bluuebunny/crossref_metadata_2025 huggingface dataset:
Indiana Social-Emotional Learning Competencies: A Neurodevelopmental, Culturally Responsive Framework
Authors: Oliver Brandie M. , Berger Christy T.
Published: March 2020

Social/emotional learning (SEL) programs and practices have gained momentum across the state of Indiana in recent years in response to the changing needs of students and families. Many school communities have adopted SEL due to the heightened challenges posed by students impacted by trauma or chronic stress. As schools began to adopt SEL programs and practices, the Indiana Department of Education responded by developing the Indiana SEL Competencies to provide a unified framework and several resources with which educators in the state continue to evolve their work. This article outlines foundational principles of SEL, highlights unique aspects of the Indiana SEL Competencies, and presents implications for the school counselor’s role in working toward systemic implementation of SEL.
School Counselors’ Impact on School-Level Academic Outcomes: Caseload and Use of Time
Authors: Shi Qi , Brown Margaux H.
Published: March 2020

Using the High School Longitudinal Study of 2009, we investigated school counselors’ caseloads, how they spent their time, and the impact of those factors on schools’ academic outcomes. Results showed that approximately 85% of the school counselors had a caseload of 455 or fewer students, with roughly one quarter reporting caseloads equal to or less than 250, and that school counselors spent more of their time on college, scheduling, and personal/social/academic/career development. We also found that how school counselors spent their time was predictive of ninth-grade retention rates, the percentage of students who enrolled in Advanced Placement (AP) courses, and the percentage of students who enrolled in 4-year universities. We provide discussion and implications for school counselors.
Demonstrating School Counselor Efficacy in Individual Interventions Using Single-Case Research Design: A Guided Process
Authors: Sowell Shaun M. , Hunter Quentin , Richey Katelyn Gosnell , Baxter Christopher
Published: March 2020

School counselors are tasked with many activities, including demonstrating the effectiveness of interventions they use with students. The American School Counselor Association recommends that school counselors include assessment, appraisal, and evaluation of delivery and program management in their school counseling program. Single-case research design is a data collection and analysis strategy that can assist school counselors with this task. We developed the Impact of Intervention tool to provide school counselors a tool to streamline the data collection process.
Evidence-Based School Counseling: Expanding the Existing Paradigm
Authors: Dimmitt Carey , Zyromski Brett
Published: March 2020

This special edition of Professional School Counseling provides some of the key proceedings from the seventh annual Evidence-based School Counseling Conference (EBSCC). As the conceptual and practical aspects of conducting evidence-based school counseling (EBSC) have evolved, those changes are reflected in the conference content. This article identifies some of the ways that EBSC has progressed, including making sure that multiple aspects of student well-being—such as mental health and social-emotional learning—are given full consideration, increased attention to complex social contexts and student intersectional identities, new ways of thinking about what data to use and how to use it to make decisions and to show impact, as well as methods for teaching prospective school counselors how to most effectively practice EBSC.
Do Cognitive Tasks Reduce Intrusive-Memory Frequency After Exposure to Analogue Trauma? An Experimental Replication
Authors: Badawi Amalia , Berle David , Rogers Kris , Steel Zachary
Published: March 2020

Cognitive task interventions that interfere with visuospatial working memory during the memory consolidation window hold promise for reducing intrusive memories in trauma-exposed people. Our study provides an independent replication study to test and verify findings that have primarily originated from a single research group. We hypothesized that participants engaging in a visuospatial task (cognitive task intervention including Tetris or D-Corsi) following a trauma-film paradigm (TFP) would report fewer intrusive memories over the course of a week compared with control participants. Participants ( N = 110) were randomly assigned to an experimental condition after viewing the TFP. Generalized linear mixed models indicated that the cognitive task including Tetris was associated with fewer intrusions for the TFP compared with both the D-Corsi-intervention and control conditions. Our findings are congruent with existing literature indicating that cognitive tasks, such as an intervention including Tetris, may promote effective memory consolidation after exposure to a potentially traumatic event.
Examining the relationship between rheumatoid arthritis, multimorbidity and adverse health-related outcomes: A systematic review protocol
Authors: Canning Jordan , Siebert Stefan , Jani Bhautesh D , Mair Frances S , Nicholl Barbara I
Published: March 2020

Background:

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterised by articular inflammation and systemic complications. Multimorbidity (the presence of two or more long-term health conditions) is highly prevalent in people with RA but the effect of multimorbidity on mortality and other health-related outcomes is poorly understood.

Objective:

To determine what is known about the effect, if any, of multimorbidity on mortality and health-related outcomes in individuals with RA.

Design:

Systematic review of the literature. The following electronic medical databases will be searched: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, The Cochrane Library and Scopus. Included studies will be quality appraised using the Quality in Prognostic Studies tool developed by the Cochrane Prognosis Methods Group. A narrative synthesis of findings will be undertaken and meta-analyses considered, if appropriate. This protocol adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols 2015 guidelines, ensuring the quality of the review.

