bluuebunny/crossref_metadata_2025 huggingface dataset:
Bayesian jackknife empirical likelihood
Authors: Cheng Y , Zhao Y
Published: June 2019

Empirical likelihood is a very powerful nonparametric tool that does not require any distributional assumptions. Lazar (2003) showed that in Bayesian inference, if one replaces the usual likelihood with the empirical likelihood, then posterior inference is still valid when the functional of interest is a smooth function of the posterior mean. However, it is not clear whether similar conclusions can be obtained for parameters defined in terms of $U$-statistics. We propose the so-called Bayesian jackknife empirical likelihood, which replaces the likelihood component with the jackknife empirical likelihood. We show, both theoretically and empirically, the validity of the proposed method as a general tool for Bayesian inference. Empirical analysis shows that the small-sample performance of the proposed method is better than its frequentist counterpart. Analysis of a case-control study for pancreatic cancer is used to illustrate the new approach.
Average Weighted Accuracy: Pragmatic Analysis for a Rapid Diagnostics in Categorizing Acute Lung Infections (RADICAL) Study
Authors: Liu Ying , Tsalik Ephraim L , Jiang Yunyun , Ko Emily R , Woods Christopher W , Henao Ricardo , Evans Scott R
Published: June 2019

Patient management relies on diagnostic information to identify appropriate treatment. Standard evaluations of diagnostic tests consist of estimating sensitivity, specificity, positive/negative predictive values, likelihood ratios, and accuracy. Although useful, these metrics do not convey the tests’ clinical value, which is critical to informing decision-making. Full appreciation of the clinical impact of a diagnostic test requires analyses that integrate sensitivity and specificity, account for the disease prevalence within the population of test application, and account for the relative importance of specificity vs sensitivity by considering the clinical implications of false-positive and false-negative results. We developed average weighted accuracy (AWA), representing a pragmatic metric of diagnostic yield or global utility of a diagnostic test. AWA can be used to compare test alternatives, even across different studies. We apply the AWA methodology to evaluate a new diagnostic test developed in the Rapid Diagnostics in Categorizing Acute Lung Infections (RADICAL) study.
The forms, functions, and varieties of weak(ened) judicial review
Authors: Dixon Rosalind
Published: June 2019

The concept of “weak” judicial review is now a core concept in comparative constitutional analysis. Yet the relative weakness of judicial review will depend on a variety of factors, including the availability of formal mechanisms for legislative override or limiting courts’ jurisdiction, the difficulty of constitutional amendment, the scope of judicial review both in first- and second-look cases, and the actual practice of legislators and judges in a jurisdiction. The strength of judicial review is therefore not a true binary but rather a concept that spans multiple dimensions and a question of degree rather than kind. The desirability of weak as opposed to strong or even super-strong forms of review will likewise depend on a range of factors, which can and do vary across time and different contexts. This article thus aims to unpack the concept of weak-form review with a view to sharpening our understanding of both its internal complexity and relationship to questions of broader political context.
Dual-Cursor: Improving User Performance and Perceived Usability for Cursor-Based Text Entry on TV Using Remote Control
Authors: Luo Shijian , Hu Yi
Published: June 2019

Entering text with a general five-key TV remote is a laborious task. A strategy for entering text with two interconnected cursors is proposed, whereby a secondary cursor is employed to maneuver the main cursor through fast-tracks. The main cursor is maneuvered in a 2D full-size onscreen keyboard space, whereas the sub-cursor moves among all predictive candidates in a 1D subspace. Each cursor is operated by a specific interaction method, and the movement of either must be mapped from one to the other. Compared to single-cursor methods, the combination of the main cursor and the sub-cursor operations usually results in fewer manual loadings, even when the target character is out of the prediction list range. A computer simulation based on a corpus of 57 258 multimedia titles (in Chinese) demonstrated that the keystrokes per character, powered by a dual-cursor technique, could be predicted to be reduced by 38.6–69.9% with very few predictive candidates for various keyboard layouts (compared with those of conventional non-predictive method). The keyboard layout and the number of candidates were further investigated by means of a usability test. The results revealed that with only 10 min of practice, novice users could achieve a mean text entry speed of 33.3, 29.5 and 22.8 characters per minute for QWERTY, alphabetic square, and alphabetic two-row layouts, respectively, which is 31.6%, 14.3% and 67.6% faster than the corresponding conventional input method, and is 12.7%, 6.9% and 25.0% faster than the current version of popup dialog method. The dual-cursor can significantly improve perceived usability and offers the potential to be applied to numerous other cursor-based text entry contexts.

