace their progeny from the initial events of vasculogenesis through the process of arterio-venous remodeling. We reveal that the genesis of both arteries and veins relies on the coordination of ten types of collective cell behaviors originating from discrete endothelial cell clusters. Within these behavioral categories, we identify a heterogeneity of collective cell dynamics specific to either arterial or venous remodeling. Using pharmacological blockade, we further show that factors known to control vascular patterning such as cell-intrinsic Notch signaling and cell-extrinsic blood flow, potentially act as regulators by coordinating endothelial cohorts behavior, which in turn instructs the future territory of arterio-venous remodeling.