bluuebunny/crossref_metadata_2025 huggingface dataset:
Introduction
Authors: Fleming Christopher T.
Published: January 2021

Something is someone’s property (when) someone is eligible to use it as desired.

Śabarasvāmin, Mīmāṃsābhāṣya (fourth century CE).1

There is nothing which so generally strikes the imagination, and engages the affections of mankind, as the right of property; or that sole and despotic dominion which one man claims and exercises over the external things of the world, in total exclusion of the right of any other individual in the universe. And yet there are very few, that will give themselves the trouble to consider the original and foundation of this right....
Anglo-Indian Schools of Hindu Law
Authors: Fleming Christopher T.
Published: January 2021

This chapter turns to the British encounter with traditional Sanskrit learning in the late eighteenth and early nineteenth centuries and traces the construction of schools of Hindu Law in colonial India between 1772 and 1864. The chapter examines three digests of Sanskrit Dharmaśāstra that were compiled at the behest of the East India Company and whose English translations were utilized by British jurists the Ṣadr Dīwānī ‘Adālats (colonial civil courts): the Vivādārṇavasetu (translated in 1776 as A Code of Gentoo Laws), the Vivādabhaṅgārṇava (translated in 1795–6 as A Digest on Contracts and Succession), and the Dharmaśāstrasamgraha (which likely served as an impetus for Henry Colebrooke’s Two Treatises). Furthermore, it argues that these colonial-era Dharmaśāstra digests articulate discernible schools of jurisprudential thought regarding ownership and inheritance that frame themselves using the regional terminology of the early modern Dharmaśāstrins whose work is examined in Chapters 2 and 3 of this book. The treatises do this by recapitulating and by enhancing the eastern and southern scales of Dharmaśāstra texts that developed originally in Navadvīpa and Vārāṇasī in the sixteenth and seventeenth centuries.
Plato On The Unity of the Political Arts (Statesman 258 D–259D)
Authors: Brown Eric
Published: January 2021

Plato argues that four political arts—politics, kingship, slaveholding, and household-management—are the same. His argument, which prompted Aristotle’s reply in Politics I, has been universally panned. I consider and reject three ways of saving the argument, and argue for a fourth. On my view, Plato assumes that politics is identical with kingship, just as he does elsewhere, but he begs no questions because the point of his argument is to identify the public arts of politics and kingship with the private arts of household-management and slaveholding. He does this successfully by addressing three reasons why one might distinguish the private from the public arts. His argument leaves room for Aristotle to propose other reasons. One of them—involving differences among men and women and slaves—is unfortunate, but another is more promising. The Aristotelian can assume that political expertise is a matter of know-how gathered by experience of the particular actions which differ in the public and private arts. But Plato might well be right to reject this, and to insist that the essential difference between the expert and non-expert—the dividing line between good and bad rule—is not in experience but in their grasp of their goals.
The Ethics of Horror Inducement
Authors: Vitale Vince R.
Published: January 2021

This chapter analyzes the concepts of harm and benefit. There is a tendency in the literature on the metaphysics of harm to assume symmetric accounts of harm and benefit. But there are deep asymmetries between harm and benefit, recommending asymmetric metaphysical accounts. For harm and benefit, in turn, this chapter considers whether counterfactual comparative, temporal comparative, and non-comparative conditions are necessary or sufficient. For harm, the judgement reached is that a non-comparative condition—whereby harm is a matter of being in a bad state even if not in a worse state—is necessary and sufficient. It is further discussed why “non-comparative” is a misleading term for this account, and a more precise terminology of trans-comparative account is recommended. For benefit, the judgement reached is that temporal comparative and counterfactual comparative conditions are individually sufficient and disjunctively necessary; being benefited is a matter of being made temporally or counterfactually better-off. It is shown that this asymmetric metaphysical accounts allow for an important ethical distinction between harm-averting and non-harm-averting benefits. Next this distinction and an analogy between the ethics of human horror-inducement and the ethics of divine creation and sustenance is used to develop an ethical framework for theodicy. A taxonomy is constructed by sketching four cases of human action where horrors are either caused, permitted, or risked, either for pure benefit (i.e. a benefit that does not avert a still greater harm) or for harm avoidance.
Cross-National Variation in Growth Models
Authors: Picot Georg
Published: January 2021

The chapter presents a new framework for categorizing economic growth models and applies it to twenty-eight OECD countries from 1995 to 2016. The framework draws on three fundamental ways in which economies can benefit from additional demand: the private sector (households and companies) can spend more than its income, the public sector can spend more than its revenues, or the economy sells more abroad than it imports. The empirical section uses fuzzy-set ideal type analysis to identify the combinations in which advanced economies used these three ways of boosting demand in three subperiods between 1995 and 2016. The results show that most economies use at least one of the three sources of extra demand to tackle the era of low growth. At the same time, there are clear differences in growth models between groups of countries. These are in line with clusters that the literature commonly identifies due to their institutional similarities. The growth models in this chapter are therefore outcomes of differences in growth regimes.
Transitions to the Knowledge Economy in Germany, Sweden, and the Netherlands
Authors: Thelen Kathleen
Published: January 2021

