bluuebunny/crossref_metadata_2025 huggingface dataset:
The Liberal Collectivist Experiment
Authors: Berry Craig
Published: February 2021

This chapter provides an overview of the historical development of UK pensions provision, focusing on the main philosophical or ideological foundations of different elements of provision, how they fit together, how they have evolved, and the major policy initiatives that have both instituted and transformed UK pensions provision at different points in time. It focuses primarily on the post-war period, but actually locates the genesis of UK pensions provision in the seventeenth century, and details the birth of occupational pensions provision in the late nineteenth century. The chapter shows that the UK policy elite’s commitment to a liberal market order both shaped and constrained the development of public and private pensions provision—providing for a fragile patchwork of institutional and industrial practices, which were unravelled by the emergence of neoliberalism. Overall, the chapter situates the development of UK private pensions provision within the context of shifts within productive activity and industrial relations.
Auto-Pilot
Authors: Berry Craig
Published: February 2021

This chapter considers in depth some of the key elements of the new landscape of individualized pensions provision in the UK, reflecting in particular on some of the state’s emerging functions as facilitator, regulator, and provider of defined contribution pensions. It charts how the Pensions Commission’s vision for state-managed defined contribution was subtly marginalized, resulting in an approach which enables and indeed privileges privatized delivery of auto-enrolment, leaving private pensions provision caught between two radically different regulatory regimes, and rendering the state unable to act decisively to protect individual welfare. The chapter also discusses decumulation processes, including the Coalition government’s radical and highly destructive reforms to the annuities market, and the peculiar role played by pensions tax relief—providing a largely ineffective saving incentive, albeit at great expense.
Rational Choice and its Limits for the Solution of Social and Legal Problems
Authors: Deakin Simon
Published: February 2021

This chapter addresses a number of methodological issues arising from the behavioural turn in law and economics and its claim to have established more realistic foundations for both positive and normative analysis. The first is whether models are necessarily better for being more realistic. Friedman’s proposal that the less realistic a model, the more useful it is as a basis for the identification of hypotheses, is rejected on the grounds that this is liable to direct research down fruitless or even erroneous paths. However, models such as the rationality axiom remain approximations of reality, not revealed truths. This leads on to a consideration of the second issue which is whether behavioural research should lead us to reject the rationality axiom. The claim that human beings are systematically wrong in their decision making is shown to be theoretically unsound and empirically unproven. Rather, theory and empirics alike suggest that rationality has a basis in social learning and institutional framing. The third issue concerns the normative conclusions to be drawn from behavioural law and economics. It is suggested that empirical research does not justify privileging ‘libertarian paternalism’ over alternative approaches to law and regulation. In the era of surveillance capitalism and the panoptic state, it is more than timely to reflect on the merits of collective learning and participatory decision making, democratic practices with adaptive qualities neglected by behavioural law and economics.
Most People Like Nudges—and Why that Matters
Authors: Reisch Lucia A. , Sunstein Cass R. , Kaiser Micha
Published: February 2021

This chapter reports the results of nationally representative surveys in fourteen countries, investigating the attitudes of people towards nudges and nudging, with a particular focus on environmental and health nudges. The countries covered are Australia, Brazil, Canada, China, Denmark, France, Germany, Hungary, Italy, Japan, Russia, South Africa, South Korea, and the United Kingdom. There is strong majority support for both health and environmental nudges in all countries, with the exception of Japan, Denmark, and Hungary. China and South Korea stand out with particularly high acceptance rates. Beyond reporting the results of the combined dataset for the first time, the chapter provides an explanation first, of why policy makers might be interested in public approval or disapproval of nudges, and second, how information of public acceptance can inform both uses of and constraints on nudging.
Regulating under Uncertainty about Rationality
Authors: Hacker Philipp
Published: February 2021

Theories of choice, and their legal consequences, dramatically differ based on whether they are premised on rational or boundedly rational actors. This chapter describes the interactions between, and regulatory implications of, three types of uncertainties that the selection of an adequate theory of choice requires. First, it suggests that Knightian uncertainty concerning the distribution of degrees of rationality between regulatees obtains in many regulatory areas. More recently, this has been described as a ‘knowledge problem’ of behavioural law and economics. This chapter argues that the best regulatory response to the knowledge problem is to frame regulation as a problem of decision making under uncertainty. Second, with the rise of machine learning, it is arguably becoming ever more possible to estimate the level of bias, or even entire rationality quotients, of individual regulatees. This opens the potential for, but also the pitfalls of, personalised law. Third, even Big Data analytics generally only offers a snapshot of a distribution of rationality at one moment in time. Recent economic analyses have suggested behavioural heterogeneity can evolve over time in unpredicted ways that may lead to unforeseen consequences, leading to economic complexity. This calls for a greater role of standards, as opposed to rules, in regulating environments with dynamic behavioural heterogeneity. The chapter focuses on the normative implications of different types of uncertainty. In the end, theories of choice can aid more transparent normative trade-offs but they cannot replace the value judgments, and normative discourses, that balance the involved interests.
Itinera Europea
Authors: Héritier Adrienne
Published: February 2021

