bluuebunny/crossref_metadata_2025 huggingface dataset:
Inferring clonal heterogeneity in cancer using SNP arrays and whole genome sequencing
Authors: Zucker Mark R , Abruzzo Lynne V , Herling Carmen D , Barron Lynn L , Keating Michael J , Abrams Zachary B , Heerema Nyla , Coombes Kevin R
Published: January 2019

Motivation

Clonal heterogeneity is common in many types of cancer, including chronic lymphocytic leukemia (CLL). Previous research suggests that the presence of multiple distinct cancer clones is associated with clinical outcome. Detection of clonal heterogeneity from high throughput data, such as sequencing or single nucleotide polymorphism (SNP) array data, is important for gaining a better understanding of cancer and may improve prediction of clinical outcome or response to treatment. Here, we present a new method, CloneSeeker, for inferring clinical heterogeneity from sequencing data, SNP array data, or both.

Results

We generated simulated SNP array and sequencing data and applied CloneSeeker along with two other methods. We demonstrate that CloneSeeker is more accurate than existing algorithms at determining the number of clones, distribution of cancer cells among clones, and mutation and/or copy numbers belonging to each clone. Next, we applied CloneSeeker to SNP array data from samples of 258 previously untreated CLL patients to gain a better understanding of the characteristics of CLL tumors and to elucidate the relationship between clonal heterogeneity and clinical outcome. We found that a significant majority of CLL patients appear to have multiple clones distinguished by copy number alterations alone. We also found that the presence of multiple clones corresponded with significantly worse survival among CLL patients. These findings may prove useful for improving the accuracy of prognosis and design of treatment strategies.

Availability and implementation

Code available on R-Forge: https://r-forge.r-project.org/projects/CloneSeeker/

Supplementary information

Supplementary data are available at Bioinformatics online.
Socioeconomic inequalities in disability in Europe: contribution of behavioral, work-related and living conditions
Authors: Pérez-Hernández Bibiana , Rubio-Valverde Jose R , Nusselder Wilma J , Mackenbach Johan P
Published: January 2019

Background

Previous studies have shown the existence of social inequalities in disability in many European countries. However, it is not clear what factors are associated with these inequalities. The aim of this study was to assess the contribution of behavioral factors, work-related factors and living conditions to educational inequalities in disability.

Methods

We pooled data from the seventh wave of the European Social Survey (2014) which included self-reported disability measured with the Global Activity Limitations Indicator for 19 European countries. We used multivariate logistic regression to determine the contributions of behavioral factors, work-related and living conditions to educational inequalities in disability among respondents aged 30–79.

Results

We found that adjusting simultaneously for three groups of determinants (behavioral, work-related and living conditions) reduces the greatest proportion of inequalities in disability in both men and women, in a range >70%. Each group of determinants contributes substantially to explain inequalities in disability.

Conclusions

Inequalities in disability are a major challenge for public health in most European countries. Our findings suggest that these inequalities can be reduced by diminishing inequalities in exposure to well-known health determinants.
Do ethnic inequalities in multimorbidity reflect ethnic differences in socioeconomic status? The HELIUS study
Authors: Verest Wim J G M , Galenkamp Henrike , Spek Bea , Snijder Marieke B , Stronks Karien , van Valkengoed Irene G M
Published: January 2019

Background

The burden of multimorbidity is likely higher in ethnic minority populations, as most individual diseases are more prevalent in minority groups. However, information is scarce. We examined ethnic inequalities in multimorbidity, and investigated to what extent they reflect differences in socioeconomic status (SES).

Methods

We included Healthy Life in an Urban Setting study participants of Dutch (N = 4582), South-Asian Surinamese (N = 3258), African Surinamese (N = 4267), Ghanaian (N = 2282), Turkish (N = 3879) and Moroccan (N = 4094) origin (aged 18–70 years). Educational level, employment status, income situation and multimorbidity were defined based on questionnaires. We described the prevalence and examined age-adjusted ethnic inequalities in multimorbidity with logistic regression analyses. To assess the contribution of SES, we added SES indicators to the age-adjusted model.

Results

The prevalence of multimorbidity ranged from 27.1 to 53.4% in men and from 38.5 to 69.6% in women. The prevalence of multimorbidity in most ethnic minority groups was comparable to the prevalence among Dutch participants who were 1–3 decades older. After adjustment for SES, the odds of multimorbidity remained significantly higher in ethnic minority groups. For instance, age-adjusted OR for multimorbidity for the Turkish compared to the Dutch changed from 4.43 (3.84–5.13) to 2.34 (1.99–2.75) in men and from 5.35 (4.69–6.10) to 2.94 (2.54–3.41) in women after simultaneous adjustment for all SES indicators.

Conclusions

We found a significantly higher prevalence of multimorbidity in ethnic minority men and women compared to Dutch, and results pointed to an earlier onset of multimorbidity in ethnic minority groups. These inequalities in multimorbidity were not fully accounted for by differences in SES.
Frailty Screening Using the Electronic Health Record Within a Medicare Accountable Care Organization
Authors: Pajewski Nicholas M , Lenoir Kristin , Wells Brian J , Williamson Jeff D , Callahan Kathryn E
Published: January 2019

Background

The accumulation of deficits model for frailty has been used to develop an electronic health record (EHR) frailty index (eFI) that has been incorporated into British guidelines for frailty management. However, there have been limited applications of EHR-based approaches in the United States.

