bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracing the quenching history of cluster galaxies in the EAGLE simulation
Authors: Pallero Diego , Gómez Facundo A , Padilla Nelson D , Torres-Flores S , Demarco R , Cerulo P , Olave-Rojas D
Published: June 2019

We use the Evolution and Assembly of GaLaxies and their Environments (EAGLE) hydrodynamical simulation to trace the quenching history of galaxies in its 10 most massive clusters. We use two criteria to identify moments when galaxies suffer significant changes in their star formation activity: (i) the instantaneous star formation rate (SFR) strongest drop, $\Gamma _{\rm SFR}^{\rm SD}$, and (ii) a ‘quenching’ criterion based on a minimum threshold for the specific SFR of ≲10$^{-11}\,\rm yr^{-1}$. We find that a large fraction of galaxies (${\gtrsim} 60\,{\rm per\,cent}$) suffer their $\Gamma _{\rm SFR}^{\rm SD}$ outside the cluster’s R200. This ‘pre-processed’ population is dominated by galaxies that are either low mass and centrals or inhabit low-mass hosts (1010.5 ≲ Mhost ≲ 1011.0 M⊙). The host mass distribution is bimodal, and galaxies that suffered their $\Gamma _{\rm SFR}^{\rm SD}$ in massive hosts ($10^{13.5} \lesssim M_{\rm host} \lesssim 10^{14.0}\, \mathrm{M}_{\odot }$) are mainly processed within the clusters. Pre-processing mainly limits the total stellar mass with which galaxies arrive in the clusters. Regarding quenching, galaxies preferentially reach this state in high-mass haloes ($10^{13.5} \lesssim M_{\rm host} \lesssim 10^{14.5}\, \mathrm{M}_{\odot }$). The small fraction of galaxies that reach the cluster already quenched have also been pre-processed, linking both criteria as different stages in the quenching process of those galaxies. For the z = 0 satellite populations, we find a sharp rise in the fraction of quenched satellites at the time of first infall, highlighting the role played by the dense cluster environment. Interestingly, the fraction of pre-quenched galaxies rise with final cluster mass. This is a direct consequence of the hierarchical cosmological model used in these simulations.
Distinct RNA-binding modules in a single PUF protein cooperate to determine RNA specificity
Authors: Qiu Chen , Dutcher Robert C , Porter Douglas F , Arava Yoav , Wickens Marvin , Hall Traci M Tanaka
Published: June 2019

PUF proteins, named for Drosophila Pumilio (PUM) and Caenorhabditis elegans fem-3-binding factor (FBF), recognize specific sequences in the mRNAs they bind and control. RNA binding by classical PUF proteins is mediated by a characteristic PUM homology domain (PUM-HD). The Puf1 and Puf2 proteins possess a distinct architecture and comprise a highly conserved subfamily among fungal species. Puf1/Puf2 proteins contain two types of RNA-binding domain: a divergent PUM-HD and an RNA recognition motif (RRM). They recognize RNAs containing UAAU motifs, often in clusters. Here, we report a crystal structure of the PUM-HD of a fungal Puf1 in complex with a dual UAAU motif RNA. Each of the two UAAU tetranucleotides are bound by a Puf1 PUM-HD forming a 2:1 protein-to-RNA complex. We also determined crystal structures of the Puf1 RRM domain that identified a dimerization interface. The PUM-HD and RRM domains act in concert to determine RNA-binding specificity: the PUM-HD dictates binding to UAAU, and dimerization of the RRM domain favors binding to dual UAAU motifs rather than a single UAAU. Cooperative action of the RRM and PUM-HD identifies a new mechanism by which multiple RNA-binding modules in a single protein collaborate to create a unique RNA-binding specificity.
Differential Spread of Grapevine Red Blotch Virus in California and New York Vineyards
Authors: Cieniewicz Elizabeth , Flasco Madison , Brunelli Melina , Onwumelu Anuli , Wise Alice , Fuchs Marc F.
Published: June 2019

Limited information is available on the spread dynamics of grapevine red blotch virus (GRBV, genus Grablovirus, family Geminiviridae) in vineyards. In this study, we investigated red blotch disease progress in three vineyards with a disparate initial inoculum prevalence. Secondary spread was documented in Cabernet Sauvignon and Cabernet franc vineyards in California, but not in a Merlot vineyard in New York. Increase in annual disease incidence (4.8, 0.13, and 0%) was unrelated to the estimated initial source of inoculum at planting (1, 40, and 40%) in the Cabernet franc, Cabernet Sauvignon, and Merlot vineyards, respectively. Limited genetic diversity of GRBV populations in newly infected vines supported localized spread in California vineyards, and suggested the planting material as the primary source of inoculum. Among the community of hemipteran insects visiting two of the three study vineyards, populations of Spissistilus festinus, the vector of GRBV, were absent in the Merlot vineyard and low in the Cabernet Sauvignon vineyard. Furthermore, all cover crop samples collected from GRBV-infected California vineyards each spring of 2016 to 2018, particularly legume species which are preferred hosts of S. festinus, tested negative for GRBV, suggesting a minimal role, if any, in GRBV spread as inoculum reservoirs. Together our findings illustrate differential disease progress in distinct vineyard ecosystems, and support the elimination of virus inoculum sources as an actionable disease management strategy across vineyards.
Pathotypes Detected Among Populations of Pratylenchus neglectus Collected From Montana
Authors: Al-Khafaji Riyadh T. , Gunnink Troth Erin E. , Lambert Kris N. , Johnston Jeffrey A. , Dyer Alan T.
Published: June 2019