The advanced economies are experiencing a set of shared challenges in the transition to a new “knowledge economy” characterized by rapid technological innovation and associated with a heightened premium on higher education. Yet individual countries are charting rather different courses as they navigate this transition. This chapter examines divergent trajectories of change in three coordinated market economies—Germany, Sweden, and the Netherlands. It argues that differences in the organization of business and labor, and in the institutions that structure their interactions with each other and with the state, have produced different coalitional alignments and led these countries onto divergent paths toward the knowledge economy today.
Strategies for Growth and Employment Creation in a Services-Based Economy
Authors: Wren Anne
Published: January 2021

This chapter focuses on the role of skill formation, wage-setting, and public service provision in shaping different national growth strategies in a post-industrial context, taking the cases of Germany, Sweden, and the UK as detailed examples and making use of data from the EU-KLEMS Growth and Productivity Accounts Database (2008). It highlights the role played by skills policy in shaping patterns of specialization in high productivity, traded sectors, which are important engines of growth even in “consumption-led” regimes. It shows that Sweden’s ability to compete in less price-sensitive, high-end services (and manufacturing) markets rests on the availability of a workforce with high levels of tertiary skills. Germany’s reliance on more traditional manufacturing sectors is rooted in its well-established system of firm-based vocational training and its limited tertiary sector. In the UK, the expansion of domestic demand has, in part, been debt-driven, although it has also, as in the Swedish case, been facilitated by rising real wages. Nevertheless, a key driver of rising real wages in the UK has also been productivity growth and the expansion of trade in high-end, ICT-intensive services. The chapter confirms that welfare state policies (including the protection of relative wages, public service provision, and, above all, strategies of skill formation) are critical to the outcomes observed in the context of deindustrialization and technological change. The development of sustainable strategies for growth and employment creation in a context of deindustrialization, and of revolutionary changes in ICT, rely on the creation of a capacity to expand into ICT-intensive, high value-added sectors, and especially in dynamic services sectors.
Intentional Action
Authors: Shepherd Joshua
Published: January 2021

The project of analyzing intentional action has been out of favor for some time. In part this is due to exhaustion over details—accounts are usually subject to very technical problems or elaborate counterexamples. This chapter builds build on the earlier accounts of control and non-deviance to offer a new account of intentional action. This account builds on Mele and Moser’s influential work, and goes beyond it in some ways. After offering the account, this chapter considers a range of ancillary issues and problem cases. It discusses, for example, side-effect cases, senseless movements, the role of belief and knowledge in intentional action, and action theoretic versions of systematic Gettier cases. Finally, it turns to issues of reductionism that motivate some rejections of causal theories of action. The upshot is that anti-causalists have a new account to contend with, and one that has answers to the problems often thought to be damning for causalism.
Rituals of Legitimacy
Authors: Pati Biswamoy
Published: January 2021

This chapter looks at the way in which colonial and the feudal ruling classes ritualized diverse aspects related to their interactions with the common people in order to tap their resources, while also simultaneously exercising control over them. Keeping the question of ‘Hinduization’ and Sanskritization at the centre, it highlights the manner in which the pre-existing system of caste was ritualized using a diverse range of strategies. At the same time, the chapter illustrates the ways in which common people challenged the exploiting classes using fascinating strategies, which reflect an entire range of counter-hegemonic rituals of protest and subversion. These included inventing a discourse of equality that was a fall-out of the interactions with modernity, which has somehow been assumed by historians to be a phenomenon limited to the urban middle classes/upper castes.
The Endoplasmic Reticulum Pathway for Membrane Lipid Synthesis Has a Significant Contribution toward Shoot Removal-Induced Root Chloroplast Development in Arabidopsis
Authors: Obata Tomoki , Kobayashi Koichi , Tadakuma Ryosuke , Akasaka Taiki , Iba Koh , Negi Juntaro
Published: January 2021

Chloroplast lipids are synthesized via two distinct pathways: the plastidic pathway and endoplasmic reticulum (ER) pathway. We previously reported that the contribution of the two pathways toward chloroplast development is different between mesophyll cells and guard cells in Arabidopsis leaf tissues and that the ER pathway plays a major role in guard cell chloroplast development. However, little is known about the contribution of the two pathways toward chloroplast development in other tissue cells, and in this study, we focused on root cells. Chloroplast development is normally repressed in roots but can be induced when the roots are detached from the shoots (root greening). We found that, similar to guard cells, root cells exhibit a higher proportion of glycolipid from the ER pathway. Root greening was repressed in the gles1 mutant, which has a defect in ER-to-plastid lipid transportation via the ER pathway, while normal root greening was observed in the ats1 mutant, whose plastidic pathway is blocked. Lipid analysis revealed that the gles1 mutation caused drastic decrease in the ER-derived glycolipids in roots. Furthermore, the gles1 detached roots showed smaller chloroplasts containing less starch than WT. These results suggest that the ER pathway has a significant contribution toward chloroplast development in the root cells.
Low Back Pain and Substance Use: Diagnostic and Administrative Coding for Opioid Use and Dependence Increased in U.S. Older Adults with Low Back Pain
Authors: Hogans Beth B , Siaton Bernadette C , Taylor Michelle N , Katzel Leslie I , Sorkin John D
Published: January 2021

Objective

Low back pain (LBP) is a leading cause of pain and disability. Substance use complicates the management of LBP, and potential risks increase with aging. Despite implications for an aging, diverse U.S. population, substance use and LBP comorbidity remain poorly defined. The objective of this study was to characterize LBP and substance use diagnoses in older U.S. adults by age, gender, and race.

