bluuebunny/crossref_metadata_2025 huggingface dataset:
Active Surveillance Versus Immediate Surgery in Clinically Complete Responders After Neoadjuvant Chemoradiotherapy for Esophageal Cancer
Authors: van der Wilk Berend J. , Noordman Bo J. , Neijenhuis Lisanne K. A. , Nieboer Daan , Nieuwenhuijzen Grard A. P. , Sosef Meindert N. , van Berge Henegouwen Mark I. , Lagarde Sjoerd M. , Spaander Manon C. W. , Valkema Roelf , Biermann Katharina , Wijnhoven Bas P. L. , van der Gaast Ate , van Lanschot J. Jan B. , Doukas Michael , Nikkessen Suzan , Luyer Misha , Schoon Erik J. , Roef Mark J. , van Lijnschoten Ineke , Oostenbrug Liekele E. , Riedl Robert G. , Gisbertz Suzanne S. , Krishnadath Kausilia K. , Bennink Roel J. , Meijer Sybren L.
Published: October 2019

Objective:

This study compared outcomes of patients with esophageal cancer and clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) undergoing active surveillance or immediate surgery.

Background:

Since nearly one-third of patients with esophageal cancer show pathologically complete response after nCRT according to CROSS regimen, the oncological benefit of immediate surgery in cCR is topic of debate.

Methods:

Patients with cCR based on endoscopic biopsies and endoscopic ultrasonography with fine-needle aspiration initially declining or accepting immediate surgery after nCRT were identified between 2011 and 2018. Primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), rate and timing of distant dissemination, and postoperative outcomes.

Results:

Some 98 patients with cCR were identified: 31 in the active surveillance- and 67 in the immediate surgery group with median followup of survivors of 27.7 and 34.8 months, respectively. Propensity score matching resulted in 2 comparable groups (n = 29 in both groups). Patients undergoing active surveillance or immediate surgery had a 3-year OS of 77% and 55% (HR 0.41; 95% CI 0.14–1.20, P = 0.104), respectively. The 3-year PFS was 60% and 54% (HR 1.08; 95% CI 0.44–2.67, P = 0.871), respectively. Patients undergoing active surveillance or immediate surgery had a comparable distant dissemination rate (both groups 28%), radical resection rate (both groups 100%), and severity of postoperative complications (Clav- ien-Dindo grade ≥ 3: 43% vs 45%, respectively).

Conclusion:

In this retrospective study, OS and PFS in patients with cCR undergoing active surveillance or immediate surgery were not significantly different. Active surveillance with postponed surgery for recurrent disease was not associated with a higher distant dissemination rate or more severe adverse postoperative outcomes.
Academic Partnerships in Global Surgery
Authors: Debas Haile , Alatise Olusegun I. , Balch Charles M. , Brennan Murray , Cusack James , Donkor Peter , Jaffe Bernard M. , Mazariegos George V. , Mock Charles , Mutiibwa David , Numann Patricia , Nyagatuba John Kennedy Muma , O’Neill James A. , Tarpley John L. , Tesfaye Samuel , Tefera Girma , Tuttle Todd M.
Published: October 2019

Most surgeons from high-income countries who work in global surgery will do so through partnerships between their institutions and institutions in low- and middle-income countries (LMICs). In this article, the American Surgical Association Working Group for Global Surgery lays out recommendations for criteria that contribute to equitable, sustainable, and effective partnerships. These include ethically engaging with the LMIC partner institution by putting its interests first and by proactively seeking to be aware of cultural issues. Formally structuring the partnership with a memorandum of understanding and clearly designating leaders at both institutions are important criteria for assuring long-term sustainability. Needs assessments can be done using existing methods, such as those established for development of national surgical, obstetric, and anesthesia plans. Such assessments help to identify opportunities for partnerships to be most effective in addressing the biggest surgical needs in the LMIC. Examples of successful high-income countries-LMIC partnerships are provided.
Meta-analysis, Meta-regression, and GRADE Assessment of Randomized and Nonrandomized Studies of Incisional Negative Pressure Wound Therapy Versus Control Dressings for the Prevention of Postoperative Wound Complications
Authors: Zwanenburg Pieter R. , Tol Berend T. , Obdeijn Miryam C. , Lapid Oren , Gans Sarah L. , Boermeester Marja A.
Published: October 2019

Objective:

The aim of this study was to evaluate the efficacy of iNPWT for the prevention of postoperative wound complications such as SSI.

Summary of Background Data:

The 2016 WHO recommendation on the use of iNPWT for the prevention of SSI is based on low-level evidence, and many trials have been published since. Preclinical evidence suggests that iNPWT may also prevent wound dehiscence, skin necrosis, seroma, and hematoma.

Methods:

PubMed, EMBASE, CINAHL, and CENTRAL were searched for randomized and nonrandomized studies that compared iNPWT with control dressings. The evidence was assessed using the Cochrane Risk of Bias Tool, the Newcastle-Ottawa scale, and GRADE. Meta-analyses were performed using random-effects models.