The root lesion nematode, Pratylenchus neglectus, is one of the most damaging nematodes to affect wheat worldwide. The nematode is widely distributed in Montana, primarily affecting winter wheat within the state. Managing the nematode primarily involves rotation to resistant and moderately resistant crops (peas, lentils, and barley). A nematode survey was conducted across the state nearly 10 years after an initial survey, to reassess the nematode threat and assess the impact of changing trends in crop rotations. To assess the broad applicability of rotation crops to control P. neglectus across Montana, greenhouse trials were conducted to challenge rotational crops using eight populations of P. neglectus collected from geographically diverse locations across the state. In the trials, conducted with four Montana crops, a significant interaction was detected between crop and nematode population (analysis of variance P < 0.001). Populations from Hill, Dawson, and Chouteau counties were found to be pathogenic on barley. Male nematodes were detected in seven of the eight pot culture populations, and these were confirmed to be P. neglectus by morphological and molecular methods. These results suggest a re-evaluation of barley and lentils as a management option for P. neglectus in Montana, as pathotypes for each exist within the state.
Population Biology and Genetic Variation of Spongospora subterranea f. sp. subterranea, the Causal Pathogen of Powdery Scab and Root Galls on Potatoes in South Africa
Authors: Muzhinji Norman , van der Waals Jacquie E.
Published: June 2019

Spongospora subterranea f. sp. subterranea, causal agent of powdery scab and root galls of potatoes, occurs worldwide and is responsible for quality and yield losses in potato production in South Africa. Despite being one of the most important potato pathogens in South Africa, little information is available on the genetic structure and diversity of S. subterranea f. sp. subterranea, which could provide insight into the factors shaping its evolution and the role of inoculum sources in disease development. A total of 172 samples were collected from four potato growing regions in South Africa. An additional 27 samples obtained from Colombia were included for comparative purposes. The samples were screened against six informative microsatellite (simple-sequence repeat) markers. Of the 172 samples obtained from potato growing regions in South Africa, there were 75 multilocus genotypes (MLGs), only 16 of which were shared between potato growing regions, indicating substantial gene flow and countrywide dispersal of the pathogen. The presence of common MLGs among the root- and tuber-derived samples indicated a lack of specialization of S. subterranea f. sp. subterranea to either tuber or root infection. Nei’s unbiased estimates of gene diversity for the clone-corrected data were low and ranged from 0.24 to 0.38. Analysis of molecular variance and discriminant analysis of principal components showed no population differentiation between different potato growing regions in South Africa and between root- and tuber-derived genotypes. The presence of MLGs, high considerable genotypic diversity, and failure to reject the null hypothesis of random mating in most populations are indicative of some kind of recombination, either sexual or asexual, in these S. subterranea f. sp. subterranea populations. Information from this study provides new insights into the genetic structure and diversity of S. subterranea f. sp. subterranea in South Africa. Continuous monitoring of the pathogen population dynamics will be helpful in implementing effective region-specific management strategies for the pathogen, especially in the development of resistant potato cultivars.
Downregulation of R-Spondin1 Contributes to Mechanical Stretch-Induced Lung Injury
Authors: Xu Chu-Fan , Liu Yu-Jian , Wang Yan , Mao Yan-Fei , Xu Dun-Feng , Dong Wen-Wen , Zhu Xiao-Yan , Jiang Lai
Published: June 2019

Objectives:

The R-spondin family attenuates tissue damage via tightening endothelium and preventing vascular leakage. This study aims to investigate whether R-spondins protect against mechanical stretch-induced endothelial dysfunction and lung injury and to reveal the underlying mechanisms.

Design:

Randomized controlled study.

Setting:

University research laboratory.

Subjects:

Patients scheduled to undergo surgery with mechanical ventilation support. Adult male Institute of Cancer Research mice. Primary cultured mouse lung vascular endothelial cells.

Interventions:

Patients underwent a surgical procedure with mechanical ventilation support of 3 hours or more. Mice were subjected to mechanical ventilation (6 or 30 mL/kg) for 0.5–4 hours. Another group of mice were intraperitoneally injected with 1 mg/kg lipopolysaccharide, and 12 hours later subjected to mechanical ventilation (10 mL/kg) for 4 hours. Mouse lung vascular endothelial cells were subjected to cyclic stretch for 4 hours.

Measurements and Main Results:

R-spondin1 were downregulated in both surgical patients and experimental animals exposed to mechanical ventilation. Intratracheal instillation of R-spondin1 attenuated, whereas knockdown of pulmonary R-spondin1 exacerbated ventilator-induced lung injury and mechanical stretch-induced lung vascular endothelial cell apoptosis. The antiapoptotic effect of R-spondin1 was mediated through the leucine-rich repeat containing G-protein coupled receptor 5 in cyclic stretched mouse lung vascular endothelial cells. We identified apoptosis-stimulating protein of p53 2 as the intracellular signaling protein interacted with leucine-rich repeat containing G-protein coupled receptor 5. R-spondin1 treatment decreased the interaction of apoptosis-stimulating protein of p53 2 with p53 while increased the binding of apoptosis-stimulating protein of p53 2 to leucine-rich repeat containing G-protein coupled receptor 5, therefore resulting in inactivation of p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells.

