bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Antibiotic Administration as a Potentially Novel Factor Associated With Tacrolimus Trough Variability in Kidney Transplant Recipients: A Preliminary Study
Authors: Zheng YuanPu , Masand Anjali , Wagner Michael , Kapur Sandip , Dadhania Darshana , Lubetzky Michelle , Lee John Richard 
Published: August 2019

Background.
Tacrolimus trough variability is an important risk factor for kidney allograft outcomes. Recent evidence suggests that the gut microbiota is associated with tacrolimus dosing requirements and direct metabolism of tacrolimus. We hypothesize that administration of antibiotics, which are known to alter the gut microbiota, is associated with tacrolimus trough variability.

Methods.
We conducted a retrospective chart review of subjects who received kidney transplants at our institution from 2012 to 2013 and evaluated subjects who received antibiotics during the first month of transplantation (Abx Group, N = 60) and subjects who did not (No Abx Group, N = 200). We evaluated whether antibiotic administration in the Abx Group had increased tacrolimus trough concentrations and concentration over tacrolimus dosage (C/D) after antibiotic administration. We also evaluated tacrolimus variability as measured by standard deviation (SD) and coefficient of variation between the Abx Group and No Abx Group.

Results.
In the Abx Group, tacrolimus trough concentration over tacrolimus dosage (C/D) increased 7 and 15 days after antibiotic administration (P = 0.001, P = 0.07, respectively, Wilcoxon signed-rank test). From postoperative day 31–45, the variability in tacrolimus trough levels in the Abx Group as measured by SD and coefficient of variation was significantly higher than the variability in the No Abx Group (P = 0.03, P = 0.02, Wilcoxon rank sum test, respectively).

Conclusions.
Our identification of antibiotic administration as a potentially new risk factor for tacrolimus trough variability suggests the need to carefully follow tacrolimus trough levels after antibiotic administration.
Outcomes After Transcervical Thymectomy for Ocular Myasthenia Gravis: A Retrospective Cohort Study With Inverse Probability Weighting
Authors: Hamedani Ali G. , Pistilli Maxwell , Singhal Sunil , Shindler Kenneth S. , Avery Robert A. , Tamhankar Madhura A. , Liu Grant T. 
Published: August 2019

Background:
The benefit of thymectomy in reducing requirement for corticosteroids, symptom severity, need for immunosuppression, and hospitalization rates in patients with seropositive generalized myasthenia has recently been established. It is unclear whether this benefit applies to patients with myasthenia and purely ocular manifestations (ocular myasthenia gravis [OMG]).

Methods:
We conducted a retrospective single-center cohort study of patients with OMG. Patients were included if their diagnosis was confirmed by acetylcholine receptor or muscle-specific kinase antibodies, abnormal electrophysiology, or a positive edrophonium test and at least 1 year of clinical follow-up. At each visit, the presence and severity of ocular and generalized symptoms was ascertained using a 4-point scale. Prednisone dose, steroid-sparing agent use, and need for intravenous immunoglobulin or plasmapheresis were recorded. The effect of thymectomy on time-weighted prednisone dose and symptom severity score was assessed using linear regression models. To adjust for nonrandomization of thymectomy, we used inverse probability weighting using a propensity score model derived from the prethymectomy observation period for thymectomy patients and a 6-month lead-in period for nonthymectomy patients that incorporated age, sex, acetylcholine receptor antibody seropositivity, disease severity (as defined by both symptom severity and treatment requirement), and treating physician preferences.

Results:
Eighty-two patients (30 with thymectomy and 52 nonthymectomy) were included. In unadjusted analyses, time-weighted daily prednisone dose was 2.9 mg higher with thymectomy compared with nonthymectomy (95% CI: 0.2–5.7), but after inverse probability weighting, this was no longer statistically significant (difference = 1.7 mg, 95% CI: −0.8 to 4.2). There was no statistically significant difference in symptom severity score (adjusted difference = 0.35, 95% CI: −0.02 to 0.72) or risk of generalization (P = 0.22).

Conclusions:
In this retrospective study that used statistical techniques to account for nonrandomization, no significant differences in prednisone dose or symptom severity after thymectomy in ocular myasthenia were demonstrated.
Orbicularis Oculi Morphological Alterations in Affected and Nonaffected Sides in Hemifacial Spasm
Authors: Osaki Midori H. , Osaki Tammy H. , Osaki Teissy , Gameiro Gustavo R. , Belfort Rubens , Marie Suely K. N. 
Published: August 2019

Background:
Although the nonaffected side appears to be clinically normal in hemifacial spasm (HFS), it is not known whether this side can be considered normal regarding histopathological findings. The purpose of this study was to objectively evaluate and compare orbicularis oculi samples of patients with HFS (not previously treated with botulinum toxin) and control patients undergoing cosmetic upper eyelid blepharoplasty.