Design

Cross-sectional study of a random national sample.

Subjects

Older adults including 1,477,594 U.S. Medicare Part B beneficiaries.

Methods

Bayesian analysis of 37,634,210 claims, with 10,775,869 administrative and 92,903,649 diagnostic code assignments.

Results

LBP was diagnosed in 14.8±0.06% of those more than 65 years of age, more in females than in males (15.8±0.08% vs. 13.4±0.09%), and slightly less in those more than 85 years of age (13.3±0.2%). Substance use diagnosis varied by substance: nicotine, 9.6±0.02%; opioid, 2.8±0.01%; and alcohol, 1.3±0.01%. Substance use diagnosis declined with advancing age cohort. Opioid use diagnosis was markedly higher for those in whom LBP was diagnosed (10.5%) than for those not diagnosed with LBP (1.5%). Most older adults (54.9%) with an opioid diagnosis were diagnosed with LBP. Gender differences were modest. Relative rates of substance use diagnoses in LBP were modest for nicotine and alcohol.

Conclusions

Older adults with LBP have high relative rates of opioid diagnoses, irrespective of gender or age. Most older adults with opioid-related diagnoses have LBP, compared with a minority of those not opioid diagnosed. In caring for older adults with LBP or opioid-related diagnoses, health systems must anticipate complexity and support clinicians, patients, and caregivers in managing pain comorbidities. Older adults may benefit from proactive incorporation of non-opioid pain treatments. Further study is needed.
Piezoelectric Machines: Achieving Non-Standard Actuation and Sensing Properties in Poled Ceramics
Authors: Saccomandi Giuseppe , Speranzini Emanuela , Zurlo Giuseppe
Published: January 2021

In the framework of linear piezoelectric ceramics, we study the deformations of a circular infinite hollow cylinder, subjected to a potential difference between the inner and outer surfaces. When the poling direction is perfectly aligned with the cylinder axis, the solution to this problem is a trivial axisymmetric anti-plane state. However, when the poling direction has an offset angle with respect to the cylinder axis, the corresponding behavior becomes more complex, with the anti-plane state coupled to an in-plane, potentially non axisymmetric, deformation. In this work, we show that this structural coupling, due to the poling direction, can be fruitfully exploited to achieve non-standard actuation and sensing properties, like the possibility to generate a torque under axially symmetric electromechanical controls.
Targeted therapies and checkpoint inhibitors in sarcoma
Authors: Vasella M , Gousopoulos E , Guidi M , Storti G , Song S Y , Grieb G , Pauli C , Lindenblatt N , Giovanoli P , Kim B -S
Published: January 2021

Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.
Institutional Order Handling and Broker-Affiliated Trading Venues
Authors: Anand Amber , Samadi Mehrdad , Sokobin Jonathan , Venkataraman Kumar
Published: January 2021

Using detailed order handling data, we find that institutional brokers who route more orders to affiliated alternative trading systems (ATSs) are associated with lower execution quality (i.e., lower fill rates and higher implementation shortfall costs). To separate clients’ preference for ATSs from brokers’ routing decisions, we confirm these results for orders where brokers have more order handling discretion, matched broker analysis that accounts for ATS usage, matched child orders that account for client intent, and based on an exogenous constraint on ATS venue choice. Our results suggest that increased transparency of order routing practices will improve execution quality.
CCL2 produced by CD68+/CD163+ macrophages as a promising clinical biomarker of microscopic polyangiitis-interstitial lung disease
Authors: Matsuda Shogo , Kotani Takuya , Kuwabara Hiroko , Suzuka Takayasu , Kiboshi Takao , Fukui Keisuke , Ishida Takaaki , Fujiki Youhei , Shiba Hideyuki , Hata Kenichiro , Shoda Takeshi , Hirose Yoshinobu , Takeuchi Tohru
Published: January 2021

Objectives

Microscopic polyangiitis (MPA) is often complicated by interstitial lung disease (ILD); however, biomarkers that can be used to diagnose and predict the progression of MPA-ILD have not been identified. In this study, we evaluated various serum biomarkers in MPA-ILD to assess their diagnostic and predictive performance.

