bluuebunny/crossref_metadata_2025_split huggingface dataset:
Progressive Functional and Neuroretinal Affectation in Patients With Multiple Sclerosis Treated With Fingolimod
Authors: Garcia-Martin Elena , Ruiz de Gopegui Erika , Satue Maria , Gil-Arribas Laura , Jarauta Laura , Ara Jose R. , Martin Jesus , Fernandez Francisco J. , Vilades Elisa , Rodrigo Maria J. 
Published: June 2020

Background:
To evaluate the effect of fingolimod in visual function and neuroretinal structures in patients with multiple sclerosis (MS) for a period of 1 year.

Methods:
This longitudinal and observational cohort study included 78 eyes of 78 patients with MS treated with fingolimod. All subjects were evaluated every 3 months during 12 months and compared with 32 patients treated with interferon beta. All patients were examined for high-contrast and low-contrast (2.5% and 1.25%) visual acuity (VA), contrast sensitivity vision (CSV) (using Pelli–Robson and CSV-1000E tests), color vision (Farnsworth D-15 and L'Anthony D-15 desaturated tests), and retinal structural measurements (retinal nerve fiber layer [RNFL] and ganglion cell layer [GCL] thickness) using optical coherence tomography (OCT) technology.

Results:
Patients with MS treated with fingolimod for a period of 1 year showed significant reduction in 100% and 1.25% contrast VA (P = 0.009 and 0.008, respectively), an alteration of contrast sensitivity and color perception (Pelli–Robson test, CSV-1000E test, Farnsworth D-15 desaturated test, and L'Anthony D-15 desaturated test; P < 0.001), GCL thickness reduction (P = 0.007), and an average macular central thickness increase of 2.6 μm (P = 0.006). Patients with MS treated with interferon beta did not show significant changes in visual function tests neither in macular thickness measurements, but they showed a significant reduction in GCL and RNFL thicknesses. The reduction in neuroretinal structures observed by OCT was significantly higher in the interferon-beta group, but patients treated with fingolimod showed a significant increase in macular central thickness and a reduction in low contrast vision (P < 0.001).

Conclusions:
Patients with MS treated with fingolimod and with no clinically observable macular edema show a significant change in visual function parameters and average macular central thickness increase compared with those treated with interferon beta. These findings are probably due to subclinical macular edema produced by fingolimod, which might be considered as an indicator for pharmacovigilance of sphingosine-1-phosphate inhibitors to be improved.
Cyclotorsion Measurement on Scanning Laser Ophthalmoscopy Imaging Compared With Fundus Photography in Patients With Fourth Nerve Palsy and Healthy Controls: CySLO-IV Study
Authors: Kanku Madeleine S. , Sele Silvano , Held Ulrike , Jaggi Gregor P. , Landau Klara , Traber Ghislaine L. 
Published: June 2020

Background:
The purpose of the study is to evaluate the agreement of the foveopapillary angle (FPA) on conventional fundus photography (c-FPA) with the FPA on scanning laser ophthalmoscopy (SLO) imaging (SLO-FPA) in patients with fourth nerve palsy and healthy controls (HCs).

Methods:
The FPA was measured in both eyes of 25 patients and 25 HCs in synedra View (c-FPA) and with the integrated algorithm of the Heidelberg Spectralis OCT (SLO-FPA). The primary endpoint was the agreement of both measurements. Furthermore, we evaluated the influence of the eye tracker, the influence of fixation on objective torsion, and the FPA cutoff between patients and HCs.

Results:
The mean SLO-FPA in patients (6/25 acquired palsies) was 11.3 ± 3.6° and 6.4 ± 2.1° in HCs. The mean c-FPA was 11.4 ± 4.0° and 5.8 ± 2.2°, respectively. The Bland–Altman plot of c-FPA vs SLO-FPA in patients and HCs shows no systematic bias (mean of −0.28°). Limits of agreement were −6.58 and 6.02°. Using the eye tracker had no systematic effect. There was no evidence for an immediate shift of torsion with change of fixation (24/25 patients and 23/25 HCs). Discrimination between patients and HCs by the SLO-FPA is very good with an area under the curve = 0.92 (95% confidence interval: 0.84–0.99).

