The breakthrough paradox: How focusing on one form of innovation jeopardizes the advancement of science

Research needs a balance of risk‐taking in “breakthrough projects” and gradual progress. For building a sustainable knowledge base, it is indispensable to provide support for both. Subject Categories: Careers, Economics, Law & Politics, Science Policy & Publishing

Science is about venturing into the unknown to find unexpected insights and establish new knowledge. Increasingly, academic institutions and funding agencies such as the European Research Council (ERC) explicitly encourage and support scientists to foster risky and hopefully ground‐breaking research. Such incentives are important and have been greatly appreciated by the scientific community. However, the success of the ERC has had its downsides, as other actors in the funding ecosystem have adopted the ERC’s focus on “breakthrough science” and respective notions of scientific excellence. We argue that these tendencies are concerning since disruptive breakthrough innovation is not the only form of innovation in research. While continuous, gradual innovation is often taken for granted, it could become endangered in a research and funding ecosystem that places ever higher value on breakthrough science. This is problematic since, paradoxically, breakthrough potential in science builds on gradual innovation. If the value of gradual innovation is not better recognized, the potential for breakthrough innovation may well be stifled.

While continuous, gradual innovation is often taken for granted, it could become endangered in a research and funding ecosystem that places ever higher value on breakthrough science.

Concerns that the hypercompetitive dynamics of the current scientific system may impede rather than spur innovative research have been voiced for many years (Alberts et al, 2014). As performance indicators continue to play a central role for promotions and grants, researchers are under pressure to publish extensively, quickly, and preferably in high‐ranking journals (Burrows, 2012). These dynamics increase the risk of mental health issues among scientists (Jaremka et al, 2020), dis‐incentivise relevant and important work (Benedictus et al, 2016), decrease the quality of scientific papers (Sarewitz, 2016) and induce conservative and short‐term thinking rather than risk‐taking and original thinking required for scientific innovation (Alberts et al, 2014; Fochler et al, 2016). Against this background, strong incentives for fostering innovative and daring research are indispensable.     

Short-term effects of wake- and bright light therapy on sleep in depressed youth

Chronotherapeutics are well established for the treatment of depression and associated sleeping problems in adults. However, effects are still understudied in adolescents. Two pilot studies highlighted the crucial role of sleep when it comes to the treatment of depression, by means of chronotherapeutics, in adolescents. The aim of the present study was to investigate the role of adjunctive wake therapy (WT) in addition to bright light therapy (BLT) with respect to sleep behaviors. In the present study, 62 depressed inpatients (aged 13–18 years; diagnosed with Beck Depression Inventory Revision) were randomly assigned to two groups: BLT only (BLT-group) and a combination of BLT and WT (COMB-group). After one night of WT adolescents in the COMB-group revealed longer sleep durations, time in bed, advanced sleep onset, less wakes during night and an improved sleep efficiency. However, one night of WT plus BLT had no additional effect on sleep parameters compared with BLT-group in the long run. Therefore, future studies should assess whether more nights of WT might lead to more sustainable effects.     

Immune suppression in the tumor microenvironment: a role for dendritic cell-mediated tolerization of T cells

Immune suppression remains a consistent obstacle to successful anti-tumor immune responses. As tumors develop, they create a microenvironment that not only supports tumor growth and metastasis but also reduces potential adaptive immunity to tumor antigens. Among the many components of this tumor microenvironment is a population of dendritic cells which exert profound immune suppressive effects on T cells. In this review, we discuss our recent findings related to these tumor-associated dendritic cells and how targeting them may serve to generate more durable anti-tumor immune responses.     

HLA-DR alpha 2 mediates negative signalling via binding to Tirc7 leading to anti-inflammatory and apoptotic effects in lymphocytes in vitro and in vivo

Classically, HLA-DR expressed on antigen presenting cells (APC) initiates lymphocyte activation via presentation of peptides to TCR bearing CD4+ T-Cells. Here we demonstrate that HLA-DR alpha 2 domain (sHLA-DRalpha2) also induces negative signals by engaging TIRC7 on lymphocytes. This interaction inhibits proliferation and induces apoptosis in CD4+ and CD8+ T-cells via activation of the intrinsic pathway. Proliferation inhibition is associated with SHP-1 recruitment by TIRC7, decreased phosphorylation of STAT4, TCR-zeta chain & ZAP70, and inhibition of IFN-gamma and FasL expression. HLA-DRalpha2 and TIRC7 co-localize at the APC-T cell interaction site. Triggering HLA-DR - TIRC7 pathway demonstrates that sHLA-DRalpha2 treatment inhibits proinflammatory-inflammatory cytokine expression in APC & T cells after lipopolysaccaride (LPS) stimulation in vitro and induces apoptosis in vivo. These results suggest a novel antiproliferative role for HLA-DR mediated via TIRC7, revise the notion of an exclusive stimulatory interaction of HLA-DR with CD4+ T cells and highlights a novel physiologically relevant regulatory pathway.     

