Development of a high-throughput colorimetric Zika virus infection assay

Zika virus (ZIKV) is an emerging pathogen that causes congenital infections which may result in birth defects, such as microcephaly. Currently, no approved treatment or vaccination is available. ZIKV can be readily detected in cell culture where virally infected cells are normally stained by specific antibodies. As ZIKV regularly causes a cytopathic effect, we were wondering whether this viral property can be used to quantitatively determine viral infectivity. We here describe the use of an 3-[4,5-dimethyl-2-thiazolyl]-2,5-diphenyl-2H-tetrazolium bromide-(MTT)-based cell viability assay that allows to determine ZIKV-induced cell death. We show that this colorimetric assay quantifies ZIKV infection over a broad range of viral dilutions in both monkey and human cells. It allows to determine inhibitory activities of antivirals that block ZIKV or to define the neutralizing antibody titers of ZIKV antisera. This MTT-based ZIKV detection assay can be evaluated by naked eye or computational tools, has a broad linear range, does not require large equipment or costly reagents, and thus represents a promising alternative to antibody-based assays, in particular in resource-poor settings. We propose to use this simple, fast, and cheap method for quantification of ZIKV neutralizing antibodies and testing of antiviral compounds.Peer reviewe

Semen inhibits Zika virus infection of cells and tissues from the anogenital region

Zika virus (ZIKV) causes severe birth defects and can be transmitted via sexual intercourse. Semen from ZIKV-infected individuals contains high viral loads and may therefore serve as an important vector for virus transmission. Here we analyze the effect of semen on ZIKV infection of cells and tissues derived from the anogenital region. ZIKV replicates in all analyzed cell lines, primary cells, and endometrial or vaginal tissues. However, in the presence of semen, infection by ZIKV and other flaviviruses is potently inhibited. We show that semen prevents ZIKV attachment to target cells, and that an extracellular vesicle preparation from semen is responsible for this anti-ZIKV activity. Our findings suggest that ZIKV transmission is limited by semen. As such, semen appears to serve as a protector against sexual ZIKV transmission, despite the availability of highly susceptible cells in the anogenital tract and high viral loads in this bodily fluid.Peer reviewe

Local conservation scores without a priori assumptions on neutral substitution rates

<p>Abstract</p> <p>Background</p> <p>Comparative genomics aims to detect signals of evolutionary conservation as an indicator of functional constraint. Surprisingly, results of the ENCODE project revealed that about half of the experimentally verified functional elements found in non-coding DNA were classified as unconstrained by computational predictions. Following this observation, it has been hypothesized that this may be partly explained by biased estimates on neutral evolutionary rates used by existing sequence conservation metrics. All methods we are aware of rely on a comparison with the neutral rate and conservation is estimated by measuring the deviation of a particular genomic region from this rate. Consequently, it is a reasonable assumption that inaccurate neutral rate estimates may lead to biased conservation and constraint estimates.</p> <p>Results</p> <p>We propose a conservation signal that is produced by local Maximum Likelihood estimation of evolutionary parameters using an optimized sliding window and present a Kullback-Leibler projection that allows multiple different estimated parameters to be transformed into a conservation measure. This conservation measure does not rely on assumptions about neutral evolutionary substitution rates and little a priori assumptions on the properties of the conserved regions are imposed. We show the accuracy of our approach (KuLCons) on synthetic data and compare it to the scores generated by state-of-the-art methods (phastCons, GERP, SCONE) in an ENCODE region. We find that KuLCons is most often in agreement with the conservation/constraint signatures detected by GERP and SCONE while qualitatively very different patterns from phastCons are observed. Opposed to standard methods KuLCons can be extended to more complex evolutionary models, e.g. taking insertion and deletion events into account and corresponding results show that scores obtained under this model can diverge significantly from scores using the simpler model.</p> <p>Conclusion</p> <p>Our results suggest that discriminating among the different degrees of conservation is possible without making assumptions about neutral rates. We find, however, that it cannot be expected to discover considerably different constraint regions than GERP and SCONE. Consequently, we conclude that the reported discrepancies between experimentally verified functional and computationally identified constraint elements are likely not to be explained by biased neutral rate estimates.</p

Fortune Favours the Bold: An Agent-Based Model Reveals Adaptive Advantages of Overconfidence in War

Overconfidence has long been considered a cause of war. Like other decision-making biases, overconfidence seems detrimental because it increases the frequency and costs of fighting. However, evolutionary biologists have proposed that overconfidence may also confer adaptive advantages: increasing ambition, resolve, persistence, bluffing opponents, and winning net payoffs from risky opportunities despite occasional failures. We report the results of an agent-based model of inter-state conflict, which allows us to evaluate the performance of different strategies in competition with each other. Counter-intuitively, we find that overconfident states predominate in the population at the expense of unbiased or underconfident states. Overconfident states win because: (1) they are more likely to accumulate resources from frequent attempts at conquest; (2) they are more likely to gang up on weak states, forcing victims to split their defences; and (3) when the decision threshold for attacking requires an overwhelming asymmetry of power, unbiased and underconfident states shirk many conflicts they are actually likely to win. These “adaptive advantages” of overconfidence may, via selection effects, learning, or evolved psychology, have spread and become entrenched among modern states, organizations and decision-makers. This would help to explain the frequent association of overconfidence and war, even if it no longer brings benefits today