Methods

We constructed an adapted eFI for patients in our Medicare Accountable Care Organization (ACO, N = 12,798) using encounter, diagnosis code, laboratory, medication, and Medicare Annual Wellness Visit (AWV) data from the EHR. We examined the association of the eFI with mortality, health care utilization, and injurious falls.

Results

The overall cohort was 55.7% female, 85.7% white, with a mean age of 74.9 (SD = 7.3) years. In the prior 2 years, 32.1% had AWV data. The eFI could be calculated for 9,013 (70.4%) ACO patients. Of these, 46.5% were classified as prefrail (0.10 < eFI ≤ 0.21) and 40.1% frail (eFI > 0.21). Accounting for age, comorbidity, and prior health care utilization, the eFI independently predicted all-cause mortality, inpatient hospitalizations, emergency department visits, and injurious falls (all p < .001). Having at least one functional deficit captured from the AWV was independently associated with an increased risk of hospitalizations and injurious falls, controlling for other components of the eFI.

Conclusions

Construction of an eFI from the EHR, within the context of a managed care population, is feasible and can help to identify vulnerable older adults. Future work is needed to integrate the eFI with claims-based approaches and test whether it can be used to effectively target interventions tailored to the health needs of frail patients.
Comparison of Treadmill Trip-Like Training Versus Tai Chi to Improve Reactive Balance Among Independent Older Adult Residents of Senior Housing: A Pilot Controlled Trial
Authors: Aviles Jessica , Allin Leigh J , Alexander Neil B , Van Mullekom Jennifer , Nussbaum Maury A , Madigan Michael L
Published: January 2019

Background

There is growing interest in using perturbation-based balance training to improve the reactive response to common perturbations (eg, tripping and slipping). The goal of this study was to compare the efficacy of treadmill-based reactive balance training versus Tai Chi performed at, and among independent residents of, older adult senior housing.

Methods

Thirty-five residents from five senior housing facilities were allocated to either treadmill-based reactive balance training or Tai Chi training. Both interventions were performed three times per week for 4 weeks, with each session lasting approximately 30 minutes. A battery of balance tests was performed at baseline, and again 1 week, 1 month, 3 months, and 6 months post-training. The battery included six standard clinical tests of balance and mobility, and a test of reactive balance performance.

Results

At baseline, no significant between-group differences were found for any balance tests. After training, reactive balance training participants had better reactive balance than Tai Chi participants. Maximum trunk angle was 13.5° smaller among reactive balance training participants 1 week after training (p = .01), and a reactive balance rating was 24%–31% higher among reactive balance training participants 1 week to 6 months after training (p < .03). Clinical tests showed minimal differences between groups at any time point after training.

Conclusion

Trip-like reactive balance training performed at senior housing facilities resulted in better rapid balance responses compared with Tai Chi training.
Distributive Justice at War: Displacement and Its Afterlives in the Central African Republic
Authors: Lombard Louisa , Picco Enrica
Published: January 2019

One of the defining features of the crisis in the Central African Republic (CAR) since 2013 has been massive displacement. Currently, about a quarter of the country’s population is displaced. People who have been forcibly displaced, whether internally or abroad, and people who stayed behind this time (but frequently have their own memories of displacement) provide particular kinds of information about war and its not particularly peaceful aftermath. In this article, based on interviews with a broad range of people affected by displacement, we show that Central African views about the prospects for peace are deeply affected by how displacement has shaped tensions over the political senses of distribution (who has a right to what, and on what basis). Who should pay for war, in senses both material and otherwise, and who should be compensated? However, distribution and belonging are not the issues prioritized in the aftermath of war, when elite deals, punitive justice and technocratic recovery plans crowd out treatment of the material justice and belonging questions that dominate neighbourhoods. The political dimensions of material justice in the aftermath of war require more thorough treatment, as listening to people who have experienced displacement makes abundantly clear.
Stoichiometric evolutions of PH3 under high pressure: implication for high-Tc superconducting hydrides
Authors: Yuan Ye , Li Yinwei , Fang Guoyong , Liu Guangtao , Pei Cuiying , Li Xin , Zheng Haiyan , Yang Ke , Wang Lin
Published: January 2019