Methods

We enrolled 49 patients with anti-neutrophil cytoplasmic antibody (ANCA)+ MPA and 10 healthy controls, with 32 of the MPA patients also presenting ILD. The presence of ILD was assessed by high-resolution CT and evaluated by ground-glass opacity and fibrosis score. We compared 16 biomarker profiles among MPA-ILD patients, those without ILD, and healthy controls and extracted biomarkers with higher levels in MPA-ILD groups to determine correlations with disease activity and other biomarkers. Three lung biopsies were examined by haematoxylin-eosin staining and immunostaining.

Results

Initial serum C–C motif chemokine ligand 2 (CCL2) levels were significantly higher in the MPA-ILD group than those of the MPA group, and were significantly higher in MPA-ILD patients 1 year after immunosuppressive therapy than those before treatment. Initial serum CCL2 levels positively correlated with an increased fibrosis score during the year after treatment and with initial serum platelet-derived growth factor levels. Immunohistochemical staining showed intense CCL2 signals in CD68+/CD163+ macrophages and metaplastic epithelial cells in MPA-ILD lungs.

Conclusion

CCL2 is associated with MPA-ILD pathogenesis and suggested its potential efficacy as a useful marker for diagnosing and predicting MPA-ILD progression. Therefore, targeting CCL2 in alveolar CD68+/CD163+ macrophages might represent a therapeutic intervention in ANCA+ MPA-ILD.
Discriminating Palates: Evaluation and Ethnoracial Inequality in American Fine Dining
Authors: Gualtieri Gillian
Published: January 2021

Elite cultural fields are often not diverse. Existing studies have examined how marginalized cultural producers are actively discriminated against or excluded from positions of prestige, but less is known about how ethnoracial inequality affects the evaluative processes used to assess products in fields of cultural production. This article analyzes 120 in-depth interviews with critically-recognized chefs in New York City and the San Francisco Bay Area and 1,380 Michelin restaurant reviews to uncover the system of insidious racial inequality that shapes evaluation in the American fine dining field. I find that there are three logics of evaluation—of (1) technique, (2) creativity, and (3) authenticity—that are differentially enacted for distinct ethnoracial categories of restaurants in the field. I show how these different, racialized evaluative processes result in the systematic devaluation of culinary products categorically associated with non-whiteness, what I call Ethnic restaurants, and disproportionate consecration of products associated with whiteness, which I term Classic and Flexible restaurants. I bring the race/ethnicity and sociology of culture literatures together to illuminate the ways in which inequality infiltrates the logics that organize systems of value in fields of cultural production.
Descriptions of eleven new species of squat lobsters (Crustacea: Anomura) from seamounts around the Yap and Mariana Trenches with notes on DNA barcodes and phylogeny
Authors: Dong Dong , Gan Zhibin , Li Xinzheng
Published: January 2021

Seamounts are well known for the high biodiversity and endemism of their macrobenthic fauna. Hundreds of squat lobster species from seamount environments have been reported in recent years, but squat lobster fauna on the seamount groups around ocean trenches in the tropical West Pacific are still poorly known. In this paper, we describe 11 new species (two Munida, three Munidopsis, one Sternostylus, one Uroptychodes and four Uroptychus) based on specimens collected during expeditions to seamounts around the Yap Trench and Mariana Trench. Of these species, six belong to the superfamily Chirostyloidea and five belong to Galatheoidea. We also provide DNA barcode data for three genes to support the taxonomic status of these new species. The morphological variations, genetic differentiation and phylogenetic relationships of these species are discussed.
Eribulin Mesylate for the Treatment of Metastatic Hormone-refractory and Triple-negative Breast Cancer
Authors: Valerio Maria R. , Arrivas Bajardi Eugenia , Arcara Carmelo C. , Borsellino Nicolo’ , Lo Mauro Mario , Cipolla Calogero , Santarpia Mariacarmela , Firenze Alberto , Motta Gianmarco , Vigneri Paolo , Gebbia Vittorio
Published: January 2021

Objective:

Eribulin mesylate (EM) is a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin. EM has been reported to be active in metastatic breast cancer. In this paper, we report efficacy and safety of data of EM in a retrospective, real-world series of patients with poor prognosis, hormone-refractory, or triple-negative metastatic breast cancer.

Materials and Methods:

The analysis was carried out at 4 interrelated oncology centers. EM was delivered at the dose of 1.4 mg/m2 in 100 mL of normal saline over 2 to 5 minutes on days 1 and 8 every 21 days. EM was continued until disease progression or unacceptable toxicity. Side effects were reported every cycle as per standard clinical practice and graded according to NCI-CTCAE, version 4.0. Time-to-progression and overall survival were reported.

Results:

In this series of 90 patients the overall response rate was 22%, and 21% and 23% in the hormonal-resistant group and the triple-negative one, respectively. Stable disease was recorded in 24%, 21%, and 27%, respectively, in the whole series, the hormonal-resistant group, and the triple-negative one, respectively. Time-to-progression was 3.5 months (range, 1 to 22 mo) in the whole series and 3.0 months (range, 1 to 14.7 mo) and 3.4 months (range, 2.2 to 16.2 mo) in the hormonal-resistant group and the triple-negative one, respectively. Overall survival reached a median of 11.4 months.