Results:

High level evidence indicated that iNPWT reduced SSI [28 RCTs, n = 4398, relative risk (RR) 0.61, 95% confidence interval [CI]: 0.49–0.76, P < 0.0001, I
2 = 27%] with a number needed to treat of 19. Low level evidence indicated that iNPWT reduced wound dehiscence (16 RCTs, n = 3058, RR 0.78, 95% CI: 0.64–0.94). Very low-level evidence indicated that iNPWT also reduced skin necrosis (RR 0.49, 95% CI: 0.33–0.74), seroma (RR 0.43, 95% CI: 0.32–0.59), and length of stay (pooled mean difference −2.01, 95% CI: −2.99 to 1.14).

Conclusions:

High-level evidence indicates that incisional iNPWT reduces the risk of SSI with limited heterogeneity. Low to very low-level evidence indicates that iNPWT also reduces the risk of wound dehiscence, skin necrosis, and seroma.
Molecular profiling of primary central nervous system lymphomas – predictive and prognostic value?
Authors: Ho K. Grace , Grommes Christian
Published: October 2019

Purpose of review

Primary central nervous system lymphoma (PCNSL) is a rare but aggressive variant of non-Hodgkin lymphoma. The diagnostic gold standard remains the pathologic review of tumor tissue mainly collected though biopsies. The majority of PCNSL are diffuse large B cell lymphoma (DLBCL). Biopsies are invasive procedures, and there have been efforts to develop minimally invasive diagnostic testing using serum and cerebral spinal fluid. This article reviews multiple markers that could potentially serve as future diagnostic tools and predictors of treatment response.

Recent findings

Many studies have attempted to classify DLBCL into different subtypes for prognostic purposes using methods such as immunohistochemistry. PCNSL often falls under the activated B-cell-like subgroup, and further genomic sequencing has identified alterations in genes within the B-cell receptor signaling axis at increased frequencies. Two such genes, MYD88 and CD79B, implicate the involvement of the NF-kB (nuclear factor kappa-light-chain enhancer of activated B cells) pathway, and targeted agents to this pathway are currently being used in the treatment of relapsed/refractory PCNSL.

Although recent genomic profiling of PCNSL has increased the understanding of drivers in this disease and has also led to the introduction of targeted inhibitors, these markers have not yet been used for diagnostic and/or prognostic purposes. Further studies will need to evaluate if they hold great diagnostic potential.
Emergent microscale gradients give rise to metabolic cross-feeding and antibiotic tolerance in clonal bacterial populations
Authors: Dal Co Alma , van Vliet Simon , Ackermann Martin
Published: October 2019

Bacteria often live in spatially structured groups such as biofilms. In these groups, cells can collectively generate gradients through the uptake and release of compounds. In turn, individual cells adapt their activities to the environment shaped by the whole group. Here, we studied how these processes can generate phenotypic variation in clonal populations and how this variation contributes to the resilience of the population to antibiotics. We grew two-dimensional populations of
Escherichia coli
in microfluidic chambers where limiting amounts of glucose were supplied from one side. We found that the collective metabolic activity of cells created microscale gradients where nutrient concentration varied over a few cell lengths. As a result, growth rates and gene expression levels varied strongly between neighbouring cells. Furthermore, we found evidence for a metabolic cross-feeding interaction between glucose-fermenting and acetate-respiring subpopulations. Finally, we found that subpopulations of cells were able to survive an antibiotic pulse that was lethal in well-mixed conditions, likely due to the presence of a slow-growing subpopulation. Our work shows that emergent metabolic gradients can have important consequences for the functionality of bacterial populations as they create opportunities for metabolic interactions and increase the populations' tolerance to environmental stressors.

This article is part of a discussion meeting issue ‘Single cell ecology'.
Reconstruction of protein domain evolution using single-cell amplified genomes of uncultured choanoflagellates sheds light on the origin of animals
Authors: López-Escardó David , Grau-Bové Xavier , Guillaumet-Adkins Amy , Gut Marta , Sieracki Michael E. , Ruiz-Trillo Iñaki
Published: October 2019

Understanding the origins of animal multicellularity is a fundamental biological question. Recent genome data have unravelled the role that co-option of pre-existing genes played in the origin of animals. However, there were also some important genetic novelties at the onset of Metazoa. To have a clear understanding of the specific genetic innovations and how they appeared, we need the broadest taxon sampling possible, especially among early-branching animals and their unicellular relatives. Here, we take advantage of single-cell genomics to expand our understanding of the genomic diversity of choanoflagellates, the sister-group to animals. With these genomes, we have performed an updated and taxon-rich reconstruction of protein evolution from the Last Eukaryotic Common Ancestor (LECA) to animals. Our novel data re-defines the origin of some genes previously thought to be metazoan-specific, like the POU transcription factor, which we show appeared earlier in evolution. Moreover, our data indicate that the acquisition of new genes at the stem of Metazoa was mainly driven by duplications and protein domain rearrangement processes at the stem of Metazoa. Furthermore, our analysis allowed us to reveal protein domains that are essential to the maintenance of animal multicellularity. Our analyses also demonstrate the utility of single-cell genomics from uncultured taxa to address evolutionary questions.