The superconductivity of hydrides under high pressure has attracted a great deal of attention since the recent observation of the superconducting transition at 203 K in strongly compressed H2S. It has been realized that the stoichiometry of hydrides might change under high pressure, which is crucial in understanding the superconducting mechanism. In this study, PH3 was studied to understand its superconducting transition and stoichiometry under high pressure using Raman, IR and X-ray diffraction measurements, as well as theoretical calculations. PH3 is stable below 11.7 GPa and then it starts to dehydrogenate through two dimerization processes at room temperature and pressures up to 25 GPa. Two resulting phosphorus hydrides, P2H4 and P4H6, were verified experimentally and can be recovered to ambient pressure. Under further compression above 35 GPa, the P4H6 directly decomposed into elemental phosphorus. Low temperature can greatly hinder polymerization/decomposition under high pressure and retains P4H6 up to at least 205 GPa. The superconductivity transition temperature of P4H6 is predicted to be 67 K at 200 GPa, which agrees with the reported result, suggesting that it might be responsible for superconductivity at higher pressures. Our results clearly show that P2H4 and P4H6 are the only stable P–H compounds between PH3 and elemental phosphorus, which is helpful for shedding light on the superconducting mechanism.
Widely Conserved Attenuation of Plant MAMP-Induced Calcium Influx by Bacteria Depends on Multiple Virulence Factors and May Involve Desensitization of Host Pattern Recognition Receptors
Authors: Lammertz Meltem , Kuhn Hannah , Pfeilmeier Sebastian , Malone Jacob , Zipfel Cyril , Kwaaitaal Mark , Lin Nai-Chun , Kvitko Brian H. , Panstruga Ralph
Published: January 2019

Successful pathogens must efficiently defeat or delay host immune responses, including those triggered by release or exposure of microbe-associated molecular patterns (MAMPs). Knowledge of the molecular details leading to this phenomenon in genuine plant–pathogen interactions is still scarce. We took advantage of the well-established Arabidopsis thaliana–Pseudomonas syringae pv. tomato DC3000 pathosystem to explore the molecular prerequisites for the suppression of MAMP-triggered host defense by the bacterial invader. Using a transgenic Arabidopsis line expressing the calcium sensor apoaequorin, we discovered that strain DC3000 colonization results in a complete inhibition of MAMP-induced cytosolic calcium influx, a key event of immediate-early host immune signaling. A range of further plant-associated bacterial species is also able to prevent, either partially or fully, the MAMP-triggered cytosolic calcium pattern. Genetic analysis revealed that this suppressive effect partially relies on the bacterial type III secretion system (T3SS) but cannot be attributed to individual members of the currently known arsenal of strain DC3000 effector proteins. Although the phytotoxin coronatine and bacterial flagellin individually are dispensable for the effective inhibition of MAMP-induced calcium signatures, they contribute to the attenuation of calcium influx in the absence of the T3SS. Our findings suggest that the capacity to interfere with early plant immune responses is a widespread ability among plant-associated bacteria that, at least in strain DC3000, requires the combinatorial effect of multiple virulence determinants. This may also include the desensitization of host pattern recognition receptors by the prolonged exposure to MAMPs during bacterial pathogenesis.
The G143A Mutation Confers Azoxystrobin Resistance to Soybean Cercospora Leaf Blight in Bolivia
Authors: Sautua Francisco J. , Searight Jacob , Doyle Vinson P. , Price Paul P. , Scandiani Maria M. , Carmona Marcelo A.
Published: January 2019

During the summer of 2017, 38 Cercospora spp. isolates were collected from soybean leaves displaying symptoms of Cercospora leaf blight (CLB) from commercial soybean fields at three locations in Santa Cruz, Bolivia. Portions of cytochrome b (N = 38) and calmodulin (N = 37) were amplified, sequenced, edited, and assembled. Two representative isolates from each lineage (with distinct calmodulin haplotypes, if present) were selected for sequencing of two additional loci, histone 3 and elongation factor 1-alpha, for species identification. Based on the corresponding multilocus phylogenetic analysis, the 37 isolates belong to three species: C. nicotianae (N = 14), C. sp. “P” (N = 16), and C. kikuchii (N = 7). All 38 isolates (100%) possessed the G143A mutation in cytochrome b, and none carried the F129L mutation. Results of phenotypic assays on a subset of 15 isolates (five from each species) supported a high level of resistance to azoxystrobin. This is the first report of the G143A mutation in Cercospora species associated with CLB in South America and the first report of C. nicotianae associated with CLB. Future monitoring for G143A mutants of Cercospora spp. in South America will be necessary to assess whether strobilurin resistance is widespread.
100 Steps of a DIEP Flap—A Prospective Comparative Cohort Series Demonstrating the Successful Implementation of Process Mapping in Microsurgery
Authors: Sharma Hrsikesa R. , Rozen Warren M. , Mathur Bhagwat , Ramakrishnan Venkat
Published: January 2019

Background:

The demand to improve the efficiency of microsurgical breast reconstruction is driven by increasing number of breast cancer and risk reducing cases, and the concurrent requirement for hospitals to cut costs. Businesses have successfully used process mapping as a tool to improve efficiency; however, process mapping has been sparsely used in surgery. This prospective cohort study has used process mapping to break down the individual components of a deep inferior epigastric artery perforator (DIEP) flap operation into a template of 100 streamlined steps.

Methods:

Through observation of the senior author’s uniform technique, refined from experience of over 5,000 cases, the DIEP flap operation was broken down into 100 individual steps, all arranged in a logical sequence with which to maximize efficiency and outcome. This created a 100-step process-mapped template. Subsequently, 2 cohorts of 10 unilateral DIEP cases were prospectively timed. One cohort following this process mapped template and the other control group was blinded to the template.

Results:

The process-mapped cohort was 56.1 minutes quicker than the control cohort, despite the addition of symmetrizing surgery being performed concurrently in 4 out of the 10 cases. Furthermore, there was no return to theater in the process-mapped cohort versus 1 return to theater in the control cohort with no flap loss in either group.