Conclusions:

Mechanical ventilation leads to down-regulation of R-spondin1. R-spondin1 may enhance the interaction of leucine-rich repeat containing G-protein coupled receptor 5 and apoptosis-stimulating protein of p53 2, thus inactivating p53-mediated proapoptotic pathway in cyclic stretched mouse lung vascular endothelial cells. R-spondin1 may have clinical benefit in alleviating mechanical ventilator-induced lung injury.
Systematic review of the hospice performance literature
Authors: He Mengying , O'Connor Stephen J. , Qu Haiyan , Menachemi Nir , Tucker Rodney , Shewchuk Richard M.
Published: June 2019

Background

Hospice is the key provider of end-of-life care to patients. As the number of U.S. hospice agencies has rapidly increased, the performance has been scrutinized more deeply.

Purpose

To foster understanding of how hospice performance is measured and what factors are associated with performance, we conducted a systematic review of empirical research on hospice performance in the United States.

Methods

Both structure–process–outcome and structure–conduct–performance frameworks were applied to categorize and summarize the hospice performance literature. A total of 36 studies were included in the systematic review.

Results

Hospice agencies adopted different strategies (e.g., service provision strategy and staffing strategy) to improve performance. Two strategic approaches (innovation and volunteer usage) were associated with better outcomes. Hospice organizational factors, market environment, and patient characteristics were related to hospice strategic conduct and performance. Majority of hospice performance studies have examined the relationship between hospice structure and strategic conduct/process, with fewer studies focusing on structure performance and even fewer concentrating on strategy performance.

Practice Implications

Patient, organizational, and market factors are associated with hospice strategic conduct and performance. The majority of the literature considered the impact of hospice organizational characteristics, whereas only a few studies included patient and market factors. The summarization of factors that may influence hospice performance provides insight to different stakeholders.
INTRAOCULAR APPLICATION OF FIBRIN GLUE AS AN ADJUNCT TO PARS PLANA VITRECTOMY FOR RHEGMATOGENOUS RETINAL DETACHMENT
Authors: Wang Qun , Zhao Jie , Xu Qing , Han Cui , Hou Baojie
Published: June 2019

Purpose:

To evaluate the efficacy of intraocular application of fibrin glue to seal the retinal breaks during standard pars plana vitrectomy for primary rhegmatogenous retinal detachment.

Methods:

Twenty-six eyes of 26 rhegmatogenous retinal detachment patients were included in the study. Fibrin glue was used to seal the retinal breaks during standard pars plana vitrectomy in all 26 eyes. Each eye was completely filled with a balanced saline solution at the end of the surgery. The success rate of the reattachment surgery, change in best-corrected visual acuity, intraocular pressure, and occurrence of intraoperative and postoperative complications were recorded and analyzed.

Results:

All eyes, with a mean age of 45.1 ± 18.3 years, were treated with pars plana vitrectomy surgery. During pars plana vitrectomy surgery, the fibrin glue showed excellent adherence and compliance to the retina. The glue was no longer visible through ultrasound scan 14.85 ± 4.56 days after surgery. The retinal breaks were sealed completely, and retina attached in all 26 eyes with no occurrence of rhegmatogenous retinal detachment during the follow-up period. The best-corrected visual acuity at 6 months after operation was significantly improved from preoperation best-corrected visual acuity. After operation, two eyes (2/26) developed an epiretinal membrane. Although three eyes (3/26) had a transient increased intraocular pressure during the 1st week after surgery, the intraocular pressure lowered to the normal range after the application of timolol. One eye (1/26) required daily topical antiglaucoma drops to lower the intraocular pressure. No adverse effects of fibrin glue were observed.

Conclusion:

The fibrin glue provided a superior adhesive effect for sealing retinal breaks, while showing no additional adverse effects. It is a worthy alternative to gas tamponade for rhegmatogenous retinal detachment vitrectomy surgery.
PATIENT-REPORTED VISUAL FUNCTION FROM THE OCRIPLASMIN FOR TREATMENT FOR SYMPTOMATIC VITREOMACULAR ADHESION, INCLUDING MACULAR HOLE (OASIS) STUDY
Authors: Mein Calvin , Dugel Pravin U. , Feiner Leonard , Drenser Kim , Miller Daniel , Benz Matthew , Meunier Esmeralda , Moro Lionel , Fineman Mitchell S.
Published: June 2019

Purpose:

To evaluate patient-reported visual function after ocriplasmin through the 25-item National Eye Institute Visual Function Questionnaire (VFQ-25) in patients with symptomatic vitreomacular adhesion/vitreomacular traction including macular hole.

Methods:

This was a prespecified analysis of a secondary endpoint from the OASIS trial. Patients received a single intravitreal injection of ocriplasmin (0.125 mg) or sham and completed the VFQ-25 questionnaire at baseline and at Months 6, 12, and 24. Clinically meaningful (≥5-point) changes from baseline were assessed.