Organismal differences in post-translational modifications in histones H3 and H4

Post-translational modifications (PTMs) of histones play an important role in many cellular processes, notably gene regulation. Using a combination of mass spectrometric and immunobiochemical approaches, we show that the PTM profile of histone H3 differs significantly among the various model organisms examined. Unicellular eukaryotes, such as Saccharomyces cerevisiae (yeast) and Tetrahymena thermophila (Tet), for example, contain more activation than silencing marks as compared with mammalian cells (mouse and human), which are generally enriched in PTMs more often associated with gene silencing. Close examination reveals that many of the better-known modified lysines (Lys) can be either methylated or acetylated and that the overall modification patterns become more complex from unicellular eukaryotes to mammals. Additionally, novel species-specific H3 PTMs from wild-type asynchronously grown cells are also detected by mass spectrometry. Our results suggest that some PTMs are more conserved than previously thought, including H3K9me1 and H4K20me2 in yeast and H3K27me1, -me2, and -me3 in Tet. On histone H4, methylation at Lys-20 showed a similar pattern as H3 methylation at Lys-9, with mammals containing more methylation than the unicellular organisms. Additionally, modification profiles of H4 acetylation were very similar among the organisms examined.     

A Pilot Randomized Controlled Trial of a Clinic and Home‐Based Behavioral Intervention to Decrease Obesity in Preschoolers

We evaluated the efficacy of a 6‐month clinic and home‐based behavioral intervention (Learning about Activity and Understanding Nutrition for Child Health; LAUNCH) to reduce obesity in preschool children ≥95th BMI percentile compared to enhanced standard of care (Pediatrician Counseling; PC). LAUNCH was a family‐based behavioral intervention that taught parents to use child behavior management strategies to increase healthy eating and activity for their children and themselves. PC presented the same diet and activity recommendations, but was delivered in a one‐time PC session. Eighteen children aged 2–5 years (mean 4.71 ± 1.01) with an average BMI percentile of 98 (±1.60) and an overweight parent were randomized to LAUNCH or PC. Assessments were conducted at baseline, 6 months (end of LAUNCH treatment) and 12 months (6 months following LAUNCH treatment). LAUNCH showed a significantly greater decrease on the primary outcomes of child at month 6 (post‐treatment) BMI z (?0.59 ± 0.17), BMI percentile (?2.4 ± 1.0), and weight gain (?2.7 kg ± 1.2) than PC and this difference was maintained at follow‐up (month 12). LAUNCH parents also had a significantly greater weight loss (?5.5 kg ± 0.9) at month 6 and 12 (?8.0 kg ± 3.5) than PC parents. Based on the data from this small sample, an intensive intervention that includes child behavior management strategies to improve healthy eating and activity appears more promising in reducing preschool obesity than a low intensity intervention that is typical of treatment that could be delivered in primary care.     

Testing Initiatives Increase Rates of HIV Diagnosis in Primary Care and Community Settings: An Observational Single-Centre Cohort Study

Objectives

The primary objective was to examine trends in new HIV diagnoses in a UK area of high HIV prevalence between 2000 and 2012 with respect to site of diagnosis and stage of HIV infection.

Design

Single-centre observational cohort study.

Setting

An outpatient HIV department in a secondary care UK hospital.

Participants

1359 HIV-infected adults.

Main Outcome Measures

Demographic information (age, gender, ethnicity, and sexual orientation), site of initial HIV diagnosis (Routine settings such as HIV/GUM clinics versus Non-Routine settings such as primary care and community venues), stage of HIV infection, CD4 count and seroconversion symptoms were collated for each participant.

Results

There was a significant increase in the proportion of new HIV diagnoses made in Non-Routine settings (from 27.0% in 2000 to 58.8% in 2012; p<0.001). Overall there was a decrease in the rate of late diagnosis from 50.7% to 32.9% (p=0.001). Diagnosis of recent infection increased from 23.0% to 47.1% (p=0.001). Of those with recent infection, significantly more patients were likely to report symptoms consistent with a seroconversion illness over the 13 years (17.6% to 65.0%; p<0.001).

Conclusions

This is the first study, we believe, to demonstrate significant improvements in HIV diagnosis and a shift in diagnosis of HIV from HIV/GUM settings to primary practice and community settings due to multiple initiatives.     