Conclusions:

This study uniquely presents an approach to process map the DIEP flap operation and demonstrates its utility in improving operative efficiency, without compromising outcomes. It also illustrates the possibility of symmetrizing surgery being carried out through parallel operating processes, without affecting overall operative times.
Cutaneous Mucormycosis in Solid Organ Transplant Recipients after Hurricane Harvey: Short- and Long-term Management
Authors: Kueht Michael , Villarreal Joshua A. , Reece Edward , Galvan N. Thao N. , Mysore Krupa , Restrepo Alejandro , Quintanilla Norma , Rana Abbas , Goss John
Published: January 2019

In the fall of 2017, Hurricane Harvey, one of the most costly hurricanes in American history, ravaged the Texas Gulf Coast, interrupting basic sanitation systems to hundreds of thousands of Texas residents. In the aftermath of Hurricane Harvey, our Houston hospitals noted an uptick in the incidence of cases of mucormycosis. Among the most vulnerable and affected have been immunocompromised transplant recipients. Here, we describe the successful management of 2 patients with atypical presentations of mucormycosis, 2 cutaneous infections after liver transplantation. Our comprehensive treatment strategy based upon guidelines and experience included coordinating aggressive surgical and medical therapies. We discuss our approach to surgical management including the extent and frequency of debridement, the methods of assessing disease-free margins, and minimizing the morbidity of radical debridement with temporary coverage and forethought to long-term reconstruction. Additionally, we describe the concurrent medical management, including type, route, and duration of antifungal therapy, minimizing suppression of the innate immune system, and optimizing the wound healing environment through maintaining nutritional status.
Epidural Nerve Blocks Increase Intraoperative Vasopressor Consumption and Delay Surgical Start Time in Deep Inferior Epigastric Perforator Free Flap Breast Reconstruction
Authors: Cormier Nicholas S. , Stein Michael J. , Zhang Tinghua , Lee Haemi , Zhang Jing
Published: January 2019

Background:

Epidural nerve blocks (EA) have been widely used in abdominal and thoracic surgery as an adjunct to general anesthesia (GA). The role for EA in microsurgical free flap breast reconstruction remains unclear with concerns regarding its impact on flap survival and operating room efficiency. The purpose of this study was to examine the effectiveness of epidural blocks in patients undergoing deep inferior epigastric perforator (DIEP) flap breast reconstruction.

Methods:

A retrospective analysis of patients undergoing DIEP breast reconstruction under GA alone was compared with those receiving EA/GA. Electronic records were analyzed for patient demographics, intraoperative data, and postoperative outcomes. The primary outcome was 48-hour narcotic usage and secondary outcomes were intraoperative vasopressor consumption, surgical delay, and safety profile.

Results:

Sixty-one patients underwent DIEP reconstruction, 46 (75%) underwent EA/GA and 15 (25%) underwent GA alone. Epidural blocks were associated with a significant delay in operating room start time (67.8 min versus 45.6 min; P = 0.0004.) Patients in the EA/GA group also had a significant increase in vasopressor use (n = 38 versus n = 8; P = 0.037); however, there was no difference in flap complication rate [1 (2%) versus 2 (13%); P = 0.15]. Postoperatively, patients who received an epidural block had a reduced average pain score (1.1 versus 2.2; P = 0.0235), but there was no difference in 48-hour narcotic usage.

Conclusions:

Although epidural blocks reduce postoperative pain following DIEP flap breast reconstruction, they increase intraoperative vasopressor use and delay the start time of the case. Further studies are required to elucidate whether the benefits of improved pain control outweigh the potential risk for increased surgical complications and increased health care costs.
Autosomal recessive cutis laxa: a novel mutation in the FBLN5 gene in a family
Authors: Tekedereli Ibrahim , Demiral Emine , Gokce Ismail K. , Esener Zeynep , Camtosun Emine , Akinci Aysehan
Published: January 2019

FBLN5-related cutis laxa (CL) is a rare syndrome that can be inherited in an autosomal dominant or recessive manner. Autosomal recessive cutis laxa (ARCL), type IA, has been reported to be more severe. The disease is characterized by microcephaly, sagging cheeks, loose, wrinkled and redundant skin, emphysema, aorta or pulmonary artery abnormalities, inguinal hernia, and anomalies of internal organs. Homozygous mutations in the FBLN5 gene are responsible for the clinical manifestations. We report a family study of a child with ARCL. FBLN5 genes of the patient and parents were sequenced using next-generation sequencing technologies. Analyses showed that the patient was homozygous for the novel c.518A>G, p.R173H mutation in exon 6 of the FBLN5 gene, whereas the parents were heterozygous. The mutation was found to be ‘possibly pathogenic’ in bioinformatic analysis. We identified a novel FBLN5 mutation in a CL patient; pedigree and parental genetic analyses suggested ARCL. Our results also suggest that the mutation analysis provides useful evidence to support the clinical diagnosis and define the inheritance mode of CL in an apparently sporadic case.
Decreased Fecal Calprotectin Levels in Cystic Fibrosis Patients After Antibiotic Treatment for Respiratory Exacerbation
Authors: Schnapp Zeev , Hartman Corina , Livnat Galit , Shteinberg Michal , Elenberg Yigal
Published: January 2019