This article is part of a discussion meeting issue ‘Single cell ecology’.
Realizing the potential of full-length transcriptome sequencing
Authors: Byrne Ashley , Cole Charles , Volden Roger , Vollmers Christopher
Published: October 2019

Long-read sequencing holds great potential for transcriptome analysis because it offers researchers an affordable method to annotate the transcriptomes of non-model organisms. This, in turn, will greatly benefit future work on less-researched organisms like unicellular eukaryotes that cannot rely on large consortia to generate these transcriptome annotations. However, to realize this potential, several remaining molecular and computational challenges will have to be overcome. In this review, we have outlined the limitations of short-read sequencing technology and how long-read sequencing technology overcomes these limitations. We have also highlighted the unique challenges still present for long-read sequencing technology and provided some suggestions on how to overcome these challenges going forward.

This article is part of a discussion meeting issue ‘Single cell ecology’.
ATR16 Syndrome: Mechanisms Linking Monosomy to Phenotype
Authors: Babbs Christian , Brown Jill , Horsley Sharon W. , Slater Joanne , Maifoshie Evie , Kumar Shiwangini , Ooijevaar Paul , Kriek Marjolein , Dixon-McIver Amanda , Harteveld Cornelis L. , Traeger-Synodinos Joanne , Higgs Douglas , Buckle Veronica
Published: October 2019

Background

Sporadic deletions removing 100s-1000s kb of DNA, and variable numbers of poorly characterised genes, are often found in patients with a wide range of developmental abnormalities. In such cases, understanding the contribution of the deletion to an individual’s clinical phenotype is challenging.

Methods

Here, as an example of this common phenomenon, we analysed 34 patients with simple deletions of ∼177 to ∼2000 kb affecting one allele of the well characterised, gene dense, distal region of chromosome 16 (16p13.3), referred to as ATR-16 syndrome. We characterised precise deletion extent and screened for genetic background effects, telomere position effect and compensatory up regulation of hemizygous genes.

Results

We find the risk of developmental and neurological abnormalities arises from much smaller terminal chromosome 16 deletions (∼400 kb) than previously reported. Beyond this, the severity of ATR-16 syndrome increases with deletion size, but there is no evidence that critical regions determine the developmental abnormalities associated with this disorder. Surprisingly, we find no evidence of telomere position effect or compensatory upregulation of hemizygous genes, however, genetic background effects substantially modify phenotypic abnormalities.

Conclusions

Using ATR-16 as a general model of disorders caused by sporadic copy number variations, we show the degree to which individuals with contiguous gene syndromes are affected is not simply related to the number of genes deleted but also depends on their genetic background. We also show there is no critical region defining the degree of phenotypic abnormalities in ATR-16 syndrome and this has important implications for genetic counselling.
A Joint Model of RNA Expression and Surface Protein Abundance in Single Cells
Authors: Gayoso Adam , Lopez Romain , Steier Zoë , Regier Jeffrey , Streets Aaron , Yosef Nir
Published: October 2019

Cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) combines unbiased single-cell transcriptome measurements with surface protein quantification comparable to flow cytometry, the gold standard for cell type identification. However, current analysis pipelines cannot address the two primary challenges of CITE-seq data: combining both modalities in a shared latent space that harnesses the power of the paired measurements, and handling the technical artifacts of the protein measurement, which is obscured by non-negligible background noise. Here we present Total Variational Inference (totalVI), a fully probabilistic end-to-end framework for normalizing and analyzing CITE-seq data, based on a hierarchical Bayesian model. In totalVI, the mRNA and protein measurements for each cell are generated from a low-dimensional latent random variable unique to that cell, representing its cellular state. totalVI uses deep neural networks to specify conditional distributions. By leveraging advances in stochastic variational inference, it scales easily to millions of cells. Explicit modeling of nuisance factors enables totalVI to produce denoised data in both domains, as well as a batch-corrected latent representation of cells for downstream analysis tasks.
Bioinformatic analysis of brain-specific miRNAs for identification of candidate traumatic brain injury blood biomarkers
Authors: Smothers Christine , Winkelman Chris , O’Connell Grant C.
Published: October 2019

Background

Detection of brain-specific miRNAs in the peripheral blood could serve as a surrogate marker of traumatic brain injury (TBI). Here, we systematically identified brain-enriched miRNAs, and tested their utility for use as TBI biomarkers in the acute phase of care.

Methods

Publically-available microarray data generated from 31 postmortem human tissues was used to rank 1,364 miRNAs in terms of their degree of brain-specific expression. Levels of the top five ranked miRNAs were then prospectively measured in serum samples collected from 10 TBI patients at hospital admission, as well as from 10 controls.

Results

The top five miRNAs identified in our analysis (miR-137, miR-219a-5p, miR-128-3p, miR-124-3p, and miR-138-5p) exhibited 31 to 74-fold higher expression in brain relative to other tissues. Furthermore, their levels were elevated in serum from TBI patients compared to controls, and were collectively able to discriminate between groups with 90% sensitivity and 80% specificity. Subsequent informatic pathway analysis revealed that their target transcripts were significantly enriched for components of signaling pathways which are active in peripheral organs such as the heart.