Methods:
Orbicularis oculi samples from 22 eyelids were evaluated. There were 7 samples from the affected and 7 samples from the nonaffected sides of patients with HFS who had not been previously treated with botulinum toxin, and 8 samples from normal control patients. Muscle samples were prepared using hematoxylin and eosin staining, and a digital image analysis software was used for objective analyses.

Results:
When compared with normal controls, endomysial and perimysial connective tissue areas were significantly increased (P = 0.015) on the affected side in HFS, suggesting that this disorder is associated with chronic alterations that lead to muscle degeneration. Cell density was significantly reduced on the affected (P = 0.028) and also on the nonaffected sides in HFS (P = 0.003) compared with normal controls. This was observed, although, clinically, there were no signs or symptoms of increased muscular contraction on the nonaffected sides in any of the patients with HFS studied.

Conclusions:
Significant morphological differences in the orbicularis oculi muscle in patients with HFS were observed on both the affected and nonaffected sides. Our findings suggest a potential role for muscle homeostasis disturbances on both sides for patients with HFS. Affected sides in patients with HFS did, however, demonstrate muscle degeneration that was not present on the nonaffected sides.
Deep Learning and Transfer Learning for Optic Disc Laterality Detection: Implications for Machine Learning in Neuro-Ophthalmology
Authors: Liu T. Y. Alvin , Ting Daniel S. W. , Yi Paul H. , Wei Jinchi , Zhu Hongxi , Subramanian Prem S. , Li Taibo , Hui Ferdinand K. , Hager Gregory D. , Miller Neil R. 
Published: August 2019

Background:
Deep learning (DL) has demonstrated human expert levels of performance for medical image classification in a wide array of medical fields, including ophthalmology. In this article, we present the results of our DL system designed to determine optic disc laterality, right eye vs left eye, in the presence of both normal and abnormal optic discs.

Methods:
Using transfer learning, we modified the ResNet-152 deep convolutional neural network (DCNN), pretrained on ImageNet, to determine the optic disc laterality. After a 5-fold cross-validation, we generated receiver operating characteristic curves and corresponding area under the curve (AUC) values to evaluate performance. The data set consisted of 576 color fundus photographs (51% right and 49% left). Both 30° photographs centered on the optic disc (63%) and photographs with varying degree of optic disc centration and/or wider field of view (37%) were included. Both normal (27%) and abnormal (73%) optic discs were included. Various neuro-ophthalmological diseases were represented, such as, but not limited to, atrophy, anterior ischemic optic neuropathy, hypoplasia, and papilledema.

Results:
Using 5-fold cross-validation (70% training; 10% validation; 20% testing), our DCNN for classifying right vs left optic disc achieved an average AUC of 0.999 (±0.002) with optimal threshold values, yielding an average accuracy of 98.78% (±1.52%), sensitivity of 98.60% (±1.72%), and specificity of 98.97% (±1.38%). When tested against a separate data set for external validation, our 5-fold cross-validation model achieved the following average performance: AUC 0.996 (±0.005), accuracy 97.2% (±2.0%), sensitivity 96.4% (±4.3%), and specificity 98.0% (±2.2%).

Conclusions:
Small data sets can be used to develop high-performing DL systems for semantic labeling of neuro-ophthalmology images, specifically in distinguishing between right and left optic discs, even in the presence of neuro-ophthalmological pathologies. Although this may seem like an elementary task, this study demonstrates the power of transfer learning and provides an example of a DCNN that can help curate large medical image databases for machine-learning purposes and facilitate ophthalmologist workflow by automatically labeling images according to laterality.
A Reliability and Comparative Analysis of the New Randomized King-Devick Test
Authors: Nguyen Minh Q. , King Doug , Pearce Alan J. 
Published: August 2019

Objective:
The King-Devick (K-D) test is a rapid visual screening tool that can assess underlying brain trauma such as concussion via impairments in saccadic rhythm. A new tablet version of the K-D test using randomized numbers is now available, but reliability for this new version and comparison to the traditional K-D test has not yet been reported. Known for learning effects in the test, the aim of this study was to determine test–retest reliability and to compare performance of the new “randomized” version to the “traditional” K-D test version. We hypothesized that the “traditional” K-D test would show a greater rate of improvement with repeat application, compared with the “randomized” K-D test.