Objectives:

In all patients with cystic fibrosis (CF), gastrointestinal (GI) tract CF transmembrane conductance regulator dysfunction occurs early in life. The identical pathophysiological triad of obstruction, infection, and inflammation causes disease of the airways and in the intestinal tract (CF enteropathy). Mucus accumulation within GI tract is a niche for abnormal microbial colonization, leading to dysbiosis. Fecal calprotectin (FC) is a neutrophil cytosolic protein released during apoptosis and necrosis and reflects inflammatory status. Systemic antibiotic treatment for pulmonary exacerbations has been shown to improve systemic inflammatory markers and serum and sputum calprotectin. Antibiotic treatment aimed at pulmonary complaints may improve GI tract inflammatory status. We hypothesized that high levels of FC present during pulmonary exacerbation are due, in part, to multiorgan dysbiosis and thus should diminish with systemic antibiotic treatment.

Methods:

This prospective pilot study enrolled 14 patients with CF, with no current GI symptoms. FC levels and lung function were measured at the beginning and end of systemic antibiotic treatment.

Results:

Compared to preantibiotic treatment baseline values, end of treatment FC levels declined significantly after antibiotic treatment, P = 0.004 and similarly, there was significant improvement in forced expiratory volume in 1 second, P = 0.002.

Conclusions:

High levels of FC during respiratory exacerbation may reflect a systemic exacerbation rather than solely pulmonary. Antibiotic treatment lowered the FC levels possibly by its impact on the intestinal microbiome.
The Cantor–Bernstein theorem: how many proofs?
Authors: Sieg Wilfried
Published: January 2019

Dedekind's proof of the Cantor–Bernstein theorem is based on his chain theory, not on Cantor's well-ordering principle. A careful analysis of the proof extracts an argument structure that can be seen in the many other proofs that have been given since. I contend there is
essentially one proof
that comes in two variants due to
Dedekind
and
Zermelo
, respectively. This paper is a case study in analysing proofs of a single theorem within a given methodological framework, here Zermelo–Fraenkel set theory (ZF). It uses tools from proof theory, but focuses on heuristic ideas that shape proofs and on logical strategies that help to construct them. It is rooted in a perspective on
Beweistheorie
that predates its close connection and almost exclusive attention to the goals of Hilbert's finitist consistency programme. This earlier perspective can be brought to life (only) with the support of powerful computational tools.

This article is part of the theme issue ‘The notion of ‘simple proof’ - Hilbert's 24th problem’.
Visual thinking and simplicity of proof
Authors: Cain Alan J.
Published: January 2019

This paper studies how spatial thinking interacts with simplicity in [informal] proof, by analysing a set of example proofs mainly concerned with Ferrers diagrams (visual representations of partitions of integers) and comparing them to proofs that do not use spatial thinking. The analysis shows that using diagrams and spatial thinking can contribute to simplicity by (for example) avoiding technical calculations, division into cases, and induction, and creating a more surveyable and explanatory proof (both of which are connected to simplicity). In response to one part of Hilbert's 24th problem, the area between two proofs is explored in one example, showing that between a proof that uses spatial reasoning and one that does not, there is a proof that is less simple yet more impure than either. This has implications for the supposed simplicity of impure proofs.

This article is part of the theme issue ‘The notion of ‘simple proof’ - Hilbert's 24th problem’.
The problem of proof identity, and why computer scientists should care about Hilbert's 24th problem
Authors: Straßburger Lutz
Published: January 2019

In this short overview article, I will discuss the problem of proof identity and explain how it is related to Hilbert's 24th problem. I will also argue that not knowing when two proofs are ‘the same’ has embarrassing consequences not only for proof theory but also for certain areas of computer science where formal proofs play a fundamental role, in particular, the formal verification of software. Then I will formulate a set of four objectives that a satisfactory notion of proof identity should obey. And finally, I discuss Hughes'combinatorial proofsand argue that they can be seen as a first step towards a possible solution to the problem of proof identity.

This article is part of the theme issue ‘The notion of ‘simple proof’ - Hilbert's 24th problem’.
Mathematical proof: from mathematics to school mathematics
Authors: Rocha Helena
Published: January 2019

Proof plays a central role in developing, establishing and communicating mathematical knowledge. Nevertheless, it is not such a central element in school mathematics. This article discusses some issues involving mathematical proof in school, intending to characterize the understanding of mathematical proof in school, its function and the meaning and relevance attributed to the notion of simple proof. The main conclusions suggest that the idea of addressing mathematical proof at all levels of school is a recent idea that is not yet fully implemented in schools. It requires an adaptation of the understanding of proof to the age of the students, reducing the level of formality and allowing the students to experience the different functions of proof and not only the function of verification. Among the different functions of proof, the function of explanation deserves special attention due to the illumination and empowerment that it can bring to the students and their learning. The way this function of proof relates to the notion of simple proof (and the related aesthetic issues) seems relevant enough to make it, in the future, a focus of attention for the teachers who address mathematical proof in the classroom.