Conclusions:

Understanding the influence of multimorbidity on mortality and other health-related outcomes in RA will provide an important basis of knowledge with the potential to improve future clinical management of RA. PROSPERO registration number: CRD42019137756.
Endodontic Management of Canal Calcification in Maxillary Central Incisor Using 3D Prototyping Technique: A Case Report
Authors: Doranala Suryasowjanya , Vemisetty Harikumar , Punna Rajani , Alwala Aditya Mohan
Published: March 2020

Teeth with calcific metamorphosis pose a challenge to the endodontist in achieving proper access, identification, and debridement of the root canal. With the conventional technique, radiographs and bur orientation have dictated the access cavity preparation, which leads to the removal of more sound tooth structure and iatrogenic errors. To overcome these issues, the recent diagnostic imaging techniques such as cone beam computed tomography followed by three-dimensional fabrication of template have been proposed, which aid the clinician to accurately locate and negotiate the obliterated canal. The present case report describes the importance of conservative access cavity preparation with the use of the guided endodontic technique for the treatment of calcified canals in the maxillary central incisor.
An Analysis of the Effects of North Carolina’s Opportunity Scholarship Program on Student Achievement
Authors: Egalite Anna J. , Stallings D. T. , Porter Stephen R.
Published: March 2020

The North Carolina Opportunity Scholarship Program is a private school voucher program that provides state-funded vouchers worth up to $4,200 to eligible students entering kindergarten through 12th grade. Because the public and private school sectors administer different assessments, we recruited approximately 700 students to take a common, nationally normed, standardized test. Matching on baseline achievement and rich demographic data, we use a quasi-experimental inverse propensity weighting approach to maximize comparability between the public and private school student samples. Our preferred specification examines first-year effects for new Opportunity Scholarship students, revealing positive estimates of .36 SD in math and .44 SD in language; there is no effect on reading scores. Results for renewal students are statistically significant in language scores only. In further analyses, we estimate separate effects for private schools that regularly administer another version of the assessment used in this study, the Iowa Test of Basic Skills. We conclude by discussing policy implications.
The history of zinc and its use in pre-modern India
Authors: Alam Ishrat
Published: March 2020

The extraction of zinc from ores began late in history, mainly because of the fact that it tended to evaporate when smelting in the open was attempted. It was only when closed stills began to be used for liquor distillation that the same method could be adopted for zinc. This technique began to be used in China and India in medieval times, the major zinc mine in India being at Jāwar in Mewar, Rajasthan. These mines remained in operation till at least well into the seventeenth century, when zinc imports from China apparently made zinc extraction at Jāwar unprofitable and the mines closed down. The famous Bidri ware datable to the eighteenth century seems to have depended for its zinc on China.
Footfall signatures and volumes: Towards a classification of UK centres
Authors: Mumford Christine , Parker Cathy , Ntounis Nikolaos , Dargan Ed
Published: March 2020

The changing nature of retail coupled with rapid technological and social developments, are posing great challenges to the attractiveness of traditional retail areas in the UK. In this paper we argue that the definitions and classifications of town centres currently adopted by UK planners and policy makers are outdated, because of their focus on retail occupancy. Instead, we propose a more dynamic definition and classification of centres, based on their activity volumes and patterns, which we obtain from footfall data. Our expectation is that adopting this activity-based approach to defining and classifying centres will radically alter the way in which they are developed and managed.
Micromachining: An overview (Part I)
Authors: Jain Vijay Kumar , Balasubramaniam R. , Mote Rakesh Ganpat , Das Manas , Sharma Anuj , Kumar Abhinav , Garg Vivek , Kamaliya Bhaveshkumar
Published: March 2020

This article gives classification of micromanufacturing in general and micromachining processes in particular. For different micromachining processes, one can have different kinds of operations through which different features, shapes, accuracy, precision, and dimensions can be achieved. This article as Part I reports an overview of only three processes as diamond turn machining (a class of traditional micromachining processes), electrochemical micromachining, and focused-ion-beam micromachining (a class of advanced micromachining processes). About all these three processes, a brief introduction to the mechanisms of material removal is reported followed by the new developments in each process which are discussed independently. In various sections, some areas where research work needs to be done are identified and very briefly discussed.
Study on ice adhesion of composite anti-/deicing component under heating condition
Authors: Zhang Yishu , Chen Long , Liu Hui
Published: March 2020

An anti-/deicing component of composite materials for wind turbine blades is usually carried out under heating conditions. In order to study the ice adhesion properties of composite anti-/deicing component under heating conditions, an experimental platform for measuring ice adhesion force on composites was set up. Based on the heating parameters such as the heating temperature, heating voltage, and heating time, the experiments of ice adhesion of composite anti-/deicing component under deicing conditions were designed by orthogonal analysis. In this article, ice adhesion forces on composite anti-/deicing component were measured at −9.74°C, −11.58°C, −14.1°C, and −16.84°C by the proposed experiment platform, and the real ice adhesion forces under various heating parameters were measured. Through the analysis of experimental data and fitting method, the relationship between various factors and ice adhesion on composite anti-/deicing component was expounded. The influence weight of each heating parameter on the ice adhesion was analyzed. In addition, the mathematical model of ice adhesion on composite anti-/deicing component under deicing condition was established to describe the influence of deicing variables on ice adhesion in the experiments. According to the fitting function of the experimental data, the relationship between the heat consumption of composite anti-/deicing component and ice adhesion force in the process of heating is in accordance with the inverse power exponential expression, which reveals the internal relationship between ice adhesion force and energy consumption.
Pseudomeisserite-(NH4), a new mineral with a novel uranyl-sulfate linkage from the Blue Lizard mine, San Juan County, Utah, USA
Authors: Kampf Anthony R. , Olds Travis A. , Plášil Jakub , Nash Barbara P. , Marty Joe
Published: March 2020