Phylogeny of haplo–diploid,fungus‐growing ambrosia beetles (Curculionidae: Scolytinae: Xyleborini) inferred from molecular and morphological data

Cognato, A. I., Hulcr, J., Dole, S. A. & Jordal, B. H. (2010). Phylogeny of haplo‐diploid, fungus‐growing ambrosia beetles (Curculionidae: Scolytinae: Xyleborini) inferred from molecular and morphological data. —Zoologica Scripta, 40, 174–186. The ambrosia beetle tribe Xyleborini currently contains 30 genera and approximately 1200 species which are distributed throughout worldwide forests with most diversity located in the tropics. They also represent the most invasive scolytines in North America. Despite economic concerns and biological curiosity with this group, a comprehensive understanding of generic boundaries and the evolutionary relationship among species is lacking. In this study, we include 155 xyleborine species representing 23 genera in parsimony and Bayesian analyses using 3925 nucleotides from mitochondrial (COI) and nuclear genomes (28S, ArgK, CAD, EF‐1α) and 39 morphological characters. The phylogenies resulting from the parsimony analyses, which treated gap positions either as missing or fifth character states, and the Bayesian analysis were generally similar. Clades with high support or posterior probabilities were found in all trees, while those with low support were not recovered by all analyses. Fourteen of the 23 genera were monophyletic although not all relationships among the genera were resolved. We show monophyly of several species groups associated with particular morphological and biological characters and suggest recognition of these groups as genera. Most interesting was the monophyly of South and Central American species representing several genera. This finding suggests recent and fast radiation of xyleborines in the New World accompanied by morphological and biological diversification.     

Rudimentary pedal grasping in mice and implications for terminal branch arboreal quadrupedalism

We use an outbred laboratory mouse strain (ICR/CD‐1, Charles River Laboratories, Inc.) to model a type of preprimate locomotion associated with rudimentary pedal grasping. Ten male mice were assigned to either control or climbing groups (n = 5 per group). Climbing mice lived within a specialized terrarium that included ～7.5 m of thin branches (5 and 10 cm long) with a thickness of 3.3mm, arranged in a reticulated canopy. Food, water, and a nest site were placed among the branches. To discourage mice from palmigrade or digitigrade locomotion, the floor of the terrarium was flooded with a few centimeters of water. Climbing mice were placed in this setting upon weaning and reared for 3 months until they were mature in size. Litter, and age‐matched controls were also maintained for comparison with climbers. Climbing mice quickly acclimated to the requirements of the fine‐branch model using the foot and tail for grasping and balance. At maturity, climbing and control mice exhibited minor, but significant, morphological plasticity. For climbers, this includes a greater angle of the femoral neck, larger patellar groove index, relatively shorter talar neck length, and more circular talar head aspect ratio (P < 0.10). Climbers also exhibit increased curvature of the distal third metacarpal, decreased talar head angle, and relatively longer caudal vertebrae transverse processes (P < 0.05). These results in a small‐bodied eutherian mammal suggest that facultative hallucial opposability and coordinated tail use enable a kind of grasping active arboreal quadrupedality relevant to the latest stages of pre‐euarchontan evolution. In light of these data, we hypothesize that a unique advantage of mouse‐sized mammals is that they exhibit a highly flexible body plan allowing them to engage in a diverse array of anatomical positions without requiring specific limb morphologies. J. Morphol.,2011. © 2010 Wiley‐Liss, Inc.     

The eyes of Macrosoma sp. (Lepidoptera: Hedyloidea): a nocturnal butterfly with superposition optics

The visual system of nocturnal Hedyloidea butterflies was investigated for the first time, using light and electron microscopy. This study was undertaken to determine whether hedylids possess the classic superposition eye design characteristic of most moths, or apposition eyes of true butterflies (Papilionoidea), and, to gain insights into the sensory ecology of the Hedyloidea. We show that Macrosoma heliconiaria possesses a superposition-type visual mechanism, characterized by long cylindrical crystalline cones, a lack of corneal processes, 8 constricted retinular sense cells, rhabdoms separated from the crystalline cones forming a translucent 'clear zone', and tight networks of trachea that form a tapetum proximal to the retina and which also surround the rhabdoms to form a tracheal sheath. Dark-adapted individuals of M. heliconiaria, M. conifera, and M. rubidinarea exhibited distal retinular pigment migration, forming an eye glow. Correspondingly, light-exposure induced pigment to migrate proximally, causing the eye glow to be replaced by a dark pseudopupil. Other characteristics of the visual system, including relative eye size, facet size, and external morphology of the optic lobes, are mostly 'moth like' and correlate with an active, nocturnal lifestyle. The results are discussed in relation to the evolution of lepidopteran eyes, and the sensory ecology of this poorly understood butterfly superfamily.