This article is part of the theme issue ‘The notion of ‘simple proof’ - Hilbert's 24th problem’.
Explanation in mathematical conversations: an empirical investigation
Authors: Pease Alison , Aberdein Andrew , Martin Ursula
Published: January 2019

Analysis of online mathematics forums can help reveal how explanation is used by mathematicians; we contend that this use of explanation may help to provide an informal conceptualization of simplicity. We extracted six conjectures from recent philosophical work on the occurrence and characteristics of explanation in mathematics. We then tested these conjectures against a corpus derived from online mathematical discussions. To this end, we employed two techniques, one based on indicator terms, the other on a random sample of comments lacking such indicators. Our findings suggest that explanation is widespread in mathematical practice and that it occurs not only in proofs but also in other mathematical contexts. Our work also provides further evidence for the utility of empirical methods in addressing philosophical problems.

This article is part of the theme issue ‘The notion of ‘simple proof’ - Hilbert's 24th problem’.
Reshaping the metaphor of proof
Authors: Vavilov Nikolai
Published: January 2019

The simplistic view of Mathematics as a logical system of formal truths deduced from a limited set of axioms by a limited set of inference rules immediately shatters when confronted with the history of Mathematics, or current mathematical practice. To become useful, mathematical Philosophy should contemplate what Mathematics actually was, over centuries, and what it is now, rather than speculate what it should be according to the philosophical orthodoxy. The first dogma that must be completely revised is the idea of proof as a text, rather than what it is for mathematicians themselves: a process, a plethora of interwoven arguments, a multi-dimensional structure.

This article is part of the theme issue ‘The notion of ‘simple proof’ - Hilbert's 24th problem’.
Visual processing and attention rather than face and emotion processing play a distinct role in ASD: an EEG study
Authors: Khuntia Adyasha Tejaswi , Divakar Rechu , Apicella Fabio , Muratori Filippo , Das Koel
Published: January 2019

Autism Spectrum Disorder results in deficit in social interaction, non-verbal communication and social reciprocity. Cognitive tasks pertaining to emotion processing are often preferred to distinguish the ASD children from the typically developing ones. We analysed the role of face and emotion processing in ASD and explored the feasibility of using EEG as a neural marker for detecting ASD. Subjects performed a visual perceptual task with face and nonface stimuli. Successful ASD detection was possible as early as 50 ms. post stimulus onset. Alpha and Beta oscillations seem to best identify autistic individuals. Multivariate pattern analysis and source localization studies points to the role of early visual processing and attention rather than emotion and face processing in detecting autism.
Neither global nor consistent: a technical comment on the tree diversity-productivity analysis of Liang et al. (2016)
Authors: Dormann Carsten F. , Schneider Helge , Gorges Jonas
Published: January 2019

The publication of Liang et al. (2016, Science) seems to demonstrate very clearly that increasing tree species richness substantially increases forest productivity. To combine data from very different ecoregions, the authors constructed a relative measure of tree species richness. This relative richness however confounds plot-level tree species richness and the polar-tropical gradient of tree species richness. We re-analysed their orginal data, computing a regional measure of tree species richness and addressing several other issues in their analysis. We find that there is virtually no effect of relative tree species richness on productivity when computing species richness at the local scale. Also, different ecoregions have very different relationships between tree species richness and productivity. Thus, neither the “global” consistency nor the actual effect can be confirmed.
Feeling left out or just surprised? Neural correlates of social exclusion and over-inclusion in adolescence
Authors: Cheng Theresa W. , Vijayakumar Nandita , Flournoy John C. , Op de Macks Zdena , Peake Shannon J. , Flannery Jessica E. , Mobasser Arian , Alberti Sarah L. , Fisher Philip A. , Pfeifer Jennifer H.
Published: January 2019

Social belonging is an important human drive that influences mood and behavior. Neural responses to social exclusion are well-characterized, but the specificity of these responses to processing rejection-related affective distress is unknown. The present study compares neural responses to exclusion and over-inclusion, a condition that similarly violates fairness expectations but does not involve rejection, with a focus on implications for models of dorsal anterior cingulate cortex (dACC) and anterior insula (AI) function. In an fMRI adaptation of the Cyberball paradigm with adolescents 11.1-17.7 years of age (N=69), we employed parametric modulators to examine scaling of neural signal with cumulative exclusion and inclusion events, an approach that overcomes arbitrary definitions of condition onsets/offsets imposed on fluid, continuous gameplay. We identified positive scaling of dACC and posterior insula response with cumulative exclusion events, but these same regions exhibited trending signal decreases with cumulative inclusion events. Furthermore, areas within the dACC and insula also responded to context incongruency (throws to the participant in the exclusion run; throws between computer players in the over-inclusion run). Taken together, these findings caution against interpretations that responses in these regions uniquely reflect aspects of affective distress within social rejection paradigms. We further identified that the left ventrolateral PFC, rostromedial PFC, and left intraparietal sulcus responded similarly to cumulative exclusion and inclusion. These findings shed light on which neural regions exhibit patterns of differential sensitivity to exclusion or over-inclusion, as well as those that are more broadly engaged by both types of social interaction.
Enhancer viruses and a transgenic platform for combinatorial cell subclass-specific labeling
Authors: Graybuck Lucas T. , Daigle Tanya L. , Sedeño-Cortés Adriana E. , Walker Miranda , Kalmbach Brian , Lenz Garreck H. , Nguyen Thuc Nghi , Garren Emma , Kim Tae Kyung , Siverts La’ Akea , Bendrick Jacqueline L. , Zhou Thomas , Mortrud Marty , Yao Shenqin , Cetin Ali H. , Larsen Rachael , Esposito Luke , Gore Bryan , Szelenyi Eric , Morin Elyse , Mich John K. , Dee Nick , Goldy Jeff , Smith Kimberly , Yao Zizhen , Gradinaru Viviana , Sunkin Susan M. , Lein Ed , Levi Boaz P. , Ting Jonathan T. , Zeng Hongkui , Tasic Bosiljka
Published: January 2019