Methods:
Using a cross-sectional, repeated measures design in a healthy university student cohort (n = 96; age 21.6 ± 2.8 years; 49 women, 47 men), participants were required to complete the K-D test twice with a one-week break between testing sessions. Participants were randomly assigned into a “traditional” group, where they completed a test–retest of the established K-D protocol, using the same numbers; or the “randomized” group, where they completed test–retest protocol using 2 different sets of numbers.

Results:
Reliability testing showed a strong intraclass correlation coefficient for both the “traditional” test group (control group; 0.95 [CI: 0.91–0.97]) and the “randomized test group” (0.97 [CI: 0.95–0.98]). However, contrary to our hypothesis, no differences were found between “traditional” and “randomized” groups for baseline (control: 42.5 seconds [CI: 40.2–44.9 s] vs randomized: 41.5 [38.7–44.4], P = 0.23) and repeated testing between groups (control: 40.0 seconds [37.9–42.1 s] vs randomized: 39.5 [36.9–42.0], P = 0.55), with both groups showing improved times with repeated testing (control: 2.1 seconds [CI: 1.1–3.2 seconds] and randomized: 1.9 seconds CI: [0.9–2.9 seconds], P < 0.001).

Conclusions:
The “randomized” version of the K-D test, using different sets of numbers, demonstrates good reliability that is comparable to the traditional K-D testing protocol that uses the same number sets. However, similar to the “traditional” K-D test, learning effects were also observed in the “randomized” test, suggesting that learning effects are not because of content memorization, but rather familiarity of the test. As a result, although either test format is suitable for sideline concussion screening or return to play decisions, comparison of data should be made to the individual's baseline rather than to normative data sets.
Epigenome-wide association study of seizures in childhood and adolescence
Authors: Caramaschi Doretta , Hatcher Charlie , Mulder Rosa H. , Felix Janine F. , Cecil Charlotte A. M. , Relton Caroline L. , Walton Esther 
Published: August 2019

ABSTRACTThe occurrence of seizures in childhood is often associated with neurodevelopmental impairments and school underachievement. Common genetic variants associated with epilepsy have been identified and epigenetic mechanisms have also been suggested to play a role. In this study we analysed the association of genome-wide blood DNA methylation with the occurrence of seizures in ∼800 children from the Avon Longitudinal Study of Parents and Children, UK, at birth (cord blood), during childhood and adolescence (peripheral blood). We also analysed the association between the lifetime occurrence of any seizures before age 13 with blood DNA methylation levels. We sought replication of the findings in the Generation R Study and explored causality using Mendelian randomization, i.e. using genetic variants as proxies. The results showed five CpG sites which were associated cross-sectionally with seizures either in childhood or adolescence (1-5% absolute methylation difference at pFDR<0.05), although the evidence of replication in an independent study was weak. One of these sites was located in the BDNF gene, which is highly expressed in the brain, and showed high correspondence with brain methylation levels. The Mendelian randomization analyses suggested that seizures might be causal for changes in methylation rather than vice-versa. In addition, seizure-associated methylation changes could affect other outcomes such as growth, cognitive skills and educational attainment. In conclusion, we present a link between seizures and DNA methylation which suggests that DNA methylation changes might mediate some of the effects of seizures on growth and neurodevelopment.
RasGRP1 (CalDAG-GEF-II) Mediates L-DOPA-induced Dyskinesia in a Mouse Model of Parkinson Disease
Authors: Ishragi Mehdi , Ramirez Jarquin Uri Nimrod , Shahani Neelam , Swarnkar Supriya , Galli Nicole , Rivera Oscar , Tsaprailis George , Scharager-Tapia Catherina , Crynen Gogce , Usiello Alessandro , Subramaniam Srinivasa 
Published: August 2019