The new mineral pseudomeisserite-(NH4) (IMA2018-166), (NH4,K)2Na4[(UO2)2(SO4)5]⋅4H2O, was found in the Blue Lizard mine, San Juan County, Utah, USA, where it occurs as light yellow prisms in a secondary assemblage with belakovskiite, blödite, changoite, ferrinatrite, gypsum, ivsite, metavoltine and tamarugite. The streak is very pale yellow and the fluorescence is bright lime green under 405 nm ultraviolet light. Crystals are transparent with vitreous lustre. The tenacity is brittle, the Mohs hardness is 2½, the fracture is curved or conchoidal and there is one perfect cleavage on {100}. The mineral is easily soluble in H2O and has a measured density of 3.22(2) g⋅cm–3. Pseudomeisserite-(NH4) is optically biaxial (–) with α = 1.536(2), β = 1.559(2) and γ = 1.565(2) (white light); 2Vmeas. = 53(1)°; dispersion is r > v, distinct; pleochroism: X colourless, Y light yellow and Z pale yellow (X < Z < Y); optical orientation: Z = b, Y ∧ c = 33° in obtuse β). Electron microprobe analyses (WDS mode) provided (NH4)1.49K0.60Na3.87U2.00S5.04O28H7.78. The five strongest X-ray powder diffraction lines are [dobs, Å(I)(hkl)]: 12.69(76)(100), 6.83(84)(012,102), 6.01(100)($\bar{2}$02), 3.959(67)($\bar{2}$21,$\bar{2}$14,$\bar{1}$23) and 3.135(76)($\bar{2}$06,223,$\bar{1}$16). Pseudomeisserite-(NH4) is monoclinic, P21/c, a = 13.1010(3), b = 10.0948(2), c = 19.4945(14) Å, β = 104.285(7)°, V = 2498.5(2) Å3 and Z = 4. The structural unit in the structure (R1 = 0.0254 for 3837 I > 2σI reflections) is a novel [(UO2)2(SO4)5]6– uranyl-sulfate band.
Ldb1 is required for Lmo2 oncogene–induced thymocyte self-renewal and T-cell acute lymphoblastic leukemia
Authors: Li LiQi , Mitra Apratim , Cui Kairong , Zhao Bin , Choi Seeyoung , Lee Jan Y. , Stamos Daniel B. , El-Khoury Dalal , Warzecha Claude , Pfeifer Karl , Hardwick Joyce , Zhao Keji , Venters Bryan , Davé Utpal P. , Love Paul E.
Published: March 2020

Prolonged or enhanced expression of the proto-oncogene Lmo2 is associated with a severe form of T-cell acute lymphoblastic leukemia (T-ALL), designated early T-cell precursor ALL, which is characterized by the aberrant self-renewal and subsequent oncogenic transformation of immature thymocytes. It has been suggested that Lmo2 exerts these effects by functioning as component of a multi-subunit transcription complex that includes the ubiquitous adapter Ldb1 along with b-HLH and/or GATA family transcription factors; however, direct experimental evidence for this mechanism is lacking. In this study, we investigated the importance of Ldb1 for Lmo2-induced T-ALL by conditional deletion of Ldb1 in thymocytes in an Lmo2 transgenic mouse model of T-ALL. Our results identify a critical requirement for Ldb1 in Lmo2-induced thymocyte self-renewal and thymocyte radiation resistance and for the transition of preleukemic thymocytes to overt T-ALL. Moreover, Ldb1 was also required for acquisition of the aberrant preleukemic ETP gene expression signature in immature Lmo2 transgenic thymocytes. Co-binding of Ldb1 and Lmo2 was detected at the promoters of key upregulated T-ALL driver genes (Hhex, Lyl1, and Nfe2) in preleukemic Lmo2 transgenic thymocytes, and binding of both Ldb1 and Lmo2 at these sites was reduced following Cre-mediated deletion of Ldb1. Together, these results identify a key role for Ldb1, a nonproto-oncogene, in T-ALL and support a model in which Lmo2-induced T-ALL results from failure to downregulate Ldb1/Lmo2-nucleated transcription complexes which normally function to enforce self-renewal in bone marrow hematopoietic progenitors.
Clonal hematopoiesis evolves from pretreatment clones and stabilizes after end of chemotherapy in patients with MCL
Authors: Eskelund Christian Winther , Husby Simon , Favero Francesco , Klausen Tobias Wirenfeldt , Rodriguez-Gonzalez Francisco German , Kolstad Arne , Pedersen Lone Bredo , Räty Riikka Katariina , Geisler Christian H. , Jerkeman Mats , Weischenfeldt Joachim , Grønbæk Kirsten
Published: March 2020