The rapid pace of cell type identification by new single-cell analysis methods has not been met with efficient experimental access to the newly discovered types. To enable flexible and efficient access to specific neural populations in the mouse cortex, we collected chromatin accessibility data from individual cells and clustered the single-cell data to identify enhancers specific for cell classes and subclasses. When cloned into adeno-associated viruses (AAVs) and delivered to the brain by retro-orbital injections, these enhancers drive transgene expression in specific cell subclasses in the cortex. We characterize several enhancer viruses in detail to show that they result in labeling of different projection neuron subclasses in mouse cortex, and that one of them can be used to label the homologous projection neuron subclass in human cortical slices. To enable the combinatorial labeling of more than one cell type by enhancer viruses, we developed a three-color Cre-, Flp- and Nigri-recombinase dependent reporter mouse line,Ai213. The delivery of three enhancer viruses driving these recombinases via a single retroorbital injection into a singleAi213transgenic mouse results in labeling of three different neuronal classes/subclasses in the same brain tissue. This approach combines unprecedented flexibility with specificity for investigation of cell types in the mouse brain and beyond.
Identifying Genomic Islands with Deep Neural Networks
Authors: Assaf Rida , Xia Fangfang , Stevens Rick
Published: January 2019

Background

Horizontal gene transfer is the main source of adaptability for bacteria, through which genes are obtained from different sources including bacteria, archaea, viruses, and eukaryotes. This process promotes the rapid spread of genetic information across lineages, typically in the form of clusters of genes referred to as genomic islands (GIs). Different types of GIs exist, often classified by the content of their cargo genes or their means of integration and mobility. Various computational methods have been devised to detect different types of GIs, but no single method currently is capable of detecting all GIs.

Results

We propose a method, which we call Shutter Island, that uses a deep learning model (Inception V3, widely used in computer vision) to detect genomic islands. The intrinsic value of deep learning methods lies in their ability to generalize. Via a technique called transfer learning, the model is pre-trained on a large generic dataset and then re-trained on images that we generate to represent genomic fragments. We demonstrate that this image-based approach generalizes better than the existing tools.

Conclusions

We used a deep neural network and an image-based approach to detect the most out of the correct GI predictions made by other tools, in addition to making novel GI predictions. The fact that the deep neural network was retrained on only a limited number of GI datasets and then successfully generalized indicates that this approach could be applied to other problems in the field where data is still lacking or hard to curate.
Waterborne, abiotic and other indirectly transmitted (W.A.I.T.) infections are defined by the dynamics of free-living pathogens and environmental reservoirs
Authors: Miller-Dickson Miles D. , Meszaros Victor A. , Baffour-Awuah Francis , Almagro-Moreno Salvador , Brandon Ogbunugafor C.
Published: January 2019

While the ecology of infectious disease is a rich field with decades worth of empirical evidence and theory, there are aspects that remain relatively under-examined. One example is the importance of the free-living survival stage of certain pathogens, and especially is cases where they are transmitted indirectly between hosts through an environmental reservoir intermediate. In this study, we develop an integrated, broadly applicable mathematical method to examine diseases fitting this description—the waterborne, abiotic and other indirectly transmitted (W.A.I.T.) infection framework. To demonstrate its utility, we construct realistic models of two very different epidemic scenarios: cholera in a densely populated setting with limited access to clean drinking water and hepatitis C virus in an urban setting of injection-drug users. Using these two exemplars, we find that the W.A.I.T. model fortifies the centrality of reservoir dynamics in the “sit and wait” infection strategy, and provides a way to simulate a diverse set of intervention strategies.
In vitro implementation of robust gene regulation in a synthetic biomolecular integral controller
Authors: Agrawal Deepak K. , Marshall Ryan , Noireaux Vincent , Sontag Eduardo D
Published: January 2019

Feedback mechanisms play a critical role in the maintenance of cell homeostasis in the presence of disturbances and uncertainties. Motivated by the need to tune the dynamics and improve the robustness of synthetic gene circuits, biological engineers have proposed various designs that mimic natural molecular feedback control mechanisms. However, practical and predictable implementations have proved challenging because of the complexity of synthesis and analysis of complex biomolecular networks. Here, we analyze and experimentally validate a first synthetic biomolecular controller executedin vitro.The controller is based on the interaction between a sigma and an anti-sigma factor, which ensures that gene expression tracks an externally imposed reference level, and achieves this goal even in the presence of disturbances. Our design relies upon an analog of the well-known principle of integral feedback in control theory. We implement the controller in anEscherichia colicell-free transcription-translation (TXTL) system, a platform that allows rapid prototyping and implementation. Modeling and theory guide experimental implementation of the controller with well-defined operational predictability.
A role for ATP Citrate Lyase in cell cycle regulation during myeloid differentiation
Authors: Rhee Jess , Solomon Lauren A. , DeKoter Rodney P.
Published: January 2019