Based on strategic interaction analysis, the chapter assesses the plausibility of the future paths of development of the European Union: a federal state, a differentiated and flexible union, covert integration, or disintegration. Systematically varying either the preferences of the main actors or the macro decision-making rules and external shocks/crises, the analysis comes to the conclusion that a differentiated and flexible union and covert integration are the most likely paths of development. The chapter discusses implications of specific scenarios, such as a possible popular backlash against ‘covert integration’ and elaborates on the desirability of practical proposals of a change in the European institutional architecture.
Decision Theory and Allocating Decision Making in the Firm
Authors: Velasco Julian
Published: February 2021

Sometimes it is possible to deal productively with the subject matter of choosing and making decisions without actually settling upon any particular theory of choice. This is the case in the law of business organisations, which does not settle upon a theory of choice because it does not consider itself the ultimate decision maker. Rather, the law develops rules to allocate decision-making authority among the various parties. Utilising only a few basic principles of decision theory, the law of business organisation creates a structure for allocating decision-making responsibility on many different levels. However, it leaves the ultimate decision makers free not only to make substantive decisions for themselves but also to select from among the various theories of choice for doing so.
Conflict of Interest and Decision Making
Authors: Helleringer Geneviève
Published: February 2021

This chapter looks at conflicts of interest (COI). It first considers tools of analytic philosophy to highlight the notion of COI, and in particular, the connection between COIs, choice and judgment, emphasising why decision making is a central element in the characterisation of COIs. Drawing on these elements, it is clear that any question of regulation and institutional design requires a sophisticated understanding of the capacity of individuals to recognise and resist bias in themselves and others when making judgments and decisions. The chapter then studies two specific mechanisms—bounded rationality and cognitive biases—that affect the behaviour of people in COI situations. It starts by analysing how rationalisation can reframe questionable behaviour as appearing acceptable, and how a sense of invulnerability encourages people to downplay the impact of COIs. The chapter then looks at techniques (policies, procedures, incentives, etc.) used to address COI situations in the light of insights from psychological studies. It concludes that both fiduciary duties and procedural requirements reflect an erroneous understanding of psychology and have led institutions and policies to deal ineffectively—if not indeed counterproductively—with the problems caused by COIs. Finally, the chapter assesses how alternative mechanisms may overcome the highlighted deficiencies. It specifically focuses on the key role that professional norms can play in dealing with unavoidable COIs while preserving trust between the affected parties, and the potential for self-regulation to provide worthwhile tools in combatting the harmful effects of COIs.
The PIF1-miR408-PLANTACYANIN repression cascade regulates light-dependent seed germination
Authors: Jiang Anlong , Guo Zhonglong , Pan Jiawei , Yang Yanzhi , Zhuang Yan , Zuo Daqing , Hao Chen , Gao Zhaoxu , Xin Peiyong , Chu Jinfang , Zhong Shangwei , Li Lei
Published: February 2021

Light-dependent seed germination is a vital process for many seed plants. A decisive event in light-induced germination is degradation of the central repressor PHYTOCHROME INTERACTING FACTOR 1 (PIF1). The balance between gibberellic acid (GA) and abscisic acid (ABA) helps to control germination. However, the cellular mechanisms linking PIF1 turnover to hormonal balancing remain elusive. Here, employing far-red light-induced Arabidopsis thaliana seed germination as the experimental system, we identified PLANTACYANIN (PCY) as an inhibitor of germination. It is a blue copper protein associated with the vacuole that is both highly expressed in mature seeds and rapidly silenced during germination. Molecular analyses showed that PIF1 binds to the miR408 promoter and represses miR408 accumulation. This in turn posttranscriptionally modulates PCY abundance, forming the PIF1-miR408-PCY repression cascade for translating PIF1 turnover to PCY turnover during early germination. Genetic analysis, RNA-sequencing, and hormone quantification revealed that PCY is necessary and sufficient to maintain the PIF1-mediated seed transcriptome and the low-GA-high-ABA state. Furthermore, we found that PCY domain organization and regulation by miR408 are conserved features in seed plants. These results revealed a cellular mechanism whereby PIF1-relayed external light signals are converted through PCY turnover to internal hormonal profiles for controlling seed germination.
Extended yeast surface display linkers enhance the enrichment of ligands in direct mammalian cell selections
Authors: Lown Patrick S , Cai Jessy J , Ritter Seth C , Otolski Jacob J , Wong Ryan , Hackel Benjamin J
Published: February 2021

Selections of yeast-displayed ligands on mammalian cell monolayers benefit from high target expression and nanomolar affinity, which are not always available. Prior work extending the yeast–protein linker from 40 to 80 amino acids improved yield and enrichment but is hypothesized to be below the optimal length, prompting evaluation of an extended amino acid linker. A 641-residue linker provided enhanced enrichment with a 2-nM affinity fibronectin ligand and 105 epidermal growth factor receptors (EGFR) per cell (14 ± 2 vs. 8 ± 1, P = 0.008) and a >600-nM affinity ligand, 106 EGFR per cell system (23 ± 7 vs. 0.8 ± 0.2, P = 0.004). Enhanced enrichment was also observed with a 310-nM affinity affibody ligand and 104 CD276 per cell, suggesting a generalizable benefit to other scaffolds and targets. Spatial modeling of the linker suggests that improved extracellular accessibility of ligand enables the observed enrichment under conditions not previously possible.
The hierarchical sensitivity to social misalignment during decision-making under uncertainty
Authors: Lin Yongling , Gu Ruolei , Luan Shenghua , Hu Li , Qin Shaozheng , Luo Yue-jia
Published: February 2021