Conclusions

The five candidate miRNAs identified in this study have promise as blood biomarkers of TBI, and could also be molecular contributors to systemic physiologic changes commonly observed post-injury.

A FINAL PEER REVIEWED VERSION OF THIS ARTICLE HAS BEEN PUBLISHED IN BRAIN INJURY AT THE FOLLOWING DOI: 10.1080/02699052.2020.1764102

There are some notable differences between the analysis presented in this preprint and our final peer-reviewed article. There was a single tissue sample originating from spinal cord that we had classified as a non-brain tissue in our original analysis outlined in this preprint. Because the composition of spinal cord and brain are highly similar in terms of gene expression, classifying this sample as a non-brain tissue dramatically reduced the levels of brain enrichment observed in the analysis. Because brain and spinal cord are molecularly highly similar, but technically distinct anatomical structures, we simply decided to exclude this sample from our final analysis published in Brain Injury to avoid confounds. The top 5 miRNAs identified in our original analysis still fell within the top 7 of this final analysis. In addition, the final analysis identified two additional miRNAs which could be candidate biomarkers based on levels of brain enrichment.

The final article published in Brain Injury also reports an additional confirmatory tissue specificity analysis performed in a second independent dataset, as well as additional analysis examining the brain specificity of several notable previously proposed miRNA TBI biomarkers, which is not described in this preprint.
Optimizing a human fecal assay that elicits bacterial swarming
Authors: Byju Arjun , Patel Deeti , Chen Weijie , Mani Sridhar
Published: October 2019

A distinct property of many bacteria is swarming: swift movement across a surface through flagella propulsion. Early research indicates that bacterial swarming can be a protective host response to intestinal inflammation. Central to the further study of bacterial swarming in human health is an effective and replicable assay for swarming that can accommodate complex material, such as fecal matter. To date, nearly all swarming assays described in the literature are specific for bacteria grown in culture, most often Pseudomonas. In this paper, we describe a protocol for discerning swarming of bacteria from frozen human fecal samples. Moreover, we tested 4 variables that may influence the effectiveness of the assay: the method by which frozen samples were thawed, the concentration of agar used in the Lysogenic broth (LB) agar plate, the volume of LB agar poured in the plate, and the volume of sample inoculated. We found that while the type of thaw and volume of LB agar had little to no effect on swarming, greater concentrations of agar were negatively correlated with swarming and greater volumes of the sample were positively correlated with swarming.
Assessing a causal relationship between circulating lipids and breast cancer risk: Mendelian randomization study
Authors: Johnson Kelsey E. , Siewert Katherine M. , Klarin Derek , Damrauer Scott M. ,   the VA Million Veteran Program, Chang Kyong-Mi , Tsao Philip S. , Assimes Themistocles L. , Maxwell Kara N. , Voight Benjamin F.
Published: October 2019

Objective

To assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein cholesterol, HDL; low-density lipoprotein cholesterol, LDL; triglycerides, TG) with risk for breast cancer.

Design

Mendelian randomization (MR) study.

Setting and Participants

Data from genome-wide association studies in up to 215,551 subjects from the Million Veterans Project were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on breast cancer risk was evaluated using genetic data from the BCAC consortium based on 122,977 breast cancer cases and 105,974 controls.

Exposures

Genetically modified plasma levels of LDL, HDL, or TG.

Main Outcomes and Measures

Odds ratio (OR) for breast cancer risk per standard-deviation increase in HDL, LDL, or TG.

Results

We observed that a 1-SD genetically determined increase in HDL levels is associated with an increased risk for all breast cancers (HDL: OR=1.08, 95% CI=1.04-1.13, P=7.4×10−5).

Multivariable MR analysis, which adjusted for the effects of LDL, TG, body mass index, and age at menarche, corroborated this observation for HDL (OR=1.06, 95% CI=1.03-1.10, P=4.9×10−4) and also a relationship between LDL and breast cancer risk (OR=1.03, 95% CI=1.01-1.07, P=0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for breast cancers (OR=1.11, 95% CI=1.06–1.16, P=1.5×10−6), including gene-specific associations at ABCA1, APOE-APOC1-APOC4-APOC2 and CETP. In addition, we find evidence that genetic variation at the ABO locus affects both lipid levels and breast cancer.

Conclusions

Genetically elevated plasma HDL levels appear to increase breast cancer risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal to develop potential therapeutic strategies aimed at altering the HDL-mediated effect on breast cancer risk.
New North American isolates of Venturia inaequalis can overcome apple scab resistance of Malus floribunda 821
Authors: Papp David , Singh Jugpreet , Gadoury David , Khan Awais
Published: October 2019