Eskelund et al examined clonal hematopoiesis (CH) in a cohort of patients with mantle cell lymphoma (MCL) treated with first-line chemotherapy and autologous stem cell transplantation. In young, good-risk MCL patients, CH after first-line therapy arises almost entirely from preexisting clones, stabilizes after a period of expansion posttransplantation, and does not negatively impact survival.
Outcomes of older patients in ZUMA-1, a pivotal study of axicabtagene ciloleucel in refractory large B-cell lymphoma
Authors: Neelapu Sattva S. , Jacobson Caron A. , Oluwole Olalekan O. , Munoz Javier , Deol Abhinav , Miklos David B. , Bartlett Nancy L. , Braunschweig Ira , Jiang Yizhou , Kim Jenny J. , Zheng Lianqing , Rossi John M. , Locke Frederick L.
Published: March 2020

Neelapu and colleagues report a post hoc subgroup analysis from the ZUMA-1 trial of chimeric antigen receptor T-cell therapy for relapsed or refractory diffuse large B cell lymphoma. In comparison with younger patients, those ≥65 years old have similar rates of complete response and durable response at 2 years, but higher rates of neurological toxicity.
Migraine, headache, and mortality in women: a cohort study
Authors: Rohmann Jessica L. , Rist Pamela M. , Buring Julie E. , Kurth Tobias
Published: March 2020

Background

Migraine carries a high global burden, disproportionately affects women, and has been implicated as a risk factor for cardiovascular disease. Migraine with aura has been consistently associated with increased risk of cardiovascular mortality. However, published evidence on relationships between migraine or non-migraine headache and all-cause mortality is inconclusive. Therefore, we aimed to estimate the effect of non-migraine headache and migraine as well as migraine subtypes on all-cause and cause-specific mortality in women.

Methods

In total, 27,844 Women’s Health Study participants, aged 45 years or older at baseline, were followed up for a median of 22.7 years. We included participants who provided information on migraine (past history, migraine without aura, or migraine with aura) or headache status and a blood sample at study start. An endpoints committee of physicians evaluated reports of incident deaths and used medical records to confirm deaths due to cardiovascular, cancer, or female-specific cancer causes. We used multivariable Cox proportional hazards models to estimate the effect of migraine or headache status on both all-cause and cause-specific mortality.

Results

Compared to individuals without any headache, no differences in all-cause mortality for individuals suffering from non-migraine headache or any migraine were observed after adjustment for confounding (HR = 1.01, 95%CI, 0.93–1.10 and HR = 0.96, 95% CI: 0.89–1.04). No differences were observed for the migraine subtypes and all-cause death. Women having the migraine with aura subtype had  a higher mortality due to cardiovascular disease (adjusted HR = 1.64, 95%CI: 1.06–2.54). As an explanation for the lack of overall association with all-cause mortality, we observed slightly protective signals for any cancer and female-specific cancers in this group.

Conclusions

In this large prospective study of women, we found no association between non-migraine headache or migraine and all-cause mortality. Women suffering from migraine with aura had an increased risk of cardiovascular death. Future studies should investigate the reasons for the increased risk of cardiovascular mortality and evaluate whether changes in migraine patterns across the life course have differential effects on mortality.
European Headache Federation recommendations for neurologists managing giant cell arteritis
Authors: Mollan S. P. , Paemeleire K. , Versijpt J. , Luqmani R. , Sinclair A. J.
Published: March 2020

Background and aim

Giant cell arteritis (GCA) remains a medical emergency because of the risk of sudden irreversible sight loss and rarely stroke along with other complications. Because headache is one of the cardinal symptoms of cranial GCA, neurologists need to be up to date with the advances in investigation and management of this condition. The aim of this document by the European Headache Federation (EHF) is to provide an evidence-based and expert-based recommendations on GCA.

Methods

The working group identified relevant questions, performed systematic literature review and assessed the quality of available evidence, and wrote recommendations. Where there was not a high level of evidence, the multidisciplinary (neurology, ophthalmology and rheumatology) group recommended best practice based on their clinical experience.

Results

Across Europe, fast track pathways and the utility of advanced imaging techniques are helping to reduce diagnostic delay and uncertainty, with improved clinical outcomes for patients. GCA is treated with high dose glucocorticoids (GC) as a first line agent however long-term GC toxicity is one of the key concerns for clinicians and patients. The first phase 2 and phase 3 randomised controlled trials of Tocilizumab, an IL-6 receptor antagonist, have been published. It is now been approved as the first ever licensed drug to be used in GCA.

Conclusion

The present article will outline recent advances made in the diagnosis and management of GCA.
LncRNA CASC2 inhibits hypoxia-induced pulmonary artery smooth muscle cell proliferation and migration by regulating the miR-222/ING5 axis
Authors: Han Yan , Liu Yuhao , Yang Chaokuan , Gao Chuanyu , Guo Xiaoyan , Cheng Jiangtao
Published: March 2020

Background

Pulmonary arterial hypertension (PAH) is often characterized by cell proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). LncRNA cancer susceptibility candidate 2 (CASC2) has been revealed to be involved in PASMC injury in hypoxia-induced pulmonary hypertension. However, the exact molecular mechanisms whereby CASC2 regulates PASMC proliferation and migration are still incompletely understood.