Conclusions:

This multicenter study, albeit retrospective, demonstrates the activity of this combination as third-line chemotherapy option in a challenging clinical setting such as triple-negative or hormone-resistant patients with breast cancer progressing after several lines of hormonal manipulations.
Mortality of Drug-resistant Tuberculosis in High-burden Countries: Comparison of Routine Drug Susceptibility Testing with Whole-genome Sequencing
Authors: Reichmuth Martina L. , Zürcher Kathrin , Ballif Marie , Loiseau Chloé , Borrell Sonia , Reihnhard Miriam , Skrivankova Veronika , Hömke Rico , Sander Peter , Avihingsanon Anchalee , Abimiku Alash’le G , Marcy Olivier , Collantes Jimena , Carter E. Jane , Wilkinson Robert J. , Cox Helen , Yotebieng Marcel , Huebner Robin , Fenner Lukas , Böttger Erik C. , Gagneux Sebastien , Egger Matthias
Published: January 2021

Background

Drug-resistant Mycobacterium tuberculosis (Mtb) strains threaten tuberculosis (TB) control. We compared data on drug resistance obtained at clinics in seven high TB burden countries during routine care with whole-genome sequencing (WGS) carried out centrally.

Methods

We collected pulmonary Mtb isolates and clinical data from adult TB patients in Africa, Latin America, and Asia, stratified by HIV status and drug resistance, from 2013 to 2016. Participating sites performed drug susceptibility testing (DST) locally, using routinely available methods. WGS was done using Illumina HiSeq 2500 at laboratories in the USA and Switzerland. We used TBprofiler to analyse the genomes. We used multivariable logistic regression adjusted for sex, age, HIV-status, history of TB, sputum positivity, and Mtb-lineage to analyse mortality.

Findings

We included 582 TB patients. The median age was 32 years (interquartile range: 27-43 years), 225 (39%) were female, and 247 (42%) were HIV-positive. Based on WGS, 339 (58%) isolates were pan-susceptible, 35 (6%) monoresistant, 146 (25%) multidrug-resistant, and 24 (4%) pre-/ extensively drug-resistant (pre-XDR/XDR-TB). The local DST results were discordant compared to WGS results in 130/582 (22%) of patients. All testing methods identified isoniazid and rifampicin resistance with relatively high agreement (kappa 0.69 for isoniazid and 0.88 rifampicin). Resistance to ethambutol, pyrazinamide, and second-line drugs was rarely tested locally. Of 576 patients with known treatment, 86 (15%) patients received inadequate treatment according to WGS results and the World Health Organization treatment guidelines. The analysis of mortality was based on 530 patients; 63 patients (12%) died and 77 patients (15%) received inadequate treatment. Mortality ranged from 6% in patients with pan-susceptible Mtb (18/310) to 39% in patients with pre-XDR/XDR-TB (9/23). The adjusted odds ratio for mortality was 4.82 (95% CI 2.43-9.44) for under-treatment and 0.52 (95% CI 0.03-2.73) for over-treatment.

Interpretation

In seven high-burden TB countries, we observed discrepancies between drug resistance patterns from local DST and WGS, which resulted in inadequate treatment and higher mortality. WGS can provide accurate and detailed drug resistance information, which is required to improve the outcomes of drug-resistant TB in high burden settings. Our results support the WHO’s call for point-of-care tests based on WGS.
Mobile brain/body imaging of landmark-based navigation with high-density EEG
Authors: Delaux Alexandre , de Saint Aubert Jean-Baptiste , Ramanoël Stephen , Bécu Marcia , Gehrke Lukas , Klug Marius , Chavarriaga Ricardo , Sahel José-Alain , Gramann Klaus , Arleo Angelo
Published: January 2021

Coupling behavioral measures and brain imaging in naturalistic, ecological conditions is key to comprehend the neural bases of spatial navigation. This highly-integrative function encompasses sensorimotor, cognitive, and executive processes that jointly mediate active exploration and spatial learning. However, most neuroimaging approaches in humans are based on static, motion constrained paradigms and they do not account for all these processes, in particular multisensory integration. Following the Mobile Brain/Body Imaging approach, we aimed to explore the cortical correlates of landmark-based navigation in actively behaving young adults, solving a Y-maze task in immersive virtual reality. EEG analysis identified a set of brain areas matching state-of-the-art brain imaging literature of landmark-based navigation. Spatial behavior in mobile conditions additionally involved sensorimotor areas related to motor execution and proprioception usually overlooked in static fMRI paradigms. Expectedly, we located a cortical source in or near the posterior cingulate, in line with the engagement of the retrosplenial complex in spatial reorientation. Consistent with its role in visuo-spatial processing and coding, we observed an alpha power desynchronization while participants gathered visual information. We also hypothesized behavior-dependent modulations of the cortical signal during navigation. Despite finding few differences between the encoding and retrieval phases of the task, we identified transient time-frequency patterns attributed, for instance, to attentional demand, as reflected in the alpha/gamma range, or memory workload in the delta/theta range. We confirmed that combining mobile high-density EEG and biometric measures can help unravel the brain structures and the neural modulations subtending ecological landmark-based navigation.
MolRep: A Deep Representation Learning Library for Molecular Property Prediction
Authors: Rao Jiahua , Zheng Shuangjia , Song Ying , Chen Jianwen , Li Chengtao , Xie Jiancong , Yang Hui , Chen Hongming , Yang Yuedong
Published: January 2021