Conclusions:
SLO-FPA measurement allows convenient and consistent assessment of objective cyclotorsion. There was no systematic bias in the difference between SLO-FPA and traditional c-FPA; thus, SLO-FPA is a valuable alternative to the commonly used c-FPA. Using the eye tracker is recommended for proper centering of the ring scan.
Idiopathic Intracranial Hypertension: Glymphedema of the Brain
Authors: Nicholson Patrick , Kedra Alice , Shotar Eimad , Bonnin Sophie , Boch Anne-Laure , Shor Natalia , Clarençon Frédéric , Touitou Valérie , Lenck Stephanie 
Published: June 2020

Background:
During the last decade, our understanding of cerebrospinal fluid (CSF) physiology has dramatically improved, thanks to the discoveries of both the glymphatic system and lymphatic vessels lining the dura mater in human brains.

Evidence Acquisition:
We detail the recent basic science findings in the field of CSF physiology and connect them with our current understanding of the pathophysiology of idiopathic intracranial hypertension (IIH).

Results:
Transverse sinus (TS) stenoses seem to play a major causative role in the symptoms of IIH, as a result of a decrease in the pressure gradient between the venous system and the subarachnoid space. However, the intracranial pressure can be highly variable among different patients, depending on the efficiency of the lymphatic system to resorb the CSF and on the severity of TS stenoses. It is likely that there is a subclinical form of IIH and that IIH without papilledema is probably under-diagnosed among patients with chronic migraines or isolated tinnitus.

Conclusions:
IIH can be summarized in the following pathological triad: restriction of the venous CSF outflow pathway—overflow of the lymphatic CSF outflow pathway—congestion of the glymphatic system. To better encompass all the stages of IIH, it is likely that the Dandy criteria need to be updated and that perhaps renaming IIH should be considered.
Saliva sampling is an excellent option to increase the number of SARS CoV2 diagnostic tests in settings with supply shortages
Authors: Moreno-Contreras Joaquín , Espinoza Marco A. , Sandoval-Jaime Carlos , Cantú-Cuevas Marco A. , Barón-Olivares Héctor , Ortiz-Orozco Oscar D. , Muñoz-Rangel Asunción V. , Hernández-de la Cruz Manuel , Eroza-Osorio César M. , Arias Carlos F. , López Susana 
Published: June 2020

AbstractAs part of any plan to lift or ease the confinement restrictions that are in place in many different countries, there is an urgent need to increase the capacity of laboratory testing for SARS CoV-2. Detection of the viral genome through RT-qPCR is the golden standard for this test, however, the high demand of the materials and reagents needed to sample individuals, purify the viral RNA, and perform the RT-qPCR test has resulted in a worldwide shortage of several of these supplies. Here, we show that directly lysed saliva samples can serve as a suitable source for viral RNA detection that is cheaper and can be as efficient as the classical protocol that involves column purification of the viral RNA. In addition, it surpasses the need for swab sampling, decreases the risk of the healthcare personnel involved in this process, and accelerates the diagnostic procedure.
Increased axon initial segment length results in increased Na+currents in spinal motoneurones at symptom onset in the G127X SOD1 mouse model of Amyotrophic Lateral Sclerosis
Authors: Jørgensen H. S. , Jensen D.B. , Dimintiyanova K.P. , Bonnevie V.S. , Hedegaard A. , Lehnhoff J. , Moldovan M. , Grondahl L. , Meehan C.F. 
Published: June 2020