Results:

Of the 220 patients enrolled, 146 received ocriplasmin and 74 received sham. At Month 24, the percentage of patients with a ≥5-point improvement from baseline in VFQ-25 composite scores was higher with ocriplasmin versus sham (51.4% vs. 30.1%, 95% confidence interval, 8.1–34.5, P = 0.003). The percentage of patients with ≥5-point worsening at Month 24 was lower with ocriplasmin versus sham (9.5% vs. 15.6%, 95% confidence interval: −15.6 to 3.5, P = 0.191). A larger percentage of patients treated with ocriplasmin versus sham experienced a ≥5-point improvement in VFQ-25 composite and subscale scores at Month 24 regardless of baseline full-thickness macular hole status.

Conclusion:

A larger percentage of patients with symptomatic vitreomacular adhesion/vitreomacular traction reported clinically meaningful improvements in self-assessed visual function with ocriplasmin than sham.
INFLUENCE OF FELLOW-EYE EXAMINATION INTERVAL ON VISUAL ACUITY AT FELLOW-EYE NEOVASCULARIZATION IN UNILATERAL TYPE 3 NEOVASCULARIZATION
Authors: Kim Jae Hui , Kim Jong Woo , Kim Chul Gu , Lee Dong Won
Published: June 2019

Purpose:

To evaluate the influence of the fellow-eye examination interval on visual acuity at fellow-eye neovascularization in unilateral Type 3 neovascularization.

Methods:

This retrospective, observational study included 55 patients who were initially diagnosed with unilateral Type 3 neovascularization and subsequently developed fellow-eye neovascularization during the follow-up period. The fellow-eye examination interval was defined as the hospital visit interval between fellow-eye neovascularization detection and immediately before neovascularization detection. The primary outcome measures were the associations between the fellow-eye examination interval and fellow-eye best-corrected visual acuity (BCVA) at fellow-eye neovascularization detection and degree of deterioration in fellow-eye BCVA.

Results:

After the initial diagnosis of the first-involved eye, fellow-eye neovascularization was noted after a period of 22.7 ± 17.5 months. The mean fellow-eye examination interval was 4.8 ± 2.2 months (range, 2–10 months). The mean logarithm of the minimum angle of resolution BCVA in the fellow eye was 0.22 ± 0.18 (Snellen equivalents, 20/33) immediately before neovascularization and 0.52 ± 0.26 (20/66) at neovascularization. There were significant associations between the fellow-eye examination interval and fellow-eye BCVA when neovascularization was detected (P = 0.005, r = 0.371) and at degree of deterioration in fellow-eye BCVA (P = 0.001, r = 0.428).

Conclusion:

A longer fellow-eye examination interval was associated with poor visual acuity and greater visual deterioration of the fellow eye at neovascularization. These results suggest the need for frequent fellow-eye examination in patients with unilateral Type 3 neovascularization.
Macular Vascular Microcirculation in Eyes With Open-angle Glaucoma Using Different Visual Field Severity Classification Systems
Authors: Bojikian Karine D. , Nobrega Priscilla , Wen Joanne C. , Zhang Qinqin , Mudumbai Raghu C. , Johnstone Murray A. , Wang Ruikang K. , Chen Philip P.
Published: June 2019

Precis:

We found significant differences in macular vascular microcirculation between normal and glaucomatous eyes using optical coherence tomography angiography (OCTA). Macular vascular microcirculation changes also showed significant correlations with visual field (VF) severity classification systems.

Purpose:

To correlate VF severity defined by different classification systems and macular vascular microcirculation in eyes with glaucoma using OCTA.

Patients and Methods:

Twenty normal and 58 open-angle glaucoma (OAG) eyes were scanned using a swept-source OCTA (Plex Elite 9000) and macular vascular microcirculation was measured by calculating the overall blood flux index (BFI) and vessel area density (VAD) over the entire 6×6 mm area excluding the big retinal vessels. Glaucomatous eyes were staged into severity groups based on 4 VF severity classifications: Hodapp-Parrish-Anderson scale, Glaucoma Severity Staging system, ICD-10 glaucoma staging definitions, and VF mean deviation. Central 10-degree VF mean sensitivity (CMS) was calculated based on 24-2 VF. One-way analysis of variance was used to analyze the differences and correlation between macular vascular microcirculation and other clinical parameters.

Results:

Glaucomatous eyes had significantly lower ganglion cell and inner plexiform layer BFI and VAD (P<0.0001) compared with normal eyes. In OAG patients, BFI and VAD were significantly higher in mild OAG compared with severe OAG with all VF disease severity classification systems (P<0.001). Glaucoma Severity Staging had the highest correlation with changes in macular vascular microcirculation metrics (r=0.734 for BFI; r=0.647 for VAD) and VF CMS had highest correlation with macular vascular microcirculation metrics (r=0.887 for BFI; r=0.903 for VAD).

Conclusion:

Macular vascular microcirculation metrics detected by OCTA correlate with disease severity in glaucomatous eyes. VF CMS, calculated from only 12 tested central 10-degree points, correlated best with macular OCTA.
Use of Topical Intraocular Pressure–lowering Medications in the US Population: Results From the NHANES Study 1999 to 2014
Authors: Lowry Eugene A. , Chansangpetch Sunee , Lin Shan C.
Published: June 2019

Precis:

We found no evidence of an increase in the number of Americans using topical intraocular pressure (IOP) medication or a number of drops used per patient from 1999 to 2014, although there were significant changes in the class of medications used.