Social misalignment occurs when a person’s attitudes and opinions deviate from those of others. We investigated how individuals react to social misalignment in risky (outcome probabilities are known) or ambiguous (outcome probabilities are unknown) decision contexts. During each trial, participants played a forced-choice gamble, and they observed the decisions of four other players after they made a tentative decision, followed by an opportunity to keep or change their initial decision. Behavioral and event-related potential data were collected. Behaviorally, the stronger the participants’ initial preference, the less likely they were to switch their decisions, whereas the more their decisions were misaligned with the majority, the more likely they were to switch. Electrophysiological results showed a hierarchical processing pattern of social misalignment. Misalignment was first detected binarily (i.e. match/mismatch) at an early stage, as indexed by the N1 component. During the second stage, participants became sensitive to low levels of misalignment, which were indexed by the feedback-related negativity. The degree of social misalignment was processed in greater detail, as indexed by the P3 component. Moreover, such hierarchical neural sensitivity is generalizable across different decision contexts (i.e. risky and ambiguous). These findings demonstrate a fine-grained neural sensitivity to social misalignment during decision-making under uncertainty.
Effects of prefrontal theta burst stimulation on neuronal activity and subsequent eating behavior: an interleaved rTMS and fNIRS study
Authors: Fatakdawala Idris , Ayaz Hasan , Safati Adrian B , Sakib Mohammad N , Hall Peter A
Published: February 2021

The dorsolateral prefrontal cortex (dlPFC) and dorsomedial prefrontal cortex (dmPFC) are both important nodes for self-control and decision-making but through separable processes (cognitive control vs evaluative processing). This study aimed to examine the effects of excitatory brain stimulation [intermittent theta burst stimulation (iTBS)] targeting the dlPFC and dmPFC on eating behavior. iTBS was hypothesized to decrease consumption of appetitive snack foods, via enhanced interference control for dlPFC stimulation and reduced delay discounting (DD) for dmPFC stimulation. Using a single-blinded, between-subjects design, participants (N = 43) were randomly assigned to one of three conditions: (i) iTBS targeting the left dlPFC, (ii) iTBS targeting bilateral dmPFC or (iii) sham. Participants then completed two cognitive tasks (DD and Flanker), followed by a bogus taste test. Functional near-infrared spectroscopy imaging revealed that increases in the medial prefrontal cortex activity were evident in the dmPFC stimulation group during the DD task; likewise, a neural efficiency effect was observed in the dlPFC stimulation group during the Flanker. Gender significantly moderated during the taste test, with females in the dmPFC showing paradoxical increases in food consumption compared to sham. Findings suggest that amplification of evaluative processing may facilitate eating indulgence when preponderant social cues are permissive and food is appetitive.
Much of the Neurocognitive Impairment in Schizophrenia is Due to Factors Other Than Schizophrenia Itself: Implications for Research and Treatment
Authors: Moritz Steffen , Silverstein Steven M , Beblo Thomas , Özaslan Zeynep , Zink Mathias , Gallinat Jürgen
Published: February 2021

Patients with schizophrenia perform worse on neuropsychological tasks than controls. While most experts ascribe poor performance to neurocognitive impairment, an emerging literature is identifying important nonspecific mediators of neurocognitive test performance, some of which can be accounted for in trials (eg, motivation, effort, defeatist performance beliefs, stress, anxiety, physical inactivity). Other factors are harder, if not impossible, to control when patients are compared to non-clinical participants (eg, hospitalization, medication effects, distraction due to positive symptoms). Effect sizes of neurocognitive performance differences are usually not adjusted for these confounders, and the level of neurocognitive impairment due to schizophrenia is thus likely exaggerated. We suggest some ways for researchers to account for the effects of these mediators. Secondary influences that negatively affect neurocognitive performance should not be treated as mere noise. They give important insight into causal mechanisms and may inform more effective treatments that go beyond cognitive remediation.
Drawing Lines in the Sand? Paths Forward for Triggering Regulation of Gene-Edited Crops
Authors: Nawaz Sara , Kandlikar Milind
Published: February 2021

Researchers are making use of new gene-editing techniques in medicine, bioenergy, industrial biotechnology, and beyond, and the field of crop breeding is no exception. These techniques, which differ from genetic modification techniques, spell difficult questions for regulatory oversight: will current rules-of-play apply, or do new techniques necessitate fundamental shifts in regulations? Thus far, little explicit attention has focused on the fundamental yet elusive questions of which technical specifics currently trigger regulation of gene-edited crops, and where different jurisdictions ‘draw’ this line. Here, we trace these regulatory lines across key jurisdictions. We argue that extant regulatory definitions are crumbling in the face of emerging technologies and assert that this breakdown poses a threat to responsible governance. Drawing upon insights from responsible research and innovation, we propose a shift away from technically based regulatory approaches and toward more risk-targeted oversight based on broader societal and ecological implications.
The investigation of the protective effect of cinnamon water extract and vitamin E on malathion-induced oxidative damage in rats
Authors: Berktas Ozlem Aydin , Peker Emine Gulceri Gulec
Published: February 2021