Apple scab, caused by Venturia inaequalis (Cke.) Wint., is a destructive fungal disease of major apple cultivars worldwide, most of which are moderately to highly susceptible. Thus, development of scab resistant cultivars is one of the highest priorities of apple breeding programs. The principal source of resistance for breeding programs has been the scab resistance gene Rvi6 that originated from the Japanese crabapple Malus floribunda (Sieb.) sel. 821. Isolates of V. inaequalis able to overcome Rvi6 have been identified in Europe, but have not yet been reported on the American continents. We recently discovered scab infection on M. floribunda 821 trees in a research orchard at Geneva, New York, USA, where approximately 10% of the leaves bore profusely sporulating apple scab lesions, many of which had coalesced to cover entire leaves. Chlorosis and pinpoint pitting symptoms typical of failed infections by V. inaequalis on hosts bearing the Rvi6 and Rvi7 genes were also observed. We assessed genetic diversity and population genetic structure of six V. inaequalis isolates collected from M. floribunda 821, one isolate from ‘Nova Easygro’, one isolate from ‘Golden Delicious’ and two isolates from Europe (11 isolates in total) using 16,321 genome-wide SNPs. Population genetic structure and PCA separated the isolates into distinct European and USA groups. The forgoing suggests that the new Rvi6 virulent isolates emerged within USA populations, rather than being transported from Europe. The overcoming of resistance in M. floribunda 821 but not in descendant cultivars suggests that durable resistance to apple scab will require a more comprehensive understanding of Rvi6 mediated resistance in diverse genetic backgrounds.
Choosing to view morbid information involves reward circuitry
Authors: Oosterwijk Suzanne , Snoek Lukas , Tekoppele Jurriaan , Engelbert Lara , Scholte H. Steven
Published: October 2019

People often seek out stories, videos or images that detail death, violence or harm. Considering the ubiquity of this behavior, it is surprising that we know very little about the neural circuits involved in choosing negative information. Here we show that choosing intensely negative stimuli engages similar brain regions as those that support extrinsic incentives and “regular” curiosity. Participants made choices to view negative and positive images, based on negative (e.g., a soldier kicks a civilian against his head) and positive (e.g., children throw flower petals at a wedding) verbal cues. We hypothesized that the conflicting, but relatively informative act of choosing to view a negative image, resulted in stronger activation of reward circuitry as opposed to the relatively uncomplicated act of choosing to view a positive stimulus. Indeed, as preregistered, we found that choosing negative cues was associated with activation of the striatum, inferior frontal gyrus, anterior insula, and anterior cingulate cortex, both when contrasting against a passive viewing condition, and when contrasting against positive cues. These findings nuance models of decision-making, valuation and curiosity, and are an important starting point when considering the value of seeking out negative content.
CaBLAM for chiropraxis in cryoEM, UnDowser to rethink “waters”, and NGL Viewer to recapture online 3D graphics in MolProbity validation
Authors: Prisant Michael G. , Williams Christopher J. , Chen Vincent B. , Richardson Jane S. , Richardson David C.
Published: October 2019

The MolProbity web service provides macromolecular model validation to help correct local errors, for the structural biology community worldwide. Here we highlight new validation features, and also describe how we are fighting back against recent outside changes that degrade or endanger that mission. Sophisticated hacking of the MolProbity server has required continual monitoring and various security measures short of restricting user access. Refinement software now increasingly restrains validation criteria in order to supplement the sparser experimental data at 3-4Å resolutions typical of modern cryoEM. But unfortunately the broad density allows optimization without fixing underlying problems, which means these structures often score much better than they really are. CaBLAM, our first new tool designed for this regime, was described in the previous Tools issue, and here we demonstrate its effectiveness in diagnosing local errors even when other validation outliers have been artificially removed. The deprecation of Java applets now prevents KiNG interactive online display of outliers on the 3D model during a MolProbity run, but that important functionality is now recaptured with a modified version of the Javascript NGL Viewer. Other new changes are more straightforwardly good. We are moving to the Neo4j database (graphical rather than relational), and will soon have cleaner as well as much larger reference datasets. In addition to several minor new features, we have developed a tool called UnDowser that analyzes the properties and context of modeled but clashing HOH “waters” to diagnose what they might actually represent. A dozen distinct scenarios are illustrated and described.
A YoeB toxin from A. tumefaciens has metal-dependent DNA cleaving activity
Authors: McGillick Julia , Ames Jessica R. , Murphy Tamiko , Reddem Eswar , Bourne Christina R.
Published: October 2019

Toxin-antitoxin (TA) systems, including YoeB-YefM, are important mediators of bacterial physiological changes. Agrobacterium tumefaciens YoeB and YefM are similar to that from E. coli, and interact as a tight heterotetramer with a KD of 653 pM. We have verified that AtYoeB can perform both ribosome-dependent and –independent RNA cleavage. We have also characterized a newly described metal-dependent and pH-sensitive DNA cleaving ability. We note that this DNA cleaving ability is observed at toxin concentrations as low as 150 nM. The dose-dependence of in vitro ribosome-independent RNA and metal-dependent DNA cleavage is equivalent, and requires a ten-fold increase in toxin concentration as opposed to in the presence of the ribosome. The toxin concentration inside bacterial cells is unknown and according to current models, should increase upon activation of YoeB through degradation of the YefM antitoxin. The discovery of general nuclease activity by AtYoeB, and perhaps other YoeB toxins, offers an opportunity to explore the plasticity of this protein fold and its potential role in the evolution of nucleases.
Sensitivity to gains during risky decision-making differentiates chronic cocaine users from stimulant-naïve controls
Authors: Kluwe-Schiavon B. , Kexel A. , Manenti G. , Cole D.M. , Baumgartner M.R. , Grassi-Oliveira R. , Tobler P.N. , Quednow B.B.
Published: October 2019

Background

Although chronic cocaine use has been frequently associated with decision-making impairments that are supposed to contribute to the development and maintenance of cocaine addiction, it has remained unclear how risk-seeking behaviours observed in chronic cocaine users (CU) come about. Here we therefore test whether risky decision-making observed in CU is driven by alterations in individual sensitivity to the available information (gain, loss, and risk).