RESEARCH HIGHLIGHTS

A new interaction strategy for TV input with two interconnected cursors. This strategy employs long-pressing for jumping around predicted candidates and short-pressing for navigating through keyboard keys. The number of keystrokes could be predicted to be reduced by 38.6–69.9% when compared with that of the conventional non-predictive input method for various keyboard layouts. Few predicted candidates were required to achieve a substantial decrement of keystrokes. The user experiment showed that novice users’ TV input speed could be substantially increased with dual-cursor.
Clinical impact of rapid susceptibility testing on MHR-SIR directly from blood cultures
Authors: Pilmis Benoît , Thy Michael , Diep Julien , Krob Sophie , Périllaud Claire , Couzigou Carine , Vidal Barbara , Mizrahi Assaf , Lourtet-Hascoët Julie , Le Monnier Alban , Nguyen Van Jean-Claude
Published: June 2019

Background

In a previous study, we demonstrated that rapid antibiotic susceptibility tests (ASTs) can be performed directly on blood culture samples tested on Mueller–Hinton Rapid agar (MHR-SIR) with a time delay of 6–8 h.

Objectives

Using this rapid disc diffusion method, we analysed the clinical impact associated with rapid reporting of results in our hospital setting.

Methods

All patients with bloodstream infections (BSIs) related to Enterobacteriaceae or Staphylococcus aureus were prospectively included in the study. The rapid ASTs were performed by incubation of positive blood cultures on MHR-SIR for 6–8 h by direct inoculation according to BSAC recommendations.

Results

One hundred and sixty-seven patients with BSIs were included as MHR-guided adaptation therapy cases. Eighty percent had Enterobacteriaceae-related BSIs, of which 12 (9%) were ESBL producers and 20% were S. aureus-related BSIs. A urinary or intra-abdominal infection was observed in 44.3% and 19.8%, respectively, of Enterobacteriaceae-related infections. The most frequent sources of infections for S. aureus BSIs were cutaneous and endovascular, in 43% and 23% of cases, respectively. Forty-four percent of the patients benefited from therapeutic modification according to the results of the MHR-SIR AST. Thus, empirical antibiotic therapy was modified by using antibiotic therapy that had too wide a spectrum or was unsuitable in 26% and 18% of cases, respectively. Compared with the 24 h required for the reference method, the median length of time to provision of susceptibility test results by MHR-SIR was 7 h.

Conclusions

This study showed a significant time saving (17 h) on the appropriateness of antibiotic prescription and demonstrated a significant impact regarding the choice and reduction of the spectrum of antibiotic therapy.
Outcomes after Surgery for Early Stage Breast Cancer in Women Staged With Preoperative Breast Magnetic Resonance Imaging According to Breast Tissue Density
Authors: Faermann Renata , Weidenfeld Jonathan , Chepelev Leonid , Kendal Wayne , Verma Raman , Scott-Moncrieff Andrew , Peddle Susan , Doherty Geoff , Lau Jackie , Ramsay Tim , Arnaout Angel , Lamb Leslie , Watters James M , Seely Jean M
Published: June 2019

Purpose

To determine surgical outcomes and breast cancer disease-free survival outcomes of women with early stage breast cancer with and without use of preoperative breast MRI according to breast tissue density.

Methods

Women with early stage breast cancer diagnosed from 2004 to 2009 were classified into 2 groups: 1) those with dense and heterogeneously dense breasts (DB); 2) those with nondense breasts (NDB) (scattered fibroglandular and fatty replaced tissue). The 2 groups were reviewed to determine who underwent preoperative MRI. Breast tissue density was determined with mammography according to ACR BI-RADS. Patients were compared according to tumor size, grade, stage, and treatment. Survival analysis was performed using Kaplan-Meier estimates.