Purpose:

The purpose of this study was to determine changes in topical IOP-lowering medication use in the United States from 1999 to 2014.

Materials and Methods:

A series of 8 nationally representative, weighted cross-sectional surveys of United States residents were performed every 2 years from 1999 to 2014. On 2-year cycles, professional interviewers performed in-home interviews of a representative sample of the nation as part of the National Health and Nutrition Examination Survey study. Participants were asked, “In the past month, have you used or taken medication for which a prescription is needed?” Adults over age 40 who responded to this question were included in the analysis. The primary outcome was number of US adults using topical IOP–lowering medication. Secondary outcomes included the number and types of medications used.

Results:

There was no change in the number of adults using topical IOP–lowering medications over the time period studied (P=0.74) with 1.4% (95% confidence interval: 0.9%-1.8%) of US residents on IOP-lowering medications in 1999 to 2000 and 1.4% of US residents (95% confidence interval: 1.1%-1.8%) on topical medications in 2013 to 2014. There was no change in the number of medications per patient over the period of the study (P=0.14). There was a significant increase in the use of prostaglandin analogs and combination medications and a decrease in the use of β-blockers (all P<0.01).

Conclusions:

In contrast to the increase in glaucoma medication use seen in several other developed nations, use in the United States remained stable from 1999 to 2014. This may be due to differential use of other procedures. Future studies of IOP-lowering medications incorporating the effect of new agents and minimally invasive surgeries are warranted.
Smartphone-aided Quantification of Iridocorneal Angle
Authors: Pujari Amar , Selvan Harathy , Asif Mohamed I. , Gupta Barkha , Dada Tanuj
Published: June 2019

As the upgrading of smartphone technology revolutionizes the field of ophthalmic imaging, we put forward one more of its novel applications. This article presents the possibility of iridocorneal angle (ICA) estimation through smartphone-captured images. Such measured inferior ICA (at 6’o clock position) was comparable to the anterior segment optical coherence tomography measured trabecular iris angle at 500 μ at 270 degrees (P=0.06). They both had an excellent positive correlation (ρ=0.81, P<0.001). Therefore, smartphone image–aided angle estimation may be a simple, effective, and economical method for quantification of ICAs, paving a more evident way for identification of angle-closure disease.
Professional Women's Softball Injuries: An Epidemiological Cohort Study
Authors: Patel Niraj , Bhatia Aditya , Mullen Chanda , Bosman Evan , Lear Aaron
Published: June 2019

Objective:

To report the epidemiology of Women's National Professional Fast-Pitch (NPF) softball injuries during the 2017 season. The secondary objective was to evaluate risk factors for pitching injuries.

Design/Setting:

Prospective injury data were collected from the primary clinical care of 6 professional softball teams.

Participants:

The NPF study population consisted of 153 players.

Independent Variables:

Data collection included the following: number of practices each week, diagnosis of the injury, game or practice injury, position played when sustaining the injury, treatment for the injury, number of missed practices and/or games as a result of the injury, and total days until return to play.

Main Outcome Measures:

Injury rate (IR) overall, IR in position players, and IR in pitchers. Secondary outcomes included risk assessment for injury in pitchers; descriptive statistics on the injuries recorded in all players.

Results:

Pitchers reported both upper extremity and lower extremity injuries equally, whereas positional players reported more lower extremity injuries. Pitchers were also most likely to be injured during a practice than a game. Overall, there were 3.26 reported game injuries per 1000 athlete exposures (AE) and 4.79 practice injuries per 1000 AE. Pitchers specifically had 1.88 reported game injuries per 1000 AE and 5.66 practice injuries per 1000 AE.

Conclusions:

In contrast to previous data, our study showed an increased IR in practice as compared to games in both position players and pitchers. Significant injuries were relatively rare, and most injuries seemed minor, usually with less than 7 days missed, suggesting a relative safety associated with this sport.
Griscelli Type 2 Syndrome and Hemophagocytic Lymphohistiocytosis: Sisters With the Same Mutation but Different Presentations
Authors: Russ Abigail , Mack Joana , Green-Murphy Audrey , Occidental Michael , Mian Amir
Published: June 2019

Griscelli syndrome type 2 (GS2) is an autosomal recessive condition associated with the development of hemophagocytic lymphohistiocytosis. GS2 is caused by a gene mutation involving RAB27A, which affects a melanosome anchoring complex in melanocytes and releases cytolytic granules from T cells and natural killer cells. GS2 is known to have immunologic compromise and oculocutaneous albinism. We present the case of 2 sisters who had vastly different phenotypic presentations despite having the same genetic frameshift mutation in the RAB27A gene. Patient 1 presented with seizures and neurological compromise, whereas patient 2 presented with pancytopenia and diarrhea. Both patients developed hemophagocytic lymphohistiocytosis.
HLA-B5, 7, 8, 27, and 51 Antigens and Immune Thrombocytopenic Purpura: Is There an Association?
Authors: Pezeshki Seyed Mohammad Sadegh , Jalali Mohammad Taha , Amin Asnafi Ali , Jaseb Kaveh , Saki Najmaldin
Published: June 2019

Background:

Immune thrombocytopenic purpura (ITP) is a bleeding disorder characterized by low platelet counts in peripheral blood, impairment of thrombopoiesis in bone marrow, and risk of mild to severe bleedings. ITP can be seen among both sexes in different ages. Although definitive pathogenesis of this disorder is still ambiguous, some of risk factors for ITP are recognized, including human leukocyte antigens (HLAs).