Methods

The expression levels of CASC2, miR-222 and inhibitor of growth 5 (ING5) were measured using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot, respectively. Cell proliferation was analyzed by Cell Counting Kit-8 (CCK-8) assay. Wound healing assay was used to analyze cell migration ability. The relationship between miR-222 and CASC2 or ING5 was confirmed using bioinformatics analysis, luciferase reporter assay and RNA immunoprecipitation assay.

Results

CASC2 was down-regulated in hypoxia-induced PASMCs in a dose- and time-dependent manner. Functional experiments showed that CASC2 overexpression could reverse hypoxia-induced proliferation and migration of PASMCs. Bioinformatics analysis indicated that CASC2 acted as a competing endogenous RNA of miR-222, thereby regulating the expression of ING5, the downstream target of miR-222, in PASMCs. In addition, rescue assay suggested that the inhibition mediated by CASC2 of hypoxia-induced PASMC proliferation and migration could be attenuated by miR-222 inhibition or ING5 overexpression.

Conclusion

CASC2 attenuated hypoxia-induced PASMC proliferation and migration by regulating the miR-222/ING5 axis to prevent vascular remodeling and the development of PAH, providing a novel insight and therapeutic strategy for hypoxia-induced PAH.
MiR-206 may suppress non-small lung cancer metastasis by targeting CORO1C
Authors: Liao Ming , Peng Lijun
Published: March 2020

Object

Non-small lung cancer (NSCLC), with a poor 5-year survival rate (16%), is the major type of lung cancer. Metastasis has been identified as the main factor that leads to NSCLC therapy failure. MiR-206 is a metastasis suppressor in many cancers, including colorectal cancer, renal cell carcinoma and breast cancer. However, the role of miR-206 in NSCLC metastasis and the underlying mechanism are still obscure.

Methods

Quantitative reverse-transcription PCR (q-RT-PCR) assay was used to detect miR-206 mRNA of NSCLC tissues and lung cancer lines. The MTT assay, scratch wound healing assay, transwell migration assay and transwell invasion assay were conducted to illuminate the effect of miR-206 on A549 cells’ proliferation, migration and invasion. Gaussia luciferase reporter assay, q-RT-PCR and western blotting assay were used to explore the underlying mechanism. Also, the A549 xenograft model was conducted to evaluate the anti-tumor effect of miR-206 in vivo.

Results

The results showed that miR-206 expression was decreased in NSCLC tissues and lung cancer cells. Further research demonstrated that miR-206 inhibited the proliferation, migration and invasion of A549 cells via negatively regulating Coronin-1C (CORO1C), and CORO1C deletion significantly rescues the miR-206 mediated inhibitory effect on A549 cells. Moreover, miR-206 exhibited a perfect anti-tumor effect in the A549 xenograft model.

Conclusion

Our study reveals that miR-206 functions as a tumor metastasis suppressor and sheds new light on the clinical significance of miR-206 in NSCLC therapy.
Identification of the ABCC4, IER3, and CBFA2T2 candidate genes for resistance to paratuberculosis from sequence-based GWAS in Holstein and Normande dairy cattle
Authors: Sanchez Marie-Pierre , Guatteo Raphaël , Davergne Aurore , Saout Judikael , Grohs Cécile , Deloche Marie-Christine , Taussat Sébastien , Fritz Sébastien , Boussaha Mekki , Blanquefort Philippe , Delafosse Arnaud , Joly Alain , Schibler Laurent , Fourichon Christine , Boichard Didier
Published: March 2020

Background

Bovine paratuberculosis is a contagious disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), with adverse effects on animal welfare and serious economic consequences. Published results on host genetic resistance to MAP are inconsistent, mainly because of difficulties in characterizing the infection status of cows. The objectives of this study were to identify quantitative trait loci (QTL) for resistance to MAP in Holstein and Normande cows with an accurately defined status for MAP.

Results

From MAP-infected herds, cows without clinical signs of disease were subjected to at least four repeated serum ELISA and fecal PCR tests over time to determine both infected and non-infected statuses. Clinical cases were confirmed using PCR. Only cows that had concordant results for all tests were included in further analyses. Positive and control cows were matched within herd according to their birth date to ensure a same level of exposure to MAP. Cows with accurate phenotypes, i.e. unaffected (control) or affected (clinical or non-clinical cases), were genotyped with the Illumina BovineSNP50 BeadChip. Genotypes were imputed to whole-genome sequences using the 1000 Bull Genomes reference population (run6). A genome-wide association study (GWAS) of MAP status of 1644 Holstein and 649 Normande cows, using either two (controls versus cases) or three classes of phenotype (controls, non-clinical and clinical cases), revealed three regions, on Bos taurus (BTA) chromosomes 12, 13, and 23, presenting significant effects in Holstein cows, while only one of those was identified in Normande cows (BTA23). The most significant effect was found on BTA13, in a short 8.5-kb region. Conditional analyses revealed that only one causal variant may be responsible for the effects observed on each chromosome with the ABCC4 (BTA12), CBFA2T2 (BTA13), and IER3 (BTA23) genes as good functional candidates.