Pesticides and other agricultural protective chemical products are widely used almost all over the world. It poses a serious threat, especially for public health. Many studies have reported that pesticide poisoning is a major problem in morbidity and mortality. Accordingly, it is aimed to determine the protective properties of the cinnamon extract against oxidative stress caused by malathion used as a pesticide within the scope of this study. In total, 30 Wistar-albino rats have fasted for 24 h. Cinnamon water extract (150 mg/kg), vitamin E, corn oil, and malathion (150 mg/kg) was administered by the oral route. Rats were sacrificed 24 h after administration and stomach and liver tissues were removed. Then, catalase, superoxide dismutase enzyme activities, glutathione, and lipid peroxidation amounts were measured in tissues biochemically. It was determined that the oxidative stress occurring in the malathion-treated group was significantly reduced (P < 0.05) in the applied spice dose and in the positive control vitamin E group. On the other hand, with the application of malathion, it has been determined that catalase and lipid peroxidation levels increase, while superoxide dismutase and glutathione levels decrease. With the measured enzyme activity differences, this spice extract was found to be an oxidative stress reducer. Oxidative stress, which can be determined with oxidative/antioxidant parameters, has been significantly prevented by the applications that do not occur.
Chlamydial clinical isolates show subtle differences in persistence phenotypes and growth in vitro
Authors: Thomas Mark , Lawrence Amba , Kroon Samuel , Vodstrcil Lenka A. , Phillips Samuel , Hocking Jane S. , Timms Peter , Huston Wilhelmina M.
Published: February 2021

Urogenital

Chlamydia trachomatis

infection is the most common sexually transmitted bacterial infection throughout the world. While progress has been made to better understand how type strains develop and respond to environmental stress in vitro, very few studies have examined how clinical isolates behave under similar conditions. Here, we examined the development and persistence phenotypes of several clinical isolates, to determine how similar they are to each other, and the type strain

C. trachomatis

D/UW-3/Cx. The type strain was shown to produce infectious progeny at a higher magnitude than each of the clinical isolates, in each of the six tested cell lines. All chlamydial strains produced the highest number of infectious progeny at 44 h post-infection in the McCoy B murine fibroblast cell line, yet showed higher levels of infectivity in the MCF-7 human epithelial cell line. The clinical isolates were shown to be more susceptible than the type strain to the effects of penicillin and iron deprivation persistence models in the MCF-7 cell line. While subtle differences between clinical isolates were observed throughout the experiments conducted, no significant differences were identified. This study reinforces the importance of examining clinical isolates when trying to relate in vitro data to clinical outcomes, as well as the importance of considering the adaptations many type strains have to being cultured in vitro.
Disentangling independent and mediated causal relationships between blood metabolites, cognitive factors, and Alzheimer’s Disease
Authors: Lord Jodie , Green Rebbeca , Choi Shing Wan , Hübel Christopher , Aarsland Dag , Velayudhan Latha , Sham Pak , Legido-Quigley Cristina , Richards Marcus , Dobson Richard , Proitsi Petra ,   the GERAD1 Consortium,   AddNeuroMed
Published: February 2021

Background

Education and cognition demonstrate consistent inverse associations with Alzheimer’s Disease (AD). The biological underpinnings, however, remain unclear. Blood metabolites can reflect the endpoint of biological processes and are accessible and malleable. Identifying metabolites with aetiological relevance to AD and disentangling how these relate to cognitive factors along the AD causal pathway could, therefore, offer unique insights into underlying causal mechanisms.

Methods

Using data from the largest metabolomics genome-wide association study (N≈24,925) and three independent AD cohorts (N=4,725), cross-trait polygenic scores were generated and meta-analyzed. Metabolites genetically associated with AD were taken forward for causal analyses. Bidirectional two-sample Mendelian randomization (MR) interrogated univariable causal relationships between (i) metabolites and AD, (ii) metabolites, education and cognition (iii) education, cognition and AD, and (iv) education and cognition. Mediating relationships were computed using multivariable MR.

Results

Thirty-four metabolites were genetically associated with AD at p<0.05. Of these, glutamine and free cholesterol in extra-large high-density lipoproteins (XL.HDL.FC) demonstrated a protective causal effect (Glutamine: 95% CI=0.70-0.92; XL.HDL.FC: 95% CI=0.75-0.92). An AD-protective effect was also observed for education (95% CI=0.61-0.85) and cognition (95% CI=0.60-0.89), with bidirectional mediation evident. Cognition as a mediator of the education-AD relationship was stronger than vice-versa, however. No evidence of mediation via any metabolite was found.