Method

A sample of 96 participants (56 CU and 40 controls) performed the no-feedback (“cold”) version of the Columbia Card Task. Structured psychiatric interviews and a comprehensive neuropsychological test battery were additionally conducted. Current and recent substance use was objectively assessed by toxicological urine and hair analysis.

Results

Compared to controls, CU showed increased risk-seeking in unfavourable decision scenarios in which the risk was high and the returns were low, and a tendency for increased risk aversion in favourable decision scenarios. These differences arose from the fact that CU were less sensitive to gain, but similarly sensitive to loss and risk information in comparison to controls. Further analysis revealed that individual differences in sensitivity to loss and risk were related to cognitive performance and impulsivity.

Conclusion

The reduced sensitivity to gain information in people with CU may contribute to their propensity for making risky decisions. While these alterations in the sensitivity to gain might be directly related to cocaine use per se, the individual psychopathological profile of CU might moderate their sensitivity to risk and loss impulsivity.
The Lipid Elongation Enzyme ELOVL2 is a molecular regulator of aging in the retina
Authors: Chen Daniel , Chao Daniel L. , Rocha Lorena , Kolar Matthew , Huu Viet Anh Nguyen , Krawczyk Michal , Dasyani Manish , Wang Tina , Jafari Maryam , Jabari Mary , Ross Kevin D. , Saghatelian Alan , Hamilton Bruce , Zhang Kang , Skowronska-Krawczyk Dorota
Published: October 2019

Methylation of the regulatory region of the Elongation Of Very Long Chain Fatty Acids-Like 2 (ELOVL2) gene, an enzyme involved in elongation of long-chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age-associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age-related eye diseases. We show that an age-related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5-Aza-2’-deoxycytidine (5-aza-dc) leads to increased Elovl2 expression and rescue of age-related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2-specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well-established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components of complement system and lipid metabolism. These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual functions, and suggest novel therapeutic strategies for treatment of age-related eye diseases.
Dynamical Systems Modeling of Bt Resistant Cornborer Population Dynamics
Authors: Rabajante Jomar F. , Jacildo Arian J. , Alcantara Edwin P.
Published: October 2019

Mathematical models provide insights for the design and optimization of strategies to control disease epidemics and evolution of pesticide resistance in crops. Here, we present a simple mathematical model to investigate the population dynamics of non-Bt resistant and Bt resistant cornborers in a field with refuge. In the presence of refuge, it is expected that the population of Bt resistant pests will decline due to the dilution effect (non-Bt resistant cornborers mate with Bt resistant pests). We have found that increasing the refuge size can be effective in reducing Bt resistant pests as long as there exists a relatively huge population of non-Bt resistant cornborers at the start of the simulation. This implies that refuge is useless in inhibiting the evolution of cornborers if a sufficient initial population of non-Bt resistant cornborers is absent.
Human astrocytes and microglia show augmented ingestion of synapses in Alzheimer’s disease via MFG-E8
Authors: Tzioras Makis , Daniels Michael J.D. , Davies Caitlin , Baxter Paul , King Declan , McKay Sean , Varga Balazs , Popovic Karla , Hernandez Madison , Stevenson Anna J. , Barrington Jack , Drinkwater Elizabeth , Borella Julia , Holloway Rebecca K. , Tulloch Jane , Latta Clare , Kandasamy Jothy , Sokol Drahoslav , Smith Colin , Miron Veronique E. , Karadottir Ragnhildur Thora , Hardingham Giles E. , Henstridge Christopher M. , Brennan Paul M. , McColl Barry W. , Spires-Jones Tara L.
Published: October 2019

Synapse loss correlates with cognitive decline in Alzheimer’s disease (AD). Data from mouse models suggests microglia are important for synapse degeneration, but direct human evidence for any glial involvement in synapse removal in human AD remains to be established. Here we observe astrocytes and microglia from human brains contain greater amounts of synaptic protein in AD compared to non-disease controls, and that proximity to amyloid-β plaques and theAPOE4risk gene exacerbate this effect. In culture, mouse and human astrocytes and primary mouse and human microglia phagocytose AD patient-derived synapses more than synapses from controls. Inhibiting MFG-E8 function rescued the elevated engulfment of AD synapses by astrocytes and microglia without affecting control synapse uptake. Thus, AD promotes increased synapse ingestion by human glial cells via an MFG-E8 opsonophagocytic mechanism with potential for targeted therapeutic manipulation.