Recently, novel representation learning algorithms have shown potential for predicting molecular properties. However, unified frameworks have not yet emerged for fairly measuring algorithmic progress, and experimental procedures of different representation models often lack rigorousness and are hardly reproducible. Herein, we have developed MolRep by unifying 16 state-of-the-art models across 4 popular molecular representations for application and comparison. Furthermore, we ran more than 12.5 million experiments to optimize hyperparameters for each method on 12 common benchmark data sets. As a result, CMPNN achieves the best results ranked the 1st in 5 out of 12 tasks with an average rank of 1.75. Relatively, ECC has good performance in classification tasks and MAT good for regression (both ranked 1st for 3 tasks) with an average rank of 2.71 and 2.6, respectively.

Availability

The source code is available at:https://github.com/biomed-AI/MolRep

Supplementary information

Supplementary data are available online.
Integrating protein networks and machine learning for disease stratification in the Hereditary Spastic Paraplegias
Authors: Vavouraki Nikoleta , Tomkins James E. , Kara Eleanna , Houlden Henry , Hardy John , Tindall Marcus J. , Lewis Patrick A. , Manzoni Claudia
Published: January 2021

The Hereditary Spastic Paraplegias are a group of neurodegenerative diseases characterized by spasticity and weakness in the lower body. Despite the identification of causative mutations in over 70 genes, the molecular aetiology remains unclear. Due to the combination of genetic diversity and variable clinical presentation, the Hereditary Spastic Paraplegias are a strong candidate for protein-protein interaction network analysis as a tool to understand disease mechanism(s) and to aid functional stratification of phenotypes. In this study, experimentally validated human protein-protein interactions were used to create a protein-protein interaction network based on the causative Hereditary Spastic Paraplegia genes. Network evaluation as a combination of both topological analysis and functional annotation led to the identification of core proteins in putative shared biological processes such as intracellular transport and vesicle trafficking. The application of machine learning techniques suggested a functional dichotomy linked with distinct sets of clinical presentations, suggesting there is scope to further classify conditions currently described under the same umbrella term of Hereditary Spastic Paraplegias based on specific molecular mechanisms of disease.
Overburdening of peer reviewers. A multi-disciplinary and multi-stakeholder perspective on causes, effects and potential policy implications
Authors: Severin Anna , Chataway Joanna
Published: January 2021

Peer review of manuscripts is labour-intensive and time-consuming. Individual reviewers often feel themselves overburdened with the amount of reviewing they are requested to do. Aiming to explore how stakeholder groups perceive reviewing burden and what they believe to be the causes of a potential overburdening of reviewers, we conducted focus groups with early-, mid-, and senior career scholars, editors, and publishers. By means of a thematic analysis, we aimed to identify the causes of overburdening of reviewers. First, we show that, across disciplines and roles, stakeholders believed that the reviewing workload has become so enormous that the academic community is no longer able to supply the reviewing resources necessary to address its demand for peer review. Second, the reviewing workload is distributed unequally across the academic community, thereby overwhelming small groups of scholars. Third, stakeholders believed the overburdening of reviewers to be caused by (i) an increase in manuscript submissions; (ii) insufficient editorial triage; (iii) a lack of reviewing instructions; (iv) difficulties in recruiting reviewers; (v) inefficiencies in manuscript handling and (vi) a lack of institutionalisation of peer review. These themes were assumed to mutually reinforce each other and to relate to an inadequate incentive structure in academia that favours publications over peer review. In order to alleviate reviewing burden, a holistic approach is required that addresses both the increased demand for and the insufficient supply of reviewing resources.
satuRn:Scalable Analysis of differential Transcript Usage for bulk and single-cell RNA-sequencing applications
Authors: Gilis Jeroen , Vitting-Seerup Kristoffer , Van den Berge Koen , Clement Lieven
Published: January 2021

Alternative splicing produces multiple functional transcripts from a single gene. Dysregulation of splicing is known to be associated with disease and as a hallmark of cancer. Existing tools for differential transcript usage (DTU) analysis either lack in performance, cannot account for complex experimental designs or do not scale to massive scRNA-seq data. We introduce satuRn, a fast and flexible quasi-binomial generalized linear modelling framework that is on par with the best performing DTU methods from the bulk RNA-seq realm, while providing good false discovery rate control, addressing complex experimental designs and scaling to scRNA-seq applications.
Dissociable mechanisms of reward learning co-mature during human adolescence as predicted by macaque lesion models
Authors: Wittmann Marco K. , Scheuplein Maximilian , Gibbons Sophie G. , Noonan MaryAnn P.
Published: January 2021