Conclusions

Glutamine and XL.HDL.FC show protective causal effects on AD. Education and cognition also demonstrate protection, though education’s effect is almost entirely mediated by cognition. These insights provide key pieces of the AD causal puzzle, important for informing future multi-modal work and progressing towards effective intervention strategies.
Probiotic supplements reduce antipsychotic-induced metabolic disturbances in drug-naïve first-episode schizophrenia
Authors: Kang Dongyu , Zhang Fengyu , Yang Ye , Liu Chenchen , Xiao Jingmei , Long Yujun , Huang Jing , Peng Xingjie , Wang Weiyan , Wang Xiaoyi , Davis John M. , Zhao Jingping , Wu Renrong
Published: February 2021

Probiotic supplements have demonstrated efficacy in improving metabolic abnormalities and may prevent antipsychotic-induced metabolic disturbance and weight gain. A few studies in rodents have found that antipsychotic-induced metabolic dysfunctions are associated with the altered composition of gut microbiota. Here, we conducted a randomized-controlled clinical trial to determine the effectiveness and safety of probiotic supplements on antipsychotic-induced metabolic disturbance and weight gain. Patients with drug-naïve first-episode schizophrenia were randomized to receive either olanzapine plus probiotics or olanzapine monotherapy and scheduled to evaluate with follow-ups for clinical and metabolic profiles. After a treatment of 12 weeks with addition of probiotics, the increase of mean fasting insulin was significantly lower than olanzapine monotherapy. Insulin resistance increased considerably in the olanzapine plus probiotics, but also significantly lower than olanzapine monotherapy. We noted a difference in the increase in body mass index and body weight between treatments at a nominal level of significance, but it became non-significant after adjusting for appetite increase. Probiotics concurrently used with olanzapine is effective and safe in attenuating antipsychotic-induced elevation of fasting insulin and insulin resistance, but not the weight gain in drug-naïve first-episode schizophrenia. Further study is warranted to assess the longer-term maintenance of efficacy and safety.
Salivary detection of COVID-19. Clinical performance of oral sponge sampling for SARS-CoV-2 testing
Authors: Marquette Charles Hugo , Boutros Jacques , Benzaquen Jonathan , Ilié Marius , Labaky Mickelina , Benchetrit Didier , Lavrut Thibaut , Leroy Sylvie , Chemla Richard , Carles Michel , Tanga Virginie , Maniel Charlotte , Bordone Olivier , Allégra Maryline , Lespinet Virginie , Fayada Julien , Griffonnet Jennifer , Hofman Véronique , Hofman Paul
Published: February 2021

Background

The current diagnostic standard for coronavirus 2019 disease (COVID-19) is reverse transcriptase-polymerase chain reaction (RT-PCR) testing with naso-pharyngeal (NP) swabs. The invasiveness and need for trained personnel make the NP technique unsuited for repeated community-based mass screening. We developed a technique to collect saliva in a simple and easy way with the sponges that are usually used for tamponade of epistaxis. This study was carried out to validate the clinical performance of oral sponge (OS) sampling for SARS-CoV-2 testing.

Methods

Over a period of 22 weeks, we collected prospectively 409 paired NP and OS samples from consecutive subjects presenting to a public community-based free screening center. Subjects were referred by their attending physician because of recent COVID-19 symptoms (n=147) or by the contact tracing staff of the French public health insurance since they were considered as close contacts of a laboratory-confirmed COVID-19 case (n=262).

Results

In symptomatic subjects, RT-PCR SARS-CoV-2 testing with OS showed a 96.5% (95%CI: 89.6-94.8) concordance with NP testing, and, a 93.3% [95%CI: 89.1-97.3] sensitivity. In close contacts the NP-OS concordance (93.8% [95%CI: 90.9-96.7]) and OS sensitivity (71.9% [95%CI: 66.5-77.3]) were slightly lower.

Conclusion

These results strongly suggest that OS testing is a straightforward, low-cost and high-throughput sampling method that can be used for frequent RT-PCR testing of COVID-19 patients and mass screening of populations.

Summary of the “take home” message

OS sampling for SARS-CoV2 RT-PCR is an easy to perform, straightforward self-administered sampling technique, which has a sensitivity of up to 93.3% in symptomatic patients and 71% in close contact subjects.
Clinical genetic risk variants inform a functional protein interaction network for tetralogy of Fallot
Authors: Reuter Miriam S. , Chaturvedi Rajiv R. , Jobling Rebekah K. , Pellecchia Giovanna , Hamdan Omar , Sung Wilson W.L. , Nalpathamkalam Thomas , Attaluri Pratyusha , Silversides Candice K. , Wald Rachel M. , Marshall Christian R. , Williams Simon , Keavney Bernard D. , Thiruvahindrapuram Bhooma , Scherer Stephen W. , Bassett Anne S.
Published: February 2021

Background

Tetralogy of Fallot (TOF), the most common cyanotic heart defect in newborns, has evidence of multiple genetic contributing factors. Identifying variants that are clinically relevant is essential to understand patient-specific disease susceptibility and outcomes, and could contribute to delineating pathomechanisms.