Conclusions

A sequence-based GWAS on cows for which resistance to MAP was accurately defined, was able to identify candidate variants located in genes that were functionally related to resistance to MAP; these explained up to 28% of the genetic variance of the trait. These results are very encouraging for efforts towards implementation of a breeding strategy aimed at improving resistance to paratuberculosis in Holstein cows.
AllEnricher: a comprehensive gene set function enrichment tool for both model and non-model species
Authors: Zhang Du , Hu Qi , Liu Xinxing , Zou Kai , Sarkodie Emmanuel Konadu , Liu Xueduan , Gao Fei
Published: March 2020

Background

Function genomic studies will generally result in lists of genes that may provide clues for exploring biological questions and discovering unanticipated functions, based on differential gene expression analysis, differential epigenomic analysis or co-expression network analysis. While tools have been developed to identify biological functions that are enriched in the genes sets, there remains a need for comprehensive tools that identify functional enrichment of genes for both model and non-model species from a different function classification perspective.

Results

We developed AllEnricher, a tool that calculates gene set function enrichment, with user-defined updatable libraries backing up for both model and non-model species as well as providing comprehensive functional interpretation from multiple dimensions, including GO, KEGG, Reactome, DO and DisGeNET.

Conclusions

AllEnricher incorporates up to date information from different public resources and provides a comprehensive resolution for biologists to make sense out of specific gene sets, making it an advanced open-source tool for gene set function analysis.
Variant effect predictions capture some aspects of deep mutational scanning experiments
Authors: Reeb Jonas , Wirth Theresa , Rost Burkhard
Published: March 2020

Background

Deep mutational scanning (DMS) studies exploit the mutational landscape of sequence variation by systematically and comprehensively assaying the effect of single amino acid variants (SAVs; also referred to as missense mutations, or non-synonymous Single Nucleotide Variants – missense SNVs or nsSNVs) for particular proteins. We assembled SAV annotations from 22 different DMS experiments and normalized the effect scores to evaluate variant effect prediction methods. Three trained on traditional variant effect data (PolyPhen-2, SIFT, SNAP2), a regression method optimized on DMS data (Envision), and a naïve prediction using conservation information from homologs.

Results

On a set of 32,981 SAVs, all methods captured some aspects of the experimental effect scores, albeit not the same. Traditional methods such as SNAP2 correlated slightly more with measurements and better classified binary states (effect or neutral). Envision appeared to better estimate the precise degree of effect. Most surprising was that the simple naïve conservation approach using PSI-BLAST in many cases outperformed other methods. All methods captured beneficial effects (gain-of-function) significantly worse than deleterious (loss-of-function). For the few proteins with multiple independent experimental measurements, experiments differed substantially, but agreed more with each other than with predictions.

Conclusions

DMS provides a new powerful experimental means of understanding the dynamics of the protein sequence space. As always, promising new beginnings have to overcome challenges. While our results demonstrated that DMS will be crucial to improve variant effect prediction methods, data diversity hindered simplification and generalization.
MethylNet: an automated and modular deep learning approach for DNA methylation analysis
Authors: Levy Joshua J. , Titus Alexander J. , Petersen Curtis L. , Chen Youdinghuan , Salas Lucas A. , Christensen Brock C.
Published: March 2020

Background

DNA methylation (DNAm) is an epigenetic regulator of gene expression programs that can be altered by environmental exposures, aging, and in pathogenesis. Traditional analyses that associate DNAm alterations with phenotypes suffer from multiple hypothesis testing and multi-collinearity due to the high-dimensional, continuous, interacting and non-linear nature of the data. Deep learning analyses have shown much promise to study disease heterogeneity. DNAm deep learning approaches have not yet been formalized into user-friendly frameworks for execution, training, and interpreting models. Here, we describe MethylNet, a DNAm deep learning method that can construct embeddings, make predictions, generate new data, and uncover unknown heterogeneity with minimal user supervision.

Results

The results of our experiments indicate that MethylNet can study cellular differences, grasp higher order information of cancer sub-types, estimate age and capture factors associated with smoking in concordance with known differences.

Conclusion

The ability of MethylNet to capture nonlinear interactions presents an opportunity for further study of unknown disease, cellular heterogeneity and aging processes.
On rare variants in principal component analysis of population stratification
Authors: Ma Shengqing , Shi Gang
Published: March 2020

Background

Population stratification is a known confounder of genome-wide association studies, as it can lead to false positive results. Principal component analysis (PCA) method is widely applied in the analysis of population structure with common variants. However, it is still unclear about the analysis performance when rare variants are used.