Amyotrophic lateral sclerosis is a neurodegenerative disease preferentially affecting motoneurones. Transgenic mouse models have been used to investigate the role of abnormal motoneurone excitability in this disease. Whilst an increased excitability has repeatedly been demonstratedin vitroin neonatal and embryonic preparations from SOD1 mouse models, the results from the only studies to recordin vivofrom spinal motoneurones in adult SOD1 models have produced conflicting findings. Deficits in repetitive firing have been reported in G93A SOD1 mice but not in presymptomatic G127X SOD1 mice despite shorter motoneurone axon initial segments (AISs) in these mice.These discrepancies may be due to the earlier disease onset and prolonged disease progression in G93A SOD1 mice with recordings potentially performed at a later sub-clinical stage of the disease in this mouse. To test this, and to explore how the evolution of excitability changes with symptom onset we performedin vivointracellular recording and AIS labelling in G127X SOD1 mice immediately after symptom onset. No reductions in repetitive firing were observed showing that this is not a common feature across all ALS models. Immunohistochemistry for the Na+channel Nav1.6 showed that motoneurone AISs increase in length in G127X SOD1 mice at symptom onset. Consistent with this, the rate of rise of AIS components of antidromic action potentials were significantly faster confirming that this increase in length represents an increase in AIS Na+channels occurring at symptom onset in this model.HighightsIn vivoelectrophysiological recordings were made in symptomatic G127X SOD1 mice.There were no deficits in repetitive firing in motoneurones in G127X mice.Increased persistent inward currents were still present in the symptomatic mice.Results suggest increases in Na+currents at axon initial segments (AISs).Immunohistochemistry showed that motoneurone AISs were longer and thinner.
Checkpoint phosphorylation sites on budding yeast Rif1 protect nascent DNA from degradation by Sgs1-Dna2
Authors: Monerawela Chandre , Hiraga Shin-ichiro , Donaldson Anne D. 
Published: June 2020

AbstractIn budding yeast the Rif1 protein is important for protecting nascent DNA at blocked replication forks, but the mechanism has been unclear. Here we show that budding yeast Rif1 must interact with Protein Phosphatase 1 to protect nascent DNA. In the absence of Rif1, removal of either Dna2 or Sgs1 prevents nascent DNA degradation, implying that Rif1 protects nascent DNA by targeting Protein Phosphatase 1 to oppose degradation by the Sgs1-Dna2 nuclease-helicase complex. This functional role for Rif1 is conserved from yeast to human cells. Yeast Rif1 was previously identified as a target of phosphorylation by the Tel1/Mec1 checkpoint kinases, but the importance of this phosphorylation has been unclear. We find that nascent DNA protection depends on a cluster of Tel1/Mec1 consensus phosphorylation sites in the Rif1 protein sequence, indicating that the intra-S phase checkpoint acts to protect nascent DNA through Rif1 phosphorylation. Our observations uncover the pathway by which budding yeast Rif1 stabilises newly synthesised DNA, highlighting the crucial role Rif1 plays in maintaining genome stability from lower eukaryotes to humans.Author summaryGenome instability is a leading factor contributing to cancer. Maintaining efficient error-free replication of the genome is key to preventing genome instability. During DNA replication, replication forks can be stalled by external and intrinsic obstacles, leading to processing of nascent DNA ends to enable replication restart. However, the nascent DNA must be protected from excessive processing to prevent terminal fork arrest, which could potentially lead to more serious consequences including failure to replicate some genome sequences. Using a nascent DNA protection assay we have investigated the role of the budding yeast Rif1 protein at blocked replication forks. We find that Rif1 protects nascent DNA through a mechanism that appears conserved from yeast to humans. We show that budding yeast Rif1 protects nascent DNA by targeting Protein Phosphatase 1 activity to prevent degradation of nascent DNA by the Sgs1-Dna2 helicase-nuclease complex. Furthermore, we find that Rif1 phosphorylation by the checkpoint pathway during replication stress is crucial for this function. Our results indicate that the S phase checkpoint machinery acts by phosphorylating Rif1 to protect nascent DNA, providing important clues concerning the conserved role of Rif1 in regulating events when replication is challenged.
Binding Ability Prediction between Spike Protein and Human ACE2 Reveals the Adaptive Strategy of SARS-CoV-2 in Humans
Authors: Xue Xia , Shi Jianxiang , Xu Hongen , Qin Yaping , Yang Zengguang , Feng Shuaisheng , Liu Danhua , Jian Liguo , Hua Linlin , Wang Yaohe , Zhang Qi , Huang Xueyong , Zhang Xiaoju , Li Xinxin , Chen Chunguang , Guo Jiancheng , Tang Wenxue , Liu Jianbo 
Published: June 2020

AbstractSARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel coronavirus causing an outbreak of COVID-19 globally in the past six months. A relatively higher divergence on the spike protein of SASR-CoV-2 enables it to transmit across species efficiently. We particularly believe that the adaptive mutations of the receptor-binding domain (RBD) of spike protein in SARS-CoV-2 might be essential to its high transmissibility among humans. Thus here we collected 2,142 high-quality genome sequences of SARS-CoV-2 from 160 regions in over 50 countries and reconstructed their phylogeny, and also analyzed the interaction between the polymorphisms of spike protein and human ACE2 (hACE2). Phylogenetic analysis of SARS-CoV-2 and coronavirus in other hosts show SARS-CoV-2 is highly possible originated from Bat-CoV (RaTG13) found in horseshoe bat and a recombination event may occur on the spike protein of Pangolin-CoV to imbue it the ability to infect humans. Moreover, compared to the S gene of SARS-CoV-2, it is more conserved in the direct-binding sites of RBD and we noticed that spike protein of SARS-CoV-2 may under a consensus evolution to adapt to human hosts better. 3,860 amino acid mutations in spike protein RBD (T333-C525) of SARS-CoV-2 were simulated and their stability and affinity binding to hACE2 (S19-D615) were calculated. Our analysis indicates SARS-CoV-2 could infect humans from different populations with no preference, and a higher divergence in the spike protein of SARS-CoV-2 at the early stage of this pandemic may be a good indicator that could show the pathway of SARS-CoV-2 transmitting from the natural reservoir to human beings.
Cis-regulatory mutations associate with transcriptional and post-transcriptional deregulation of the gene regulatory program in cancers
Authors: Castro-Mondragon Jaime A. , Ragle Aure Miriam , Lingjærde Ole Christian , Langerød Anita , Martens John W. M. , Børresen-Dale Anne-Lise , Kristensen Vessela , Mathelier Anthony 
Published: June 2020

ABSTRACTBackgroundMost cancer alterations occur in the noncoding portion of the human genome, which contains important regulatory regions acting as genetic switches to ensure gene expression occurs at correct times and intensities in correct tissues. However, large scale discovery of noncoding events altering the gene expression regulatory program has been limited to a few examples with high recurrence or high functional impact.ResultsWe focused on transcription factor binding sites (TFBSs) that show similar mutation loads than what is observed in protein-coding exons. By combining cancer somatic mutations in TFBSs and expression data for protein-coding and miRNA genes, we evaluated the combined effects of transcriptional and post-transcriptional alteration on the dysregulation of the regulatory programs in cancer. The analysis of seven cancer cohorts culminated with the identification of protein-coding and miRNA genes linked to mutations at TFBSs that were associated with a cascading trans-effect deregulation on the cells’ regulatory program. Our analyses of cis-regulatory mutations associated with miRNAs recurrently predicted 17 miRNAs as pan-cancer-associated through deregulation of their target gene networks. Overall, our predictions were enriched for protein-coding and miRNA genes previously annotated as cancer drivers. Functional enrichment analyses highlighted that cis-regulatory mutations are associated with the dysregulation of key pathways associated with carcinogenesisConclusionsThese pan-cancer results suggest that our method predicts cis-regulatory mutations related to the dysregulation of key gene regulatory networks in cancer patients. It highlights how the gene regulatory program is disrupted in cancer cells by combining transcriptional and post-transcriptional regulation of gene expression.
When do apples stop growing, and why does it matter?
Authors: Christodoulou Maria D , Culham Alastair 
Published: June 2020

AbstractBackgroundApples in the commercial food chain are harvested up to two weeks before maturity. We explore apple fruit development through the growing season to establish the point at which the features differentiating those cultivars become evident. This is relevant both for the understanding of the growing process and to ensure that any identification and classification tools can be used both on ripened-on-tree and stored fruit. Current literature presents some contradictory findings on apple development, we explored the size development of 12 apple cultivars in the Brogdale National Fruit Collection, UK over two growing seasons.MethodsFruit were sampled at regular time points throughout the growing season and four morphometrics (maximum length, maximum diameter, weight, and centroid size) were collected. These were regressed against growing degree days in order to appropriately describe the growth pattern observed.ResultsAll four morphometrics were adequately described using log-log linear regressions, with adjusted R2estimates ranging from 78.3% (maximum length) to 86.7% (weight). For all four morphometrics, a 10% increase in growing degree days was associated with a 1% increase in the morphometric measurement.DiscussionOur findings refine previous work presenting rapid early growth followed by a plateau in later stages of development and are in disagreement with published expo-linear models. We established that apples harvested for commercial storage purposes, two weeks prior to maturity, showed only a modest decrease in size, demonstrating that size morphometric approaches are appropriate for classification of apples, both ripened-on-tree and stored.
Expansin-controlled cell wall stiffness regulates root growth inArabidopsis
Authors: Samalova Marketa , Elsayad Kareem , Melnikava Alesia , Peaucelle Alexis , Gahurova Evelina , Gumulec Jaromir , Spyroglou Ioannis , Zemlyanskaya Elena V. , Ubogoeva Elena V. , Hejatko Jan 
Published: June 2020