ABSTRACTThe therapeutic benefits of L–3,4–dihydroxyphenylalanine (L-DOPA) in Parkinson disease (PD) patients diminishes with the onset of abnormal involuntary movements (L-DOPA induced dyskinesia), a debilitating motor side effect. L-DOPA induced dyskinesia are due to altered dopaminergic signaling in the striatum, a brain region that controls motor and cognitive functions. However, the molecular mechanisms that promote L-DOPA-induced dyskinesia remain unclear. Here, we have reported that RasGRP1 (also known as CalDAG-GEF-II) physiologically mediated L-DOPA induced dyskinesia in a 6-hydroxy dopamine (6-OHDA) lesioned mouse model of PD. In this study, L-DOPA treatment rapidly upregulated RasGRP1 in the striatum. Our findings showed that RasGRP1 deleted mice (RasGRP1−/−) had drastically diminished L-DOPA-induced dyskinesia, andRasGRP1−/−mice did not interfere with the therapeutic benefits of L-DOPA. In terms of its mechanism, RasGRP1 mediates L-DOPA-induced extracellular regulated kinase (ERK), the mammalian target of rapamycin kinase (mTOR) and the cAMP/PKA pathway and binds directly with Ras-homolog-enriched in the brain (Rheb), which is a potent activator of mTOR, both in vitro and in the intact striatum. High-resolution tandem mass tag mass spectrometry analysis of striatal tissue revealed significant targets, such as phosphodiesterase (Pde1c), Pde2a, catechol-o-methyltransferase (comt), and glutamate decarboxylase 1 and 2 (Gad1 and Gad2), which are downstream regulators of RasGRP1 and are linked to L-DOPA-induced dyskinesia vulnerability. Collectively, the findings of this study demonstrated that RasGRP1 is a major regulator of L-DOPA-induced dyskinesia in the striatum. Drugs or gene-depletion strategies targeting RasGRP1 may offer novel therapeutic opportunities for preventing L-DOPA-induced dyskinesia in PD patients.
Oncogenic herpesvirus engages the endothelial transcription factors SOX18 and PROX1 to increase viral genome copies and virus production
Authors: Gramolelli Silvia , Elbasani Endrit , Nurminen Veijo , Tuohinto Krista , Günther Thomas , Kallinen Riikka E. , Kaijalainen Seppo P. , Diaz Raquel , Grundhoff Adam , Haglund Caj , Ziegelbauer Joseph M. , Bower Mark , Francois Mathias , Ojala Päivi M. 
Published: August 2019

ABSTRACTKaposi sarcoma (KS) is a tumour of endothelial origin caused by KS herpesvirus (KSHV) infection and suggested to originate from lymphatic endothelial cells (LECs). While KSHV establishes latency in virtually all susceptible cell types, LECs support a spontaneous lytic gene expression program with high viral genome copies and release of infectious virus. Here, we investigated the role of PROX1, SOX18 and COUPTF2, drivers of lymphatic endothelial fate during embryogenesis, in this unique KSHV infection program. We found that these factors were co-expressed in KS tumours with the viral lytic marker K8.1, and that SOX18 and PROX1 regulate KSHV infection via two independent mechanisms. SOX18 binds to the viral origins of replication and its depletion or chemical inhibition significantly reduced the KSHV genome copies in LECs. PROX1 interacts with ORF50, the initiator of the lytic cascade, increases lytic gene expression and virus production and its depletion reduces KSHV spontaneous lytic reactivation. Upon lytic replication, PROX1 binds to the KSHV genome in the promoter region of ORF50 and enhances its transactivation activity. These results demonstrate the importance of two endothelial transcription factors in the regulation of the KSHV life cycle and introduce SOX18 inhibition as a potential, novel therapeutic modality for KS.
Cell-based Simulations of Biased Epithelial Lung Growth
Authors: Stopka Anna , Kokic Marco , Iber Dagmar 
Published: August 2019

AbstractDuring morphogenesis, epithelial tubes elongate. In case of the mammalian lung, biased elongation has been linked to a bias in cell shape and cell division, but it has remained unclear whether a bias in cell shape along the axis of outgrowth is sufficient for biased outgrowth and how it arises. Here, we use our 2D cell-based tissue simulation softwareLBIBCellto investigate the conditions for biased epithelial outgrowth. We show that the observed bias in cell shape and cell division can result in the observed bias in outgrowth only in case of strong cortical tension, and comparison to biological data suggests that the cortical tension in epithelia is likely sufficient. We explore mechanisms that may result in the observed bias in cell division and cell shapes. To this end, we test the possibility that the surrounding tissue or extracellular matrix acts as a mechanical constraint that biases growth in longitudinal direction. While external compressive forces can result in the observed bias in outgrowth, we find that they do not result in the observed bias in cell shapes. We conclude that other mechanisms must exist that generate the bias in lung epithelial outgrowth.
Expansion of CRISPR loci with multiple memories of infection enables the survival of structured bacterial communities
Authors: Pyenson Nora C. , Marraffini Luciano A. 
Published: August 2019