Reward-guided learning and decision-making is a fundamental adaptive ability and depends on a number of component processes. We investigate how such component processes mature during human adolescence. Our approach was guided by analyses of the effects of lateral orbitofrontal lesions in macaque monkeys, as this part of the brain shows clear developmental maturation in humans during adolescence. Using matched tasks and analyses in humans (n=388, 11-35yrs), we observe developmental changes in two key learning mechanisms as predicted from the monkey data. First, choice-reward credit assignment – the ability to link a specific outcome to a specific choice – is reduced in adolescents. Second, the effects of the global reward state – how good the environment is overall recently − exerts a distinctive pattern of influence on learning in humans compared to other primates and across adolescence this pattern becomes more pronounced. Both mechanisms were correlated across participants suggesting that associative learning of correct reward assignments and GRS based learning constitute two complementary mechanisms of reward-learning that co-mature during adolescence.
Mitochondrial function is essential for humoral immunity by controlling flux of the TCA cycle, phosphatidic acid and mTOR activity in B cells
Authors: Urbanczyk Sophia , Baris Olivier R. , Hofmann Jörg , Golombek Florian , Castiglione Kathrin , Meng Xianyi , Bozec Aline , Mougiakakos Dimitrios , Schulz Sebastian R. , Schuh Wolfgang , Schlötzer-Schrehardt Ursula , Steinmetz Tobit D. , Brodesser Susanne , Wiesner Rudolf J. , Mielenz Dirk
Published: January 2021

The function of mitochondrial respiration during B cell fate decisions and differentiation remains equivocal. This study reveals that selection for mitochondrial fitness occurs during B cell activation and is essential for subsequent plasma cell differentiation. By expressing a mutated mitochondrial helicase in transitional B cells, we depleted mitochondrial DNA during B cell maturation, resulting in reduced oxidative phosphorylation. Although no changes in follicular B cell development were evident, germinal centers, class switch recombination to IgG, plasma cell generation and humoral immunity were diminished. Defective oxidative phosphorylation led to aberrant flux of the tricarboxylic acid cycle and lowered the amount of saturated phosphatidic acid. Consequently, MTOR activity and BLIMP-1 induction were curtailed whereas HIF1α, glycolysis and AMPK activity were amplified. Exogenous phosphatidic acid increased mTOR activity in activated B cells. Hence, mitochondrial function is required and selected for in activated B cells for the successful generation of functional plasma cells.
Locally confined IFNγproduction by CD4+T cells provides niches for murine cytomegalovirus replication in the salivary gland
Authors: Oderbolz Josua , Zangger Nathan , Zimmermann Lea , Sandu Ioana , Starruß Jörn , Graw Frederik , Oxenius Annette
Published: January 2021

Cytomegalovirus (CMV) has evolved a unique virus-host relationship in the salivary glands (SGs) to sustain prolonged viral replication and hence chances for horizontal transmission. Previous reports have established a decisive role for IFNγproducing CD4+T cells to control murine CMV (MCMV) infection in the SGs; however, micro-anatomical information regarding their mode of action is largely missing. Here, we provide a spatiotemporal analysis of defined antiviral immune actions that eventually culminate in control of lytic MCMV replication in this preferred mucosal niche. CXCR3-mediated guidance of CD4+T cells towards CXCL9 and CXCL10 expressing cells resulted in discrete clusters close to infection foci where they reported TCR engagement and produced IFNγ. Of note, these clusters occasionally contained CD11c+antigen-presenting cells with engulfed virus-associated remnants, most likely apoptotic bodies derived from previously infected cells, enabling antigen presentation to CD4+T cells. The induced IFNγproduction within these CD4+T cell accumulations triggered IFNγR signaling in a confined perimeter, thereby inducing local, but not organ-wide protection, and allowing MCMV replication to continue at not yet protected sites. Combining experimental data with a mathematical model of the spatiotemporal dynamics of infection and CD4+T cell dynamics revealed a scenario, in which ultimate MCMV control is achieved through accumulating sites of regionally-confined tissue protection.
Atopic Biomarker Changes after Exposure toPorphyromonas gingivalisLipopolysaccharide: A Small Experimental Study in Wistar Rat
Authors: Nelwan Sindy Cornelia , Nugraha Ricardo Adrian , Endaryanto Anang , Meizarini Asti , Tedjosasongko Udijanto , Pradopo Seno , Utomo Haryono
Published: January 2021

Background

IgE and IgG4are implicated in atopic development and clinically utilized as major biomarkers. Atopic responses following certain pathogens such asPorphyromonas gingivalisis currently an area of interest for further research.

Purpose

The aim of this study is to measure the level of IgE, IgG4, and IgG4/IgE ratio periodically after exposure of periodontal pathogenPorphyromonas gingivalis(Pg) lipopolysaccharide (LPS).

Methods

We used 16 wistar rats (Rattus norvegicus) randomly subdivided into 4 groups, group 1 were injected by placebo, group 2 by LPS Pg 0.3 μg/mL,group 3 by LPS Pg 1 μg/mL, and group 4 by LPS Pg 3 μg/mL. Sera from both groups were taken from retro-orbital plexus before and after exposure.