Resources, Capabilities, and Routines in Public Organizations

States, state agencies, multilateral agencies, and other non-market actors are relatively under-studied in strategic management and organization science. While important contributions to the study of public actors have been made within the agency-theoretic and transaction-cost traditions, there is little research in political economy that builds on resource-based, dynamic capabilities, and behavioral approaches to the firm. Yet public organizations can be characterized as stocks of human and non-human resources, including routines and capabilities; they can possess excess capacity in these resources; and they may grow and diversify in predictable patterns according to behavioral and Penrosean logic. This paper shows how resource-based, dynamic capabilities, and behavioral approaches to understanding public agencies and organizations shed light on their nature and governance

Cortical thickness and resting-state cardiac function across the lifespan: a cross-sectional pooled mega analysis

Understanding the association between autonomic nervous system [ANS] function and brain morphology across the lifespan provides important insights into neurovisceral mechanisms underlying health and disease. Resting state ANS activity, indexed by measures of heart rate [HR] and its variability [HRV] has been associated with brain morphology, particularly cortical thickness [CT]. While findings have been mixed regarding the anatomical distribution and direction of the associations, these inconsistencies may be due to sex and age differences in HR/HRV and CT. Previous studies have been limited by small sample sizes, which impede the assessment of sex differences and aging effects on the association between ANS function and CT. To overcome these limitations, 20 groups worldwide contributed data collected under similar protocols of CT assessment and HR/HRV recording to be pooled in a mega-analysis (N = 1,218 (50.5% female), mean age 36.7 years (range: 12-87)). Findings suggest a decline in HRV as well as CT with increasing age. CT, particularly in the orbitofrontal cortex, explained additional variance in HRV, beyond the effects of aging. This pattern of results may suggest that the decline in HRV with increasing age is related to a decline in orbitofrontal CT. These effects were independent of sex and specific to HRV; with no significant association between CT and HR. Greater CT across the adult lifespan may be vital for the maintenance of healthy cardiac regulation via the ANS – or greater cardiac vagal activity as indirectly reflected in HRV may slow brain atrophy. Findings reveal an important association between cortical thickness and cardiac parasympathetic activity with implications for healthy aging and longevity that should be studied further in longitudinal research

Effectiveness of a specialist palliative home care nurse–patient consultation followed by an interprofessional telephone case conference compared with usual care among patients with non-oncological palliative care needs: protocol for the multicentre KOPAL cluster-randomised controlled trial

Introduction Progressive chronic, non-malignant diseases (CNMD) like congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) and dementia are of growing relevance in primary care. Most of these patients suffer from severe symptoms, reduced quality of life and increased numbers of hospitalisations. Outpatient palliative care can help to reduce hospitalisation rate by up to 50%. Due to the complex medical conditions and prognostic uncertainty of the course of CNMD, early interprofessional care planning among general practitioners who provide general palliative care and specialist palliative home care (SPHC) teams seems mandatory. The KOPAL study (a concept for strenghtening interprofessional collaboration for patients with palliative care needs) will test the effectiveness of a SPHC nurse–patient consultation followed by an interprofessional telephone case conference.Methods and analysis Multicentre two-arm cluster randomised controlled trial KOPAL with usual care as control arm. The study is located in Northern Germany and aims to recruit 616 patients in 56 GP practices (because of pandemic reasons reduced to 191 participants). Randomisation will take place on GP practice level immediately after inclusion (intervention group/control group). Allocation concealment is carried out on confirmation of participation. Patients diagnosed with CHF (New York Heart Association (NYHA) classification 3–4), COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage classification 3–4, group D) or dementia GDS stage 4 or above). Primary outcome is a reduced hospital admission within 48 weeks after baseline, secondary outcomes include symptom burden, quality of life and health costs. The primary analysis will follow the intention-to-treat principle. Intervention will be evaluated after the observation period using qualitative methods.Ethics and dissemination The responsible ethics committees of the cooperating centres approved the study. All steps of data collection, quality assurance and data analysis will continuously be monitored. The concept of KOPAL could serve as a blueprint for other regions and meet the challenges of geographical equity in end-of-life care.Trial registration number DRKS00017795; German Clinical Trials Register

Fusionen und Übernahmen im Licht der Hybris – Überblick über den Forschungsstand

Eine hohe Anzahl von Fusionen und Übernahmen scheitert. Gleichwohl sind Fusionen und Übernahmen an der Tagesordnung. Als eine Erklärung hierfür wird die Hybris-Hypothese diskutiert, d.h. die These, dass sich Entscheidungsträger der aufnehmenden Unternehmen systematisch überschätzen. Um diese These zu testen und um gegebenenfalls Maßnahmen gegen Hybris zu ergreifen, sind verlässliche Indikatoren für Hybris erforderlich. Die Arbeit stellt die in der Literatur entwickelten Indikatoren vor und diskutiert deren Vor- und Nachteile. Although corporate acquisitions are ubiquitous a large number of M&A fails. One explanation for such failure is the hubris hypothesis for corporate takeovers. A decision maker affected with hubris (or overconfidence) will overestimate his abilities in raising potential synergies and is likely to make investment decisions destroying shareholder wealth. The growing literature on CEO hubris proposes various ways to measure hubris. We present these indicators and discuss possible advantages and drawbacks. (71 words) Schlüsselwörter Hybris - Mergers & Acquisitions Keywords Hubris - Mergers & Acquisitions JEL Classification G34 - M1