AbstractType II CRISPR-Cas systems provide immunity against phages and plasmids that infect bacteria. Following infection, a short sequence of the phage genome known as the “spacer” is inserted into the CRISPR locus to capture a memory of the infection and immunize the host. Spacers are transcribed and processed into guide RNAs that direct the Cas9 nuclease to its target on the invader. Thousands of spacers are acquired to target the viral genome at multiple locations and neutralize phage mutants that evade the immunity specified by a single guide RNA. In liquid cultures, where phages and their hosts are constantly mixed, spacer diversity is generated at the population level, and a single immunization per cell is sufficient to confer robust immunity. Although rare, bacteria that acquire multiple spacers can also be found, demonstrating that type II CRISPR-Cas systems also have the capability of generating spacer diversity at the cellular level. However, conditions in which this feature is important for survival are poorly understood. Here we found that when phage infections occur on solid media, a high proportion of the surviving colonies display sectored morphologies that contain individual cells with multiple spacers. We show that this is the result of the bacteria-host co-evolution, in which the immunity provided by the initial acquired spacer is easily overcome by escaper phages that decimate all the progeny of the founder cell that do not acquire additional spacers. Our results reveal the versatility of type II CRISPR-Cas immunity, which can respond with both single or multiple spacer acquisition schemes to solve challenges presented by different environments.
Human ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy regulation
Authors: Barthez Marine , Poplineau Mathilde , Elrefaey Marwa , Caruso Nathalie , Graba Yacine , Saurin Andrew J. 
Published: August 2019

AbstractAutophagy is an essential cellular process that maintains homeostasis by recycling damaged organelles and nutrients during development and cellular stress. ZKSCAN3 is the sole identified master transcriptional repressor of autophagy in humans. How ZKSCAN3 achieves autophagy repression at the mechanistic or organismal level however still remains to be elucidated. Here, we demonstrate that vertebrate ZKSCAN3 and Drosophila M1BP are functionally homologous transcription factors in autophagy repression. Expression of ZKSCAN3 in Drosophila prevents premature autophagy onset due to loss of M1BP function and conversely, M1BP expression in human cells can prevent starvation-induced autophagy due to loss of nuclear ZKSCAN3 function. In Drosophila ZKSCAN3 binds genome-wide to sequences targeted by M1BP and transcriptionally regulates the majority of M1BP-controlled genes. These data allow the potential for transitioning the mechanisms, gene targets and plethora metabolic processes controlled by M1BP onto ZKSCAN3 and opens up Drosophila as a tool in studying the function of ZKSCAN3 in autophagy and tumourigenesis.
Identification of genes involved in the differentiation of R7y and R7p photoreceptor cells inDrosophila
Authors: Earl James B , Vanderlinden Lauren A , Saba Laura M , Britt Steven G 
Published: August 2019

AbstractThe R7 and R8 photoreceptor cells of theDrosophilacompound eye mediate color vision. Throughout the majority of the eye, these cells occur in two principal types of ommatidia. Approximately 35% of ommatidia are of the pale type and express Rh3 in R7 cells and Rh5 in R8 cells. The remaining 65% are of the yellow type and express Rh4 in R7 cells and Rh6 in R8 cells. The specification of an R8 cell in a pale or yellow ommatidium depends on the fate of the adjacent R7 cell. However, pale and yellow R7 cells are specified by a stochastic process that requires the genesspineless,tangoandklumpfuss. To identify additional genes involved in this process we performed a genetic screen using a collection of 480P{EP}transposon insertion strains. We identified genes that when inactivated and/or ectopically expressed in R7 cells resulted in a significantly altered percentage of Rh3 expressing R7 cells (Rh3%) from wild-type. 53 strains resulted in altered Rh3% in the heterozygous inactivation arm of the screen. 36 strains resulted in altered Rh3% in the ectopic expression arm of the screen, where the P{EP} insertion strains were crossed to asevEP-GAL4driver line. 4 strains showed differential effects between the two screens. Analyses of these results suggest that R7 cell fate specification is sensitive to perturbations in transcription, growth inhibition, glycoprotein ligand binding, WNT signaling, ubiquitin protease activity and Ser/Thr kinase activity, among other diverse signaling and cell biological processes.