Results

We derive a mathematical expectation of the genetic relationship matrix. Variance and covariance elements of the expected matrix depend explicitly on allele frequencies of the genetic markers used in the PCA analysis. We show that inter-population variance is solely contained inKprincipal components (PCs) and mostly in the largestK-1 PCs, whereKis the number of populations in the samples. We propose FPC, ratio of the inter-population variance to the intra-population variance in theKpopulation informative PCs, andd2, sum of squared distances among populations, as measures of population divergence. We show analytically that when allele frequencies become small, the ratio FPCabates, the population distanced2decreases, and portion of variance explained by theKPCs diminishes. The results are validated in the analysis of the 1000 Genomes Project data. The ratio FPCis 93.85, population distanced2is 444.38, and variance explained by the largest five PCs is 17.09% when using with common variants with allele frequencies between 0.4 and 0.5. However, the ratio, distance and percentage decrease to 1.83, 17.83 and 0.74%, respectively, with rare variants of frequencies between 0.0001 and 0.01.

Conclusions

The PCA of population stratification performs worse with rare variants than with common ones. It is necessary to restrict the selection to only the common variants when analyzing population stratification with sequencing data.
Genome relationships and LTR-retrotransposon diversity in three cultivated Capsicum L. (Solanaceae) species
Authors: de Assis Rafael , Baba Viviane Yumi , Cintra Leonardo Adabo , Gonçalves Leandro Simões Azeredo , Rodrigues Rosana , Vanzela André Luís Laforga
Published: March 2020

Background

Plant genomes are rich in repetitive sequences, and transposable elements (TEs) are the most accumulated of them. This mobile fraction can be distinguished as Class I (retrotransposons) and Class II (transposons). Retrotransposons that are transposed using an intermediate RNA and that accumulate in a “copy-and-paste” manner were screened in three genomes of peppers (Solanaceae). The present study aimed to understand the genome relationships among Capsicum annuum, C. chinense, and C. baccatum, based on a comparative analysis of the function, diversity and chromosome distribution of TE lineages in the Capsicum karyotypes. Due to the great commercial importance of pepper in natura, as a spice or as an ornamental plant, these genomes have been widely sequenced, and all of the assemblies are available in the SolGenomics group. These sequences were used to compare all repetitive fractions from a cytogenomic point of view.

Results

The qualification and quantification of LTR-retrotransposons (LTR-RT) families were contrasted with molecular cytogenetic data, and the results showed a strong genome similarity between C. annuum and C. chinense as compared to C. baccatum. The Gypsy superfamily is more abundant than Copia, especially for Tekay/Del lineage members, including a high representation in C. annuum and C. chinense. On the other hand, C. baccatum accumulates more Athila/Tat sequences. The FISH results showed retrotransposons differentially scattered along chromosomes, except for CRM lineage sequences, which mainly have a proximal accumulation associated with heterochromatin bands.

Conclusions

The results confirm a close genomic relationship between C. annuum and C. chinense in comparison to C. baccatum. Centromeric GC-rich bands may be associated with the accumulation regions of CRM elements, whereas terminal and subterminal AT- and GC-rich bands do not correspond to the accumulation of the retrotransposons in the three Capsicum species tested.
ITR-Seq, a next-generation sequencing assay, identifies genome-wide DNA editing sites in vivo following adeno-associated viral vector-mediated genome editing
Authors: Breton Camilo , Clark Peter M. , Wang Lili , Greig Jenny A. , Wilson James M.
Published: March 2020

Background

Identifying nuclease-induced double-stranded breaks in DNA on a genome-wide scale is critical for assessing the safety and efficacy of genome editing therapies. We previously demonstrated that after administering adeno-associated viral (AAV) vector-mediated genome-editing strategies in vivo, vector sequences integrated into the host organism’s genomic DNA at double-stranded breaks. Thus, identifying the genomic location of inserted AAV sequences would enable us to identify DSB events, mainly derived from the nuclease on- and off-target activity.

Results

Here, we developed a next-generation sequencing assay that detects insertions of specific AAV vector sequences called inverted terminal repeats (ITRs). This assay, ITR-Seq, enables us to identify off-target nuclease activity in vivo. Using ITR-Seq, we analyzed liver DNA samples of rhesus macaques treated with AAV vectors expressing a meganuclease. We found dose-dependent off-target activity and reductions in off-target events induced by further meganuclease development. In mice, we identified the genomic locations of ITR integration after treatment with Cas9 nucleases and their corresponding single-guide RNAs.

Conclusions

In sum, ITR-Seq is a powerful method for identifying off-target sequences induced by AAV vector-delivered genome-editing nucleases. ITR-Seq will help us understand the specificity and efficacy of different genome-editing nucleases in animal models and clinical studies. This information can help enhance the safety profile of gene-editing therapies.
Genetic dissection of grain water content and dehydration rate related to mechanical harvest in maize
Authors: Liu Jianju , Yu Hui , Liu Yuanliang , Deng Suining , Liu Qingcai , Liu Baoshen , Xu Mingliang
Published: March 2020

Background

The low grain water content (GWC) at harvest is a prerequisite to mechanical harvesting in maize, or otherwise would cause massive broken kernels and increase drying costs. The GWC at harvest in turn depends on GWC at the physiological maturity (PM) stage and grain dehydration rate (GDR). Both GWC and GDR are very complex traits, governed by multiple quantitative trait loci (QTL) and easily influenced by environmental conditions. So far, a number of experiments have been conducted to reveal numbers of GWC and GDR QTL, however, very few QTL have been confirmed, and no QTL has been fine-mapped or even been cloned.