One-Sentence Summary

Glial cells ingest synapses in Alzheimer’s disease and antibody treatment reduces this ingestion in cultured human cells.
Measurement and alleviation of subsurface damage in a thick-crystal neutron interferometer
Authors: Heacock Benjamin , Haun Robert , Hirota Katsuya , Hosobata Takuya , Huber Michael G. , Jamer Michelle E. , Kitaguchi Masaaki , Pushin Dmitry A. , Shimizu Hirohiko , Taminiau Ivar , Yamagata Yutaka , Yamamoto Tomoki , Young Albert R.
Published: October 2019

The construction is described of a monolithic thick-crystal perfect silicon neutron interferometer using an ultra-high-precision grinding technique and a combination of annealing and chemical etching that differs from the construction of prior neutron interferometers. The interferometer is the second to have been annealed after machining and the first to be annealed prior to chemical etching. Monitoring the interference signal at each post-fabrication step provides a measurement of subsurface damage and its alleviation. In this case, the strain caused by subsurface damage manifests itself as a spatially varying angular misalignment between the two relevant volumes of the crystal and is reduced from ∼10−5 rad to ∼10−9 rad by way of annealing and chemical etching.
A universal algorithm for finding the shortest distance between systems of points
Authors: Blatov Igor A. , Kitaeva Elena V. , Shevchenko Alexander P. , Blatov Vladislav A.
Published: October 2019

Three universal algorithms for geometrical comparison of abstract sets of n points in the Euclidean space R
3 are proposed. It is proved that at an accuracy ∊ the efficiency of all the algorithms does not exceed O(n
3/∊3/2). The most effective algorithm combines the known Hungarian and Kabsch algorithms, but is free of their deficiencies and fast enough to match hundreds of points. The algorithm is applied to compare both finite (ligands) and periodic (nets) chemical objects.
Observer-based reaction wheel fault reconstruction for spacecraft attitude control systems
Authors: Jia Qingxian , Li Huayi , Chen Xueqin , Zhang Yingchun
Published: October 2019

Purpose

The purpose of this paper is to achieve fault reconstruction for reaction wheels in spacecraft attitude control systems (ACSs) subject to space disturbance torques.

Design/methodology/approach

Considering the influence of rotating reaction wheels on spacecraft attitude dynamics, a novel non-linear learning observer is suggested to robustly reconstruct the loss of reaction wheel effectiveness faults, and its stability is proven using Lyapunov’s indirect method. Further, an extension of the proposed approach to bias faults reconstruction for reaction wheels in spacecraft ACSs is performed.

Findings

The numerical example and simulation demonstrate the effectiveness of the proposed fault-reconstructing methods.

Practical implications

This paper includes implications for the development of reliability and survivability of on-orbit spacecrafts.

Originality/value

This paper proposes a novel non-linear learning observer-based reaction wheels fault reconstruction for spacecraft ACSs.
Examining the impact of case-based learning on student engagement, learning motivation and learning performance among university students
Authors: Raza Syed Ali , Qazi Wasim , Umer Bushra
Published: October 2019

Purpose

The purpose of this paper is to examine the impact of case study-based learning on student’s engagement, learning motivation and learning performance among university students of Pakistan.

Design/methodology/approach

The research model is analyzed with structural equation modeling. The analysis is done with the application of the measurement model and the structural model.

Findings

The findings revealed that case study-based learning enhances student engagement, and a significant and positive relationship between case-based learning and all four aspects of engagement, i.e. behavioral, emotional, cognitive and agentic engagement, was observed statistically. According to the findings, case-based learning leads toward an understanding of concepts learned in class and the development of skills among students and results in the enhancement of learning motivation. Furthermore, it is suggested by the results that the impact of student engagement on learning performance varies with respect to its different aspects. As among all the four aspects, only agentic engagement was found to be statistically significant in establishing the link with the learning performance of the students.

Research limitations/implications

The mixed findings pertaining to the impact of student engagement’s aspects on learning performance of the students pave the way for future research. The future researchers should incorporate individual traits and the specific context to analyze the relationships between the proposed constructs because students vary in their responses to learning activities.

Practical implications

The present study holds significance for the field of educational research and emphasizes the importance of incorporating case-based teaching in the higher education curriculum in order to ensure the implementation of effective learning strategies. Also, this research will be beneficial for future researchers in understanding the phenomenon of student learning and engagement.

Originality/value

In view of the limited academic literature in the Asian context, the present study extends the findings and examined the impact of case-based learning on student’s engagement, student’s learning motivation and the role of such engagement in enhancing learning performance of university students.
Learnings from implementing telemonitoring – the LITE study
Authors: Chow Josephine S.F. , Gonzalez-Arce Veronica Eugenia , Knight Andrew , Maurya Nutan , Kohler Friedbert
Published: October 2019

Purpose

A recent study on the implementation of telemonitoring has provided an opportunity to explore how telemonitoring could be further developed to enhance better patient, carer and clinician experiences for patients living with chronic disease. The purpose of this paper is to identify the challenges and lessons of the telemonitoring implementation and to identify strategies to inform future implementation.