ABSTRACTExpansins facilitate cell expansion via mediating pH-dependent cell wall (CW) loosening. However, the role of expansins in the control of biomechanical CW properties in the tissue and organ context remains elusive. We determined hormonal responsiveness and specificity of expression and localization of expansins predicted to be direct targets of cytokinin signalling. We found EXPA1 homogenously distributed throughout the CW of columella/ lateral root cap, while EXPA10 and EXPA14 localized predominantly at the three-cell boundaries of epidermis/cortex in various root zones. Cell type-specific localization of EXPA15 overlaps with higher CW stiffness measured via Brillouin light scattering microscopy. As indicated by both Brillouin frequency shift and AFM-measured Young’s modulus,EXPA1overexpression upregulated CW stiffness, associated with shortening of the root apical meristem and root growth arrest. We propose that root growth inArabidopsisrequires delicate orchestration of biomechanical CW properties via tight regulation of various expansins’ localization to specific cell types and extracellular domains.
Fi-score: a novel approach to characterise protein topology and aid in drug discovery studies
Authors: Kanapeckaitė Austė , Beaurivage Claudia , Hancock Matthew , Verschueren Erik 
Published: June 2020

AbstractTarget evaluation is at the centre of rational drug design and biologics development. In order to successfully engineer antibodies, T-cell receptors or small molecules it is necessary to identify and characterise potential binding or contact sites on therapeutically relevant target proteins. Currently, there are numerous challenges in achieving a better docking precision as well as characterising relevant sites. We devised a first-of-its-kindin silicoprotein fingerprinting approach based on dihedral angle and B-factor distribution to probe binding sites and sites of structural importance. In addition, we showed that the entire protein regions or individual structural subsets can be profiled using our derived fi-score based on amino acid dihedral angle and B-factor distribution. We further described a method to assess the structural profile and extract information on sites of importance using machine learning Gaussian mixture models. In combination, these biophysical analytical methods could potentially help to classify and systematically analyse not only targets but also drug candidates that bind to specific sites which would greatly improve pre-screening stage, target selection and drug repurposing efforts in finding other matching targets.
The genome of North American beaver provides insights into the mechanisms of its longevity and cancer resistance
Authors: Zhang Quanwei , Tombline Gregory , Ablaeva Julia , Zhang Lei , Zhou Xuming , Smith Zachary , Xiaoli Alus M. , Wang Zhen , Lin Jhih-Rong , Jabalameli M. Reza , Mitra Joydeep , Nguyen Nha , Vijg Jan , Seluanov Andrei , Gladyshev Vadim N. , Gorbunova Vera , Zhang Zhengdong D. 
Published: June 2020

AbstractThe North American beaver (Castor canadensis) is an exceptionally long-lived and cancer-resistant rodent species, and thus an excellent model organism for comparative genomic studies of longevity. Here, we utilize a significantly improved beaver genome assembly to assess evolutionary changes in gene coding sequences, copy number, and expression. We found that the beaverAldh1a1, a stem cell marker gene encoding an enzyme required for detoxification of ethanol and aldehydes, is expanded (~10 copies vs. two in mouse and one in human). We also show that the beaver cells are more resistant to ethanol, and beaver liver extracts show higher ability to metabolize aldehydes than the mouse samples. Furthermore,Hpgd, a tumor suppressor gene, is uniquely duplicated in the beaver among rodents. Our evolutionary analysis identified beaver genes under positive selection which are associated with tumor suppression and longevity. Genes involved in lipid metabolism show positive selection signals, changes in copy number and altered gene expression in beavers. Several genes involved in DNA repair showed a higher expression in beavers which is consistent with the trend observed in other long-lived mammals. In summary, we identified several genes that likely contribute to beaver longevity and cancer resistance, including increased ability to detoxify aldehydes, enhanced tumor suppression and DNA repair, and altered lipid metabolism.