Results

We demonstrated that GWCs after PM were positively correlated with GWC at PM, whereas negatively with GDRs after PM. With a recombinant inbred line (RIL) population, we identified totally 31 QTL related to GWC and 17 QTL related to GDR in three field trials. Seven GWC QTL were consistently detected in at least two of the three field trials, each of which could explain 6.92–24.78% of the total GWC variation. Similarly, one GDR QTL was consistently detected, accounting for 9.44–14.46% of the total GDR variation. Three major GWC QTL were found to overlap with three GDR QTL in bins 1.05/06, 2.06/07, and 3.05, respectively. One of the consistent GWC QTL, namelyqGwc1.1, was fine-mapped from a 27.22 Mb to a 2.05 Mb region by using recombinant-derived progeny test. TheqGwc1.1acted in a semi-dominant manner to reduce GWC by 1.49–3.31%.

Conclusions

A number of consistent GWC and GDR QTL have been identified, and one of them, QTL-qGwc1.1, was successfully refined into a 2.05 Mb region. Hence, it is realistic to clone the genes underlying the GWC and GDR QTL and to make use of them in breeding of maize varieties with low GWC at harvest.
The association between anthropometric measures of adiposity and the progression of carotid atherosclerosis
Authors: Imahori Yume , Mathiesen Ellisiv B. , Morgan Katy E. , Frost Chris , Hughes Alun D. , Hopstock Laila A. , Johnsen Stein Harald , Emaus Nina , Leon David A.
Published: March 2020

Background

Few reports are available on the contribution of general and abdominal obesity to the progression of carotid atherosclerosis in late adulthood. This study investigated the impact of four simple anthropometric measures of general and abdominal obesity on the progression of carotid atherosclerosis and the extent to which the association between adiposity and the progression of plaque burden is mediated by cardiometabolic markers.

Methods

Four thousand three hundred forty-five adults (median age 60) from the population-based Tromsø Study were followed over 7 years from the first carotid ultrasound screening to the next. The progression of carotid atherosclerosis was measured in three ways: incidence of plaques in previously plaque-free participants; change in the number of plaques; and total plaque area (TPA). We used generalised linear models to investigate the association between each adiposity measure – body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) – and each outcome. Models were adjusted for potential confounders (age, sex, smoking, education, physical activity). The pathways through which any associations observed might operate were investigated by further adjusting for cardiometabolic mediators (systolic blood pressure, cholesterol, and HbA1c).

Results

There was little evidence that adiposity was related to the formation of new plaques during follow-up. However, abdominal adiposity was associated with TPA progression. WHtR showed the largest effect size (mean change in TPA per one standard deviation (SD) increase in WHtR of 0.665 mm2, 95% confidence interval 0.198, 1.133) while BMI showed the smallest. Effect sizes were substantially reduced after the adjustment for potential mediators.

Conclusions

Abdominal obesity indirectly measured with WC seems more strongly associated with the progression of TPA than general obesity. These associations appear to be largely mediated by known cardiometabolic markers.
A framework for extending trial design to facilitate missing data sensitivity analyses
Authors: Mason Alexina J. , Grieve Richard D. , Richards-Belle Alvin , Mouncey Paul R. , Harrison David A. , Carpenter James R.
Published: March 2020

Background

Missing data are an inevitable challenge in Randomised Controlled Trials (RCTs), particularly those with Patient Reported Outcome Measures. Methodological guidance suggests that to avoid incorrect conclusions, studies should undertake sensitivity analyses which recognise that data may be ‘missing not at random’ (MNAR). A recommended approach is to elicit expert opinion about the likely outcome differences for those with missing versus observed data. However, few published trials plan and undertake these elicitation exercises, and so lack the external information required for these sensitivity analyses. The aim of this paper is to provide a framework that anticipates and allows for MNAR data in the design and analysis of clinical trials.

Methods

We developed a framework for performing and using expert elicitation to frame sensitivity analysis in RCTs with missing outcome data. The framework includes the following steps: first defining the scope of the elicitation exercise, second developing the elicitation tool, third eliciting expert opinion about the missing outcomes, fourth evaluating the elicitation results, and fifth analysing the trial data. We provide guidance on key practical challenges that arise when adopting this approach in trials: the criteria for identifying relevant experts, the outcome scale for presenting data to experts, the appropriate representation of expert opinion, and the evaluation of the elicitation results.The framework was developed within the POPPI trial, which investigated whether a preventive, complex psychological intervention, commenced early in ICU, would reduce the development of patient-reported post-traumatic stress disorder symptom severity, and improve health-related quality of life. We illustrate the key aspects of the proposed framework using the POPPI trial.

Results

For the POPPI trial, 113 experts were identified with potentially suitable knowledge and asked to participate in the elicitation exercise. The 113 experts provided 59 usable elicitation questionnaires. The sensitivity analysis found that the results from the primary analysis were robust to alternative MNAR mechanisms.

Conclusions

Future studies can adopt this framework to embed expert elicitation within the design of clinical trials. This will provide the information required for MNAR sensitivity analyses that examine the robustness of the trial conclusions to alternative, but realistic assumptions about the missing data.