Methods and Results

We used a clinically-driven strategy and current guidelines to re-analyze exome sequencing data from 811 probands with TOF, focused on identifying rare loss-of-function and other likely pathogenic variants in congenital heart disease (CHD) genes. In addition to confirming a major contribution of likely pathogenic variants inFLT4(VEGFR3; n=14) andNOTCH1(n=11), we identified 1-3 such variants in each of 21 other CHD genes, includingATRX, DLL4, EP300, GATA6, JAG1, NF1, PIK3CA, RAF1, RASA1, SMAD2, andTBX1. There were also three emerging CHD/TOF candidate genes with multiple loss-of-function variants in this cohort:KDR(n=4),IQGAP1(n=3), andGDF1(n=8). In total, these variants were identified in 64 probands (7.9%). Using the 26 composite genes in a STRING protein interaction enrichment analysis revealed a biologically relevant network (p-value 3.3e-16), with VEGFR2 (KDR) and NOTCH1 representing central nodes. Variants associated with arrhythmias/sudden death and/or heart failure indicated factors that could influence long-term outcomes.

Conclusions

The results are relevant to precision medicine for TOF. They suggest considerable clinical yield from genome-wide sequencing, and further evidence forKDRas a CHD/TOF gene and VEGF and Notch signaling as mechanisms in human disease. Harnessing genetic heterogeneity of single gene defects could inform etiopathogenesis and help prioritize novel candidate genes for TOF.
Are fast test results preferable to high test sensitivity in contact-tracing strategies?
Authors: Juul Jonas L. , Græsbøll Kaare
Published: February 2021

Across the world, countries are fighting to reduce the spread of COVID-19. The backbone of the response is a test-trace-isolate strategy, where suspected infected get tested and isolated and possible secondary cases get traced, tested and isolated. Because more accurate tests often take longer to analyze, and the benefits of contact tracing are strengthened by rapid diagnosis, there exists a trade-off in test sensitivity and test waiting time in test-trace-isolate strategies. Here we ask: How many false negatives can be tolerated in a rapid test so that it reduces transmission better than a slower, more accurate test? How does this change with contact tracing efficiency and test waiting time? We find that a rapid, less sensitive test performs best for many test-parameter choices and that this is true even for modest contact tracing efficiency. For COVID-19-like viral parameters, a test with 40% false negatives and immediate result might reduce transmission as well as a test with no false negatives and a 3-day waiting time. Our analysis suggests employing rapid tests to reduce test waiting times as a viable strategy to reduce transmission when testing infrastructure is under stress.
SARS-CoV-2 Seroprevalence in a University Community: A Longitudinal Study of the Impact of Student Return to Campus on Infection Risk Among Community Members
Authors: Arnold Callum R.K. , Srinivasan Sreenidhi , Rodriguez Sophie , Rydzak Natalie , Herzog Catherine M. , Gontu Abhinay , Bharti Nita , Small Meg , Rogers Connie J. , Schade Margeaux M. , Kuchipudi Suresh V , Kapur Vivek , Read Andrew , Ferrari Matthew J.
Published: February 2021

Background

Returning university students represent large-scale, transient demographic shifts and a potential source of transmission to adjacent communities during the COVID-19 pandemic.

Methods

In this prospective longitudinal cohort study, we tested for IgG antibodies against SARS-CoV-2 in a non-random cohort of residents living in Centre County prior to the Fall 2020 term at the Pennsylvania State University and following the conclusion of the Fall 2020 term. We also report the seroprevalence in a non-random cohort of students collected at the end of the Fall 2020 term.

Results

Of 1313 community participants, 42 (3.2%) were positive for SARS-CoV-2 IgG antibodies at their first visit between 07 August and 02 October 2020. Of 684 student participants who returned to campus for fall instruction, 208 (30.4%) were positive for SARS-CoV-2 antibodies between 26 October and 21 December. 96 (7.3%) community participants returned a positive IgG antibody result by 19 February. Only contact with known SARS-CoV-2-positive individuals and attendance at small gatherings (20-50 individuals) were significant predictors of detecting IgG antibodies among returning students (aOR, 95% CI: 3.1, 2.07-4.64; 1.52, 1.03-2.24; respectively).

Conclusions

Despite high seroprevalence observed within the student population, seroprevalence in a longitudinal cohort of community residents was low and stable from before student arrival for the Fall 2020 term to after student departure. The study implies that heterogeneity in SARS-CoV-2 transmission can occur in geographically coincident populations.

Author’s summary

Despite high seroprevalence observed within the student population, seroprevalence in a longitudinal cohort of community residents remained low and stable from before student arrival for the Fall term to after their departure, implying limited transmission between these subpopulations.
Temporal differentiation of resource capture and biomass accumulation as a driver of yield increase in intercropping
Authors: Engbersen Nadine , Brooker Rob W. , Stefan Laura , Studer Björn , Schöb Christian
Published: February 2021

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Intercropping, i.e. the simultaneous cultivation of different crops on the same field, has demonstrated yield advantages compared to monoculture cropping. These yield advantages have often been attributed to complementary resource use, but few studies quantified the temporal complementarity of nutrient acquisition and biomass production. Our understanding of how nutrient uptake rates of nitrogen (N) and phosphorous (P) and biomass accumulation change throughout the growing season and between different neighbors is limited.

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We conducted weekly destructive harvests to measure temporal trajectories of N and P uptake and biomass production in three crop species (oat, lupin and camelina) growing either as isolated single plants, in monocultures or as intercrops. Additionally, we quantified organic acid exudation in the rhizosphere and biological N2-fixation of lupin throughout the growing season. Logistic models were fitted to characterize nutrient acquisition and biomass accumulation trajectories.