Design/methodology/approach

A qualitative study was conducted with a purposive sample using semi-structured interviews to explore their views about the issues identified in the research aims. Interview themes were informed by current literature and the findings from local studies. Interviews were recorded, transcribed verbatim and analyzed thematically.

Findings

A total of 16 participants were interviewed. Overall the recruitment of 56 percent were from identified potential participants. Five core themes were identified, linking different aspects of the telemonitoring implementation: impact of telemonitoring; implementation and management lessons; program risks; program main changes from beginning; and future strategies and recommendations.

Originality/value

This study will inform the wider roll out of telemonitoring across the region with the goal of ensuring future interventions achieve better clinical outcomes, patient, carer experience and deliver better value.
Patient and public involvement in integrated psychosocial care
Authors: Vassiliadou Io , Tolani Esther , Ip Lindsay , Smith Abigail , Papachristou Nadal Iliatha
Published: October 2019

Purpose

Recent models of care incorporate service user involvement within the development and sustainability of a quality improvement project. The purpose of this paper is to demonstrate the significance of working with patients and members of the public for the integration of psychosocial care into long-term condition (LTC) management.

Design/methodology/approach

Research shows that mental health difficulties are more prevalent in people with LTC. The three Dimensions for Long-term Conditions (3DLC) is a patient-centred multidisciplinary service which integrates psychological and social care into the usual physical care. Thematic analysis was conducted on the discussions of the two patient and public involvement workshops that were facilitated by the service. The workshops included healthcare professionals, patients with LTC and their carers.

Findings

Several themes and subthemes emerged which highlighted the importance of discussing and treating mental health in a physical health setting, the challenges that both the patients and healthcare professionals encounter and the ways in which an integrated care service may address these barriers. The findings show that there was an emphasis on patient-centeredness, accessibility of services and the need for better communication.

Practical implications

People with LTC can be empowered to better self-manage their condition, whilst having access to all types of care, physical, social and psychological. By involving service users in the implementation process of the 3DLC service, the components of an effective integrated service are delineated.

Originality/value

The service users have identified barriers and facilitators of integrating a biopsychosocial model in care pathways. This has helped the 3DLC team to further develop the model to ensure improvements in condition-specific outcomes, quality of life and healthcare utilisation.
Integrated care: a definition from the perspective of the four quality paradigms
Authors: Van Kemenade Everard , van der Vlegel-Brouwer Wilma
Published: October 2019

Purpose

The purpose of this paper is to support the ongoing dialogue and shed light on the different views on integrated care. An overarching definition of integrated care is proposed combining the ways of thinking of the four quality paradigms the authors identify. The idea of epistemic fluency offers a way-out of ongoing discussions about “what integration is”.

Design/methodology/approach

Four paradigms of quality are presented and applied to healthcare. Epistemic fluency is proposed as the capacity to understand, switch between and combine different kinds of knowledge. The authors compare previously developed definitions of integrated care to the various combinations of paradigms.

Findings

All four paradigms of care quality are present in healthcare and in the most used definitions of integrated care. The Reflective Paradigm and the Emergence Paradigm receive least attention. Some definitions combine more than one paradigm. An overarching definition of integrated care is proposed.

Research limitations/implications

In this paper, only the most prominent definitions of integration have been considered.

Practical implications

Integration research and practice requires a widely accepted definition of integrated care, embracing all four paradigms of care quality. Our suggestion provides a common foundation that may prevent misunderstanding.

Originality/value

The use of quality management paradigms to frame the debate on defining integrated care is new and leads to new insights for teaching, research and practice.
Linking knowledge sharing to innovative behavior: the moderating role of collectivism
Authors: Pian Qian Ya , Jin Hui , Li Hui
Published: October 2019

Purpose

The purpose of this study is to examine the relationship between behavior-oriented knowledge sharing and innovative behavior and the moderating effects of collectivism on the aforementioned relationship. It also assesses the impact of epistemic motivation and pro-social motivation on behavior-oriented knowledge sharing.

Design/methodology/approach

Focusing on Chinese context, the study conducts a questionnaire survey to test the research model. Linear regression analysis is used to examine the main effects of the independent variables, and the multi-level linear regression model is used to evaluate the moderating effects of the controlled variables.

Findings

The findings reveal that epistemic motivation stimulates individual-oriented knowledge sharing and pro-social motivation stimulates organization-oriented knowledge sharing. Organization-oriented knowledge sharing impacts more than individual-oriented knowledge sharing on innovative behavior. Moreover, collectivism is shown to positively moderate the relationship between behavior-oriented knowledge sharing and innovative behavior.

Practical implications

The study provides evidence that motivation should be significantly considered when sharing knowledge. Managers should prioritize the promotion of employees’ epistemic and pro-social motivation. The study also suggests that encouraging collectivism should be an important objective, as it moderates the relationship between knowledge sharing and innovative behavior positively.

Originality/value

The study emphasized how individual-oriented and organization-oriented knowledge sharing impacts innovative behavior differently and how collectivism moderates that relationship. It also illustrates how epistemic and pro-social motivation affects behavior-oriented knowledge sharing. The study contributes to a stream of research that links knowledge sharing and innovative behavior.