Objective:

Our goal was to evaluate the possible association between HLA-B5, 7, 8, 27, and 51 antigens with ITP for the first time. We were hoping to achieve new hypothetical diagnostic/prognostic biomarkers to introduce a new subject for further studies on HLA class I antigens as possible risk factors for ITP.

Materials and Methods:

A total of 37 patients with ITP were included in this study. After confirmation of ITP diagnosis, peripheral blood samples were collected from them. The expression of each of HLA antigens was evaluated by standard lymphocytotoxicity technique.

Results:

Compared with other studied antigens, the expression of HLA-B5 and HLA-B51 was more prevalent among our patients. According to the results, 22% of patients were positive for HLA-B5 and HLA-B51. Furthermore, no significant association was found between HLAs expressions with complete blood count parameters.

Conclusions:

We conclude that there is an association between HLA-B5 and HLA-B51 with ITP and that they are not likely to be used as diagnostic or prognostic biomarkers. We suggest studying the association between HLA-B antigens and ITP in large-scale studies to determine whether or not there is a significant association.
Outcomes of Liver Transplantation for Hepatocellular Carcinoma Beyond the University of California San Francisco Criteria: A Single-center Experience
Authors: Victor David W. , Monsour Howard P. , Boktour Maha , Lunsford Keri , Balogh Julius , Graviss Edward A. , Nguyen Duc T. , McFadden Robert , Divatia Mukul K. , Heyne Kirk , Ankoma-Sey Victor , Egwim Chukwuma , Galati Joseph , Duchini Andrea , Saharia Ashish , Mobley Constance , Gaber A. Osama , Ghobrial R. Mark
Published: June 2019

Background.

Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor. Currently, liver transplantation may be the optimal treatment for HCC in cirrhotic patients. Patient selection is currently based on tumor size. We developed a program to offer liver transplantation to selected patients with HCC outside of traditional criteria.

Methods.

Retrospective review for patients transplanted with HCC between April 2008 and June 2017. Patients were grouped by tumor size according to Milan, University of California San Francisco (UCSF), and outside UCSF criteria. Patient demographics, laboratory values, and outcomes were compared. Patients radiographically outside Milan criteria were selected based on tumor control with locoregional therapy (LRT) and 9 months of stability from LRT. α-fetoprotein values were not exclusionary.

Results.

Two hundred twenty HCC patients were transplanted, 138 inside Milan, 23 inside UCSF, and 59 beyond UCSF criteria. Patient survival was equivalent at 1, 3, or 5 years despite pathologic tumor size. Waiting time to transplantation was not significantly different at an average of 344 days. In patients outside UCSF, tumor recurrence was equivalent to Milan and UCSF criteria recipients who waited >9 months from LRT. Although tumor recurrence was more likely in outside of UCSF patients (3% versus 9% versus 15%; P = 0.02), recurrence-free survival only trended toward significance among the groups (P = 0.053).

Conclusions.

Selective patients outside of traditional size criteria can be effectively transplanted with equivalent survival to patients with smaller tumors, even when pathologic tumor burden is considered. Tumor stability over time can be used to help select patients for transplantation.
Development and Validation of Phenotype Classifiers across Multiple Sites in the Observational Health Sciences and Informatics (OHDSI) Network
Authors: Kashyap Mehr , Seneviratne Martin , Banda Juan M , Falconer Thomas , Ryu Borim , Yoo Sooyoung , Hripcsak George , Shah Nigam H
Published: June 2019

Objective

Accurate electronic phenotyping is essential to support collaborative observational research. Supervised machine learning methods can be used to train phenotype classifiers in a high-throughput manner using imperfectly labeled data. We developed ten phenotype classifiers using this approach and evaluated performance across multiple sites within the Observational Health Sciences and Informatics (OHDSI) network.

Materials and Methods

We constructed classifiers using the Automated PHenotype Routine for Observational Definition, Identification, Training and Evaluation (APHRODITE) R-package, an open-source framework for learning phenotype classifiers using datasets in the OMOP CDM. We labeled training data based on the presence of multiple mentions of disease-specific codes. Performance was evaluated on cohorts derived using rule-based definitions and real-world disease prevalence. Classifiers were developed and evaluated across three medical centers, including one international site.

Results

Compared to the multiple mentions labeling heuristic, classifiers showed a mean recall boost of 0.43 with a mean precision loss of 0.17. Performance decreased slightly when classifiers were shared across medical centers, with mean recall and precision decreasing by 0.08 and 0.01, respectively, at a site within the USA, and by 0.18 and 0.10, respectively, at an international site.