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Nutrient uptake and biomass accumulation trajectories were curtailed by competitive interactions, resulting in earlier peak rates and lower total accumulated nutrients and biomass compared to cultivation as isolated single plants. Different pathways led to overyielding in the two mixtures. The oat–camelina mixture was characterized by a shift from belowground temporal niche partitioning of resource uptake to aboveground competition for light during the growing season. The oat–lupin mixture showed strong competitive interactions, where lupin eventually overyielded due to reliance on atmospheric N and stronger competitiveness for soil P.

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Synthesis: This study demonstrates temporal shifts to earlier peak rates of plants growing with neighbors compared to those growing alone, suggesting that the observed temporal shifts in our experiment are driven by competitive interactions rather than active plant behavior to reduce competition. The two differing pathways to overyielding in the two mixtures highlight the importance of examining temporal dynamics in intercropping systems to understand the underlying mechanisms of overyielding.
Epitranscriptomic Dysregulation in Stress-induced Psychopathologies
Authors: Ohtan Wang Dan , Joshi Kandarp , Gururajan Anand
Published: February 2021

To date, over 100 different chemical modifications to RNA have been identified. Collectively known as the epitranscriptome, these modifications function to regulate RNA stability and as such, represent another mechanistic layer of post-transcriptional gene regulation. N6-methyladenosine (m6A) is the most common RNA modification in the mammalian brain and has been implicated in a number of processes relevant to neurodevelopment, brain function and behaviour. Here, following brief descriptions on epitranscriptomic mechanisms, we will review the literature on the potential functions of the m6A-methylome in fine-tuning gene expression which include prescribing localisation of transcripts in distal compartments as well as interactions with microRNAs and long non-coding RNAs. We will then discuss findings from rodent and human studies for stress-induced disorders - major depression and post-traumatic stress disorder – which support a hypothesis for a dysregulation of the m6A-methylome and the m6A-machinery in the pathophysiology. To support this, we have included a bioinformatic analysis of publicly available single-cell RNA-sequencing and bulk transcriptomics datasets which suggests an altered m6A-methylome as a consequence of dysregulated cell- and regionally-specific expression of key enzymes involved in the ‘writing, reading and erasing’ of m6A. We hope this review will generate further interest in the field of epitranscriptomics, opening up new lines of research into its involvement in psychiatric disorders.
Cell-type specific arousal-dependent modulation of thalamic activity in the lateral geniculate nucleus
Authors: Molnár Benedek , Sere Péter , Bordé Sándor , Koós Krisztián , Horváth Péter , Lőrincz Magor L.
Published: February 2021

State dependent thalamocortical activity is important for sensory coding, oscillations and cognition. The lateral geniculate nucleus (LGN) relays visual information to the cortex, but the state dependent spontaneous and visually evoked activity of LGN neurons in awake behaving animals remains controversial. Using a combination of pupillometry, extracellular and intracellular recordings from identified LGN neurons we show that thalamocortical neurons and interneurons are distinctly correlated to arousal forming two complementary coalitions. Intracellular recordings indicated that the membrane potential of LGN TC neurons was tightly correlated to fluctuations in pupil size. Inactivating the corticothalamic feedback to the LGN suppressed the arousal dependency of LGN neurons. Taken together our results show that LGN neuronal membrane potential and action potential output are dynamically linked to arousal dependent brain states in awake mice and this might have important functional implications.
Fetal gut colonization: meconium does not have a detectable microbiota before birth
Authors: Kennedy Katherine M. , Gerlach Max J. , Adam Thomas , Heimesaat Markus M. , Rossi Laura , Surette Michael G. , Sloboda Deborah M. , Braun Thorsten
Published: February 2021

Microbial colonization of the human intestine impacts host metabolism and immunity, however when colonization occurs is unclear. Although numerous studies have reported bacterial DNA in first-pass meconium samples, these samples are collected hours to days after birth. We investigated whether bacteria could be detected in meconium prior to birth. Fetal meconium (n = 20) was collected by rectal swab during elective breech Cesarean sections without labour prior to antibiotics and compared to technical and procedural controls (n = 5), first-pass meconium (neonatal meconium; n = 14), and infant stool (n = 25). Unlike first-pass meconium, no microbial signal distinct from negative controls was detected in fetal meconium by 16S rRNA gene sequencing. Additionally, positive aerobic (n = 10 of 20) and anaerobic (n = 12 of 20) clinical cultures of fetal meconium (13 of 20 samples positive in at least one culture) were identified as likely skin contaminants, most frequently Staphylococcus epidermidis, and not detected by sequencing in most samples (same genera detected by culture and sequencing in 2 of 13 samples with positive culture). We conclude that fetal gut colonization does not occur before birth, and that microbial profiles of neonatal meconium reflect populations acquired during and after birth.
A glimpse into the diverse cellular immunity against SARS-CoV-2
Authors: Chang Cheng-Wei , Liu Yuchen , Jiao Cheng , Liu Hongwei , Chen Xiaochuan , Chang Lung-Ji
Published: February 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific cellular immune response may prove to be essential for long-term immune protection against the novel coronavirus disease 2019 (COVID-19). To assess COVID-19-specific immunity in the population, we synthesized selected peptide pools of SARS-CoV-2 structural and functional proteins, including Spike (S), Membrane (M), Envelope (E), Nucleocapsid (N) and Protease (P) as target antigens. Survey of the T cell precursur frequencies in healthy individuals specific to these viral antigens demonstrated a diverse cellular immunity, including high, medium, low and no responders. This was further confirmed by in vitro induction of anti-SARS-CoV-2 T cell immune responses using dendritic cell (DC)/T cell coculture, which supported the corresponding T cell precursor frequencies in each of the individuals tested. In general, the combination of all five viral antigen pools induced the strongest cellular immune response, yet individual donors responded differently to different viral antigens. Importantly, in vitro restimulation of the T cells with the DC-peptides induced increased anti-viral immune responses in all individuals even in the no responders, suggesting that repeated antigen stimulation could elicit a broad protection in immune naïve population. Our analysis recapitulates the critical role of cellular immunity in fighting COVID-19 and the importance of analyzing anti-SARS-CoV-2 T cell response in addition to antibody response in the population.