Results

Level of IgE and IgG4increased significantly following exposure of LPS Pg at day-4 and day-11. Greater increase of IgE rather than IgG4contributes to rapid decline of IgG4/IgE ratio, detected in the peripheral blood at day-4 and day-11.

Conclusion

Modulation of atopic responses following exposure to LPS Pg is reflected by decrease in IgG4/IgE ratio that accompanies an increase of IgE.

Clinical significance

Porphyromonas gingivalis, a keystone pathogen during periodontal disease, may have a tendency to disrupt atopic biomarkers.
Systemic antisense therapeutics inhibitingDUX4expression improves muscle function in an FSHD mouse model
Authors: Lu-Nguyen Ngoc , Malerba Alberto , Dickson George , Popplewell Linda
Published: January 2021

Aberrant expression of the double homeobox 4 (DUX4) gene in skeletal muscle causes muscle deterioration and weakness in Facioscapulohumeral Muscular Dystrophy (FSHD). Since the presence of a permissive pLAM1 polyadenylation signal is essential for stabilization ofDUX4mRNA and translation of DUX4 protein, disrupting the function of this structure can prevent expression of DUX4. We and others have shown promising results using antisense approaches to reduceDUX4expressionin vitroandin vivofollowing local intramuscular administration. Our group has developed further the antisense chemistries, and demonstrate here enhancedin vitroantisense efficacy. The optimal chemistry was conjugated to a cell-penetrating moiety, and for the first time in FSHD research has been systemically administered into a double-transgenic mouse model of FSHD. After four weekly treatments, mRNA quantities ofDUX4and target genes were reduced by 50% that led to a 5% increase in muscle mass, a 52% improvement inin situmuscle strength, and reduction of muscle fibrosis by 17%. Systemic DUX4 inhibition also improved the locomotor activity significantly and reduced the fatigue level by 22%. Our data overall demonstrate that the optimized antisense approach can contribute to future development of a therapeutic strategy for FSHD.
Environment-Dependent Switch between Two Immune Systems againstRalstonia solanacearumInfections in Pepper
Authors: Yang Sheng , Cai Weiwei , Shen Lei , Wu Ruijie , Cao Jianshen , Cai Jinsen , He Shicong , Zheng Yutong , Zhang Qixiong , Wang Aiwen , Guan Deyi , He Shuilin
Published: January 2021

Although plant diseases generally cause more severe symptoms under conditions of high temperature and high humidity(HTHH), how plant respond to pathogen attack under this condition remains elusive.

As an example, we herein comparatively studied pepper(Capsicum annuum) immunity againstRalstonia solanacearumunder HTHH and ambient temperature by approaches of reverse genetics. We found that pepper respond toR.solanacearuminfection by activating salicylic-acid- and jasmonic-acid-mediated immunity at ambient temperature. Under HTHH, However, it no longer activates JA-mediated immunity and activates only transient SA signaling at the early stage ofR.solanacearuminfection, but instead induces cytokinin mediated immunity.

These two immune systems are positively regulated by CaWRKY40 via binding the WT-box and a novel W-box like (WL) box, respectively, in an environment-dependent manner:CaWRKY40is activated uponR. solanacearuminfection under HTHH, thereby upregulating ISOPENTENYLTRANSFERASE5(IPT5). The resulting cytokinin then works synergistically with CaWRKY40 in activating a subset of glutathione S-transferase genes via chromatin activation and WL-box binding, but prevent CaWRKY40 from activating ISOCHORISMATE SYNTHASE1 (ICS1) or SA-/JA-dependent pathogenesis-related genes by chromatin inactivation or by blocking WT-box binding.

These results highlight the specific pepper immune response toR. solanacearuminfection under HTHH and its synergistic activation byCaWRKY40 and cytokinins.
Transient mitochondria dysfunction confers fungal cross-resistance between macrophages and fluconazole
Authors: Siscar-Lewin Sofía , Gabaldón Toni , Aldejohann Alexander M. , Kurzai Oliver , Hube Bernhard , Brunke Sascha
Published: January 2021

Loss or inactivation of antivirulence genes is an adaptive strategy in pathogen evolution.Candida glabratais an important opportunistic pathogen related to baker’s yeast, with the ability to both, quickly increase its intrinsic high level of azole resistance and persist within phagocytes. DuringC. glabrata’s evolution as a pathogen, the mitochondrial DNA polymerase, CgMip1, has been under positive selection. We show thatCgMIP1deletion not only triggers loss of mitochondrial function and apetitephenotype, but increasesC. glabrata’s azole and ER stress resistance, and importantly, its survival in phagocytes. The same phenotype is induced by fluconazole and by exposure to macrophages, conferring a cross-resistance between antifungals and immune cells, and can be found in clinical isolates despite its slow growth. This suggests thatpetiteconstitutes a bet-hedging strategy ofC. glabrata, and potentially a relevant cause of azole resistance. Mitochondrial function may therefore be considered a potential antivirulence factor.