Discussion and Conclusion

We demonstrate a high-throughput pipeline for constructing and sharing phenotype classifiers across multiple sites within the OHDSI network using APHRODITE. Classifiers exhibit good portability between sites within the USA, however limited portability internationally, indicating that classifier generalizability may have geographic limitations, and consequently, sharing the classifier-building recipe, rather than the pre-trained classifiers, may be more useful for facilitating collaborative observational research.
Glycan size and attachment site location affect electron transfer dissociation (ETD) fragmentation and automated glycopeptide identification
Authors: Alagesan Kathirvel , Hinneburg Hannes , Seeberger Peter H , Varón Silva Daniel , Kolarich Daniel
Published: June 2019

We used a small synthetic glycopeptide library to systematically evaluate the effect of glycosylation site location and glycan size on the efficiency of ETD MS/MS fragmentation and subsequent automated identification. Understanding how the physico-chemical properties of glycopeptides influence glycopeptide fragmentation allows for optimizing fragmentation conditions and software assisted data analyses, which rely on informative fragmentation spectra for subsequent data processing to identify glycopeptides. Often, mis-assignment of glycopeptides occurs due to uncertainties such as failure to produce sufficient peptide backbone fragment ions. Our synthetic glycopeptide library contained glycopeptides differing in glycosylation site position within the peptide as well as glycan size (from the pentasaccharide N-glycan core to fully sialylated, biantennary N-glycans). Different software solutions such as SEQUEST and Amanda were compared for ETD glycopeptide identification. We found that all, glycan size, glycosylation site position within a glycopeptide and individual precursor m/z significantly impacted the number and quality of assignable glycopeptide backbone fragments, and thus the likelihood to be correctly identified in software assisted data analyses.
genesorteR: Feature Ranking in Clustered Single Cell Data
Authors: Ibrahim Mahmoud M , Kramann Rafael
Published: June 2019

Marker genes identified in single cell experiments are expected to be highly specific to a certain cell type and highly expressed in that cell type. Detecting a gene by differential expression analysis does not necessarily satisfy those two conditions and is typically computationally expensive for large cell numbers.

Here we present genesorteR, an R package that ranks features in single cell data in a manner consistent with the expected definition of marker genes in experimental biology research. We benchmark genesorteR using various data sets and show that it is distinctly more accurate in large single cell data sets compared to other methods. genesorteR is orders of magnitude faster than current implementations of differential expression analysis methods, can operate on data containing millions of cells and is applicable to both single cell RNA-Seq and single cell ATAC-Seq data.

genesorteR is available at https://github.com/mahmoudibrahim/genesorteR.
Genome-wide characterization of satellite DNA arrays in a complex plant genome using nanopore reads
Authors: Vondrak Tihana , Robledillo Laura Ávila , Novák Petr , Koblížková Andrea , Neumann Pavel , Macas Jiří
Published: June 2019

Background

Amplification of monomer sequences into long contiguous arrays is the main feature distinguishing satellite DNA from other tandem repeats, yet it is also the main obstacle in its investigation because these arrays are in principle difficult to assemble. Here we explore an alternative, assembly-free approach that utilizes ultra-long Oxford Nanopore reads to infer the length distribution of satellite repeat arrays, their association with other repeats and the prevailing sequence periodicities.

Results

We have developed a computational workflow for similarity-based detection and downstream analysis of satellite repeats in individual nanopore reads that led to genome-wide characterization of their properties. Using the satellite DNA-rich legume plantLathyrus sativusas a model, we demonstrated this approach by analyzing eleven major satellite repeats using a set of nanopore reads ranging from 30 to over 200 kb in length and representing 0.73x genome coverage. We found surprising differences between the analyzed repeats because only two of them were predominantly organized in long arrays typical for satellite DNA. The remaining nine satellites were found to be derived from short tandem arrays located within LTR-retrotransposons that occasionally expanded in length. While the corresponding LTR-retrotransposons were dispersed across the genome, this array expansion occurred mainly in the primary constrictions of theL. sativuschromosomes, which suggests that these genome regions are favorable for satellite DNA accumulation.

Conclusions

The presented approach proved to be efficient in revealing differences in long-range organization of satellite repeats that can be used to investigate their origin and evolution in the genome.
Discovering candidate imprinted genes and Imprinting Control Regions in the human genome
Authors: Bina Minou
Published: June 2019

Genomic imprinting is a process thereby a subset of genes is expressed in a parent-of-origin specific manner. This evolutionary novelty is restricted to mammals and controlled by genomic DNA segments known as Imprinting Control Regions (ICRs). The known imprinted genes function in many important developmental and postnatal processes including organogenesis, neurogenesis, and fertility. Furthermore, defects in imprinted genes could cause severe diseases and abnormalities. Because of the importance of the ICRs to the regulation of parent-of-origin specific gene expression, I developed a genome-wide strategy for their localization. This strategy located clusters of the ZFBS-Morph overlaps along the entire human genome. Previously, I showed that in the mouse genome, clusters of 2 or more of these overlaps correctly located ∼ 90% of the fully characterized ICRs and germline Differentially Methylated Regions (gDMRs). The ZFBS-Morph overlaps are composite-DNA-elements comprised of the ZFP57 binding site (ZFBS) overlapping a subset of the MLL1 morphemes. My strategy consists of creating plots to display the density of ZFBS-Morph overlaps along genomic DNA. Peaks in these plots pinpointed several of the known ICRs/gDMRs within relatively long genomic DNA sections and even along entire chromosomal DNA. Therefore, peaks in the density-plots are likely to reflect the positions of known or candidate ICRs. I also found that by locating the genes in the vicinity of candidate ICRs, I could discover potential and novel human imprinting genes. Additionally, my exploratory assessments revealed a connection between several of the potential imprinted genes and human developmental anomalies including syndromes.
Temperature-Dependent Regulation of Upstream Open Reading Frame Translation inS. Cerevisiae
Authors: Kulkarni Shardul D. , Zhou Fujun , Sen Neelam Dabas , Zhang Hongen , Hinnebusch Alan G. , Lorsch Jon R.
Published: June 2019