Differentiation of myeloid progenitor cells into macrophages is accompanied by increased PU.1 concentration and increasing cell cycle length, culminating in cell cycle arrest. Induction of PU.1 expression in a cultured myeloid cell line expressing low PU.1 concentration results in decreased levels of mRNA encoding ATP-Citrate Lyase (ACL) and cell cycle arrest. ACL is an essential enzyme for generating acetyl-CoA, a key metabolite for the first step in fatty acid synthesis as well as for histone acetylation. We hypothesized that ACL may play a role in cell cycle regulation in the myeloid lineage. In this study, we found that acetyl-CoA or acetate supplementation was sufficient to rescue cell cycle progression in cultured BN cells treated with an ACL inhibitor or induced for PU.1 expression. Acetyl-CoA supplementation was also sufficient to rescue cell cycle progression in BN cells treated with a fatty acid synthase (FASN) inhibitor. We demonstrated that acetyl-CoA was utilized in both fatty acid synthesis and histone acetylation pathways to promote proliferation. Finally, we found thatAclymRNA transcript levels decrease during normal macrophage differentiation from bone marrow precursors. Our results suggest that regulation of ACL activity is a potentially important point of control for cell cycle regulation in the myeloid lineage.
Automated Brain Masking of Fetal Functional MRI
Authors: Rutherford Saige , Sturmfels Pascal , Angstadt Mike , Hect Jasmine , Wiens Jenna , van den Heuval Marion , Scheinost Dustin , Thomason Moriah , Sripada Chandra
Published: January 2019

Abstract

Fetal resting-state functional magnetic resonance imaging (rs-fMRI) has emerged as a critical new approach for characterizing brain development before birth. Despite rapid and widespread growth of this approach, at present we lack neuroimaging processing pipelines suited to address the unique challenges inherent in this data type. Here, we solve the most challenging processing step, rapid and accurate isolation of the fetal brain from surrounding tissue across thousands of non-stationary 3D brain volumes. Leveraging our library of 1,241 manually traced fetal fMRI images from 207 fetuses (gestational age 24-39 weeks, M=30.9, SD=4.2), we trained a Convolutional Neural Network (CNN) that achieved excellent performance across two held-out test sets from separate scanners and populations. Furthermore, we unite the auto-masking model with additional fMRI preprocessing steps from existing software and provide insight into our adaptation of each step. This work represents an initial advancement towards a fully comprehensive, open source workflow for fetal functional MRI data preprocessing.
Detection of cross-contamination and strong mitonuclear discordance in two species groups of sawfly genus Empria (Hymenoptera, Tenthredinidae)
Authors: Prous Marko , Min Lee Kyung , Mutanen Marko
Published: January 2019

In several sawfly taxa strong mitonuclear discordance has been observed, with nuclear genes supporting species assignments based on morphology, whereas the barcode region of the mitochondrial COI gene suggesting different relationships. As previous studies were based on only few nuclear genes, the causes and the degree of mitonuclear discordance remain ambiguous. Here, we obtain genomic-scale ddRAD data together with Sanger sequencing of mitochondrial COI and two to three nuclear protein coding genes to investigate species limits and mitonuclear discordance in two closely related species groups within the sawfly genusEmpria. As found previously based on nuclear ITS and mitochondrial COI sequences, species are in most cases supported as monophyletic based on previous and new nuclear data reported here, but not based on mitochondrial COI. This mitonuclear discordance can be explained by occasional mitochondrial introgression with little or no nuclear gene flow, a pattern that might be common in haplodiploid taxa with slowly evolving mitochondrial genomes. Some species inE. immersagroup are not recovered as monophyletic also based on nuclear data, but this could partly be because of unresolved taxonomy. Preliminary analyses of ddRAD data did not recover monophyly ofE. japonicawithinE. longicornisgroup (three Sanger sequenced nuclear genes strongly supported monophyly), but closer examination of the data and additional Sanger sequencing suggested that both specimens were substantially (possibly 10–20% of recovered loci) cross-contaminated. A reason could be due to specimen identification tag jumps during sequencing library preparation of pooled specimens that in previous studies have been shown to affect up to 2.5% of the sequenced reads. We provide an R script to examine patterns of identical loci among the specimens and estimate that cross-contamination rate is not unusually high for our ddRAD dataset as a whole (based on counting identical sequences betweenimmersaandlongicornisgroups that are well separated from each other and probably do not hybridise). The high rate of cross-contamination for bothE. japonicaspecimens might be explained by small number of recovered loci (~1000) compared to most other specimens (>10 000 in some cases) because of poor sequencing results. We caution drawing unexpected biological conclusions when closely related specimens are pooled before sequencing and tagged only at one end of the molecule or at both ends using unique combination of limited number of tags (less than the number of specimens).