Results

In total, 261 patients with mean follow-up of 85 months (25–133) were included: 156 DB and 105 NDB. Disease-free survival outcomes were better in the DB group in patients with MRI than in those without MRI: patients with MRI had significantly fewer local recurrences (P < 0.016) and metachronous contralateral breast cancers (P < 0.001), but this was not the case in the NDB group. Mastectomies were higher in the DB group with preoperative MRI than in those without MRI (P < 0.01), as it was in the NDB group (P > 0.05).

Conclusions

Preoperative breast MRI was associated with reduced local recurrence and metachronous contralateral cancers in the DB group, but not in the NDB group; however, the DB patients with MRI had higher mastectomy rates.
Screening Guidelines and Supplemental Screening Tools: Assessment of the Adequacy of Patient–Provider Discussions
Authors: Aminololama-Shakeri Shadi , Soo Mary Scott , Grimm Lars J , Destounis Stamatia
Published: June 2019

Purpose

To assess breast imaging radiologists’ perceptions of the adequacy of provider–patient discussions regarding the benefits and risks of screening mammography and supplemental screening in women with elevated risk and dense breasts.

Methods

A 36-item questionnaire developed by the Society of Breast Imaging Patient Care and Delivery Task Force was distributed electronically to Society of Breast Imaging members to evaluate patient communication, education, and screening practices. Data from the 11 items specifically pertaining to screening practices were analyzed.

Results

The response rate was 14% (275/1992). Seventy-four percent of survey respondents perceived provider–patient discussions regarding mammography screening guidelines as inadequate, and they agreed that provider–patient discussions regarding screening guidelines (82%) and supplemental screening for increased breast density (74%) should be standardized. Only 38% indicated that mammography screening guidelines are officially endorsed by their institution. Similarly, 37% reported that recommendations were up to the primary provider. Although most respondents include information about breast density in lay letters (73%) and radiology reports (89%), many feel that further patient education regarding breast density, supplemental screening, risk assessment, and screening guidelines should be performed by radiologists, and they are willing to provide additional patient education in these areas in practice.

Conclusions

Survey respondents perceived current provider–patient discussions about the risks and benefits of breast cancer mammography screening and supplemental screening as inadequate and felt that standards should be developed. Respondents reported a willingness to take on patient education as part of their daily practice. These findings could inform future initiatives for radiologists to contribute to enhancing provider–patient education.
Exile at Home: Jewish Amateur Photography under National Socialism, 1933–1939
Authors: Ashkenazi Ofer
Published: June 2019

Between 1933 and 1939, Ludwig Simon and his family avidly photographed their daily life. At first glance, their photo albums contain undistinguishable documentation of conventional family routines, including leisure activities at home, encounters with relatives, and vacations away from the city. Yet a closer look shows that many of the photographs in this collection can be read as contemplative responses to the intensifying exclusion of Jews in the Third Reich. The article focuses on photographs that were (repeatedly) taken in two major locations: on the Alps, during vacations, and by the family home in Bingen am Rhein, which Ludwig left when he moved to Berlin in the 1920s. I argue that these photographs manifest an enduring endeavour to reflect critically on the tensions between Jewish belonging and estrangement in the new Germany. Constantly engaged in a dialogue with the (private and public) visual memory of the time—from restaging photographs of previous years to appropriating the visual iconography of German nationalism—the Simon family photographers recurrently negotiated the perspective of the outcasts at home. In analysing these strategies of photography, and of the arrangement of individual photographs within the collection, this article reads them within the paradigm of exile photography. As the Simon family collection demonstrates, the extension of this paradigm to cases of ‘exile-at-home’ enriches our understanding of the German-Jewish experience under National Socialist rule.
A new line on the wide binary test of gravity
Authors: Banik Indranil
Published: June 2019

The relative velocity distribution of wide binary (WB) stars is sensitive to the law of gravity at the low accelerations typical of galactic outskirts. I consider the feasibility of this wide binary test using the ‘line velocity’ method. This involves considering only the velocity components along the direction within the sky plane orthogonal to the systemic proper motion of each WB. I apply this technique to the WB sample of Hernandez et al., carefully accounting for large-angle effects at one order beyond leading. Based on Monte Carlo trials, the uncertainty in the one-dimensional velocity dispersion is ≈100 m s−1 when using sky-projected relative velocities. Using line velocities reduces this to ≈30 m s−1 because these are much less affected by distance uncertainties. My analysis does not support the Hernandez et al. claim of a clear departure from Newtonian dynamics beyond a radius of