Background

Translation of an mRNA in eukaryotes starts at AUG in most cases. Near-cognate codons (NCCs) such as UUG, ACG and AUU are also used as start sites at low levels inS. cerevisiae. Initiation from NCCs or AUGs in the 5’-untranslated regions (UTRs) of mRNAs can lead to translation of upstream open reading frames (uORFs) that might regulate expression of the main ORF (mORF). Although there is some circumstantial evidence that the translation of uORFs can be affected by environmental conditions, little is known about how it is affected by changes in growth temperature.

Results

Using reporter assays, we found that changes in growth temperature can affect translation from NCC start sites in yeast cells, suggesting the possibility that gene expression could be regulated by temperature by altering use of different uORF start codons. Using ribosome profiling, we provide evidence that growth temperature regulates the efficiency of translation of nearly 200 uORFs inS. cerevisiae. Of these uORFs, most that start with an AUG codon have increased translational efficiency at 37 °C relative to 30 °C and decreased efficiency at 20 °C. For translationally regulated uORFs starting with NCCs, we did not observe a general trend for the direction of regulation as a function of temperature, suggesting mRNA-specific features can determine the mode of temperature-dependent regulation. Consistent with this conclusion, the position of the uORFs in the 5’-leader relative to the 5’-cap and the start codon of the main ORF correlates with the direction of temperature-dependent regulation of uORF translation. We have identified several novel cases in which changes in uORF translation are inversely correlated with changes in the translational efficiency of the downstream main ORF. Our data suggest that translation of these mRNAs is subject to temperature-dependent, uORF-mediated regulation.

Conclusions

Overall, our data suggest that alterations in the translation of specific uORFs by temperature can regulate gene expression inS. cerevisiae.
Vascular Progenitors Generated from Tankyrase Inhibitor-Regulated Naïve Diabetic Human iPSC Potentiate Efficient Revascularization of Ischemic Retina
Authors: Park Tea Soon , Zimmerlin Ludovic , Evans-Moses Rebecca , Thomas Justin , Huo Jeffrey S. , Kanherkar Riya , He Alice , Ruzgar Nensi , Grebe Rhonda , Bhutto Imran , Lutty Gerard , Zambidis Elias T.
Published: June 2019

Vascular regenerative therapies with conventional human induced pluripotent stem cells (hiPSC) currently remain limited by high interline variability of differentiation and poor efficiency for generating functionally transplantable vascular progenitors (VP). Here, we report the advantage of tankyrase inhibitor-regulated naïve hiPSC (N-hiPSC) for significantly improving vascular cell therapies. Conventional hiPSC reprogrammed from type-1 diabetic donor fibroblasts (DhiPSC) were stably reverted to naïve epiblast-like state with high functional pluripotency with a cocktail of LIF and three small molecules inhibiting the tankyrase, MEK, and GSK3β signaling pathways (LIF-3i). Naïve diabetic VP (N-DVP) differentiated from naïve DhiPSC (N-DhiPSC) expanded more efficiently, possessed higher proliferation, possessed more stable genomic integrity and displayed higher in vitro vascular functionality than primed diabetic VP (DVP) generated from isogenic conventional DhiPSC. Moreover, N-DVP survived, migrated, and engrafted in vivo into the deep vasculature of the neural retinal layers with significantly higher efficiencies than isogenic primed DVP in a murine model of ischemic retinopathy. Epigenetic analyses of CpG DNA methylation and histone configurations at developmental promoters of N-hiPSC revealed tight regulation of lineage-specific gene expression and a de-repressed naïve epiblast-like epigenetic state that was highly poised for multi-lineage transcriptional activation. We propose that reprogramming of patient donor cells to a tankyrase inhibitor-regulated N-hiPSC may more effectively erase epigenetic aberrations sustained from chronic diseases such as diabetes for subsequent regenerative therapies. More broadly, tankyrase inhibitor-regulated N-hiPSC represent a new class of human stem cells with high epigenetic plasticity, improved multi-lineage functionality, and potentially high impact for regenerative medicine.
A Universal Phase Transition in Plankton Trait Dynamics
Authors: Held Jenny , Lorimer Tom , Stoop Ruedi , Pomati Francesco , Albert Carlo
Published: June 2019

Key ecological traits, like cell size, often follow scale-free or self-similar distributions. This indicates that these systems might operate near a critical (i.e. second-order) phase transition where macroscopic system behaviour is largely decoupled from microscopic system details, allowing an extremely simple, yet accurate and robust mathematical system characterisation. However, how trait-distribution scaling results from a critical transition has not yet been explicitly demonstrated. Here, we demonstrate that a generic class of cell growth and division models exhibits a critical transition from a growth-dominated to a division-dominated phase. We find experimental evidence for this transition, both in the population dynamics and in the moment scaling of chlorophyll distributions, for prokaryotic and eukaryotic phytoplankton growth under different light intensities. Our approach offers testable predictions of the response of unicellular trait-distributions to perturbations.