Importance

Facing the rapid evolving SARS-CoV-2 variants in the world, current emphasis on antibody-producing vaccines needs a quick revisit. The virus-specific cellular immunity may prove to be essential for long-term protection against COVID-19. This study designed a series of antigenic peptides encompassing the conserved and/or essential domains of Spike (S), Membrane (M), envelope (E), Nucleocapsid (N) and Protease (P) as targets to assess Covid-19-specific immunity in the population. The results demonstrated a diverse cellular immunity, including high, medium, low and no responders. This was verified by in vitro generation of anti-SARS-CoV-2 T-cells from these subjects. The study suggested that individuals responded differently to the different viral antigens, and importantly, repeated stimulation could produce virus specific T cells in all individuals, including the no responders. This study illustrates the needs for assessing anti-viral cellular immunity in addition to antibody response in the general population.
CK2 phosphorylation of human papillomavirus 16 E2 on serine 23 promotes interaction with TopBP1 and is critical for E2 plasmid retention function
Authors: Prabhakar Apurva T. , James Claire D. , Das Dipon , Otoa Raymonde , Day Matthew , Burgner John , Fontan Christian T. , Wang Xu , Wieland Andreas , Donaldson Mary M. , Bristol Molly L. , Li Renfeng , Oliver Anthony W. , Pearl Laurence H. , Smith Brian O. , Morgan Iain M.
Published: February 2021

During the human papillomavirus 16 (HPV16) life cycle, the E2 protein interacts with host factors to regulate viral transcription, replication and genome segregation/retention. Our understanding of host partner proteins and their roles in E2 functions remains incomplete. Here, we demonstrate that CK2 phosphorylation of E2 on serine 23 promotes interaction with TopBP1in vitroandin vivo, and that E2 is phosphorylated on this residue during the HPV16 life cycle. We investigated the consequences of mutating serine 23 on E2 functions. E2-S23A activates and represses transcription identically to E2-WT (wild-type), and E2-S23A is as efficient as E2-WT in transient replication assays. However, E2-S23A has compromised interaction with mitotic chromatin when compared with E2-WT. In E2-WT cells, both E2 and TopBP1 levels increase during mitosis when compared with vector control cells. In E2-S23A cells, neither E2 nor TopBP1 levels increase during mitosis. We next tested whether this difference in E2-S23A levels during mitosis disrupts E2 plasmid retention function. We developed a novel plasmid retention assay and demonstrate that E2-S23A is deficient in plasmid retention when compared with E2-WT. siRNA targeted knockdown of TopBP1 abrogates E2-WT plasmid retention function. Introduction of the S23A mutation into the HPV16 genome resulted in delayed immortalization of human foreskin keratinocytes (HFK) and higher episomal viral genome copy number in resulting established HFK. Overall, our results demonstrate that CK2 phosphorylation of E2 on serine 23 promotes interaction with TopBP1, which is critical for E2 plasmid retention function and in HPV16 immortalization of keratinocytes.

Importance

Human papillomaviruses are causative agents in around 5% of all cancers, with no specific anti-viral therapeutics available for treating infections or resultant cancers. In this report, we demonstrate that phosphorylation of HPV16 E2 by CK2 promotes formation of a complex formation with the cellular protein TopBP1in vitroandin vivo. This complex results in stabilization of E2 during mitosis and mediates plasmid retention by E2. This function promotes the partitioning of viral genomes into the nuclei of daughter cells following mitosis. We demonstrate that CK2 phosphorylates E2 on serine 23in vivo, and that CK2 inhibitors disrupt the E2-TopBP1 complex. Mutation of E2 serine 23 to alanine disrupts the HPV16 life cycle, demonstrating a critical function for this residue. Together, our results suggest that CK2 inhibitors may disrupt the E2-TopBP1 dependent HPV16 life cycle and potentially kill HPV16 positive cancers, which lays a molecular foundation to develop novel therapeutic approaches for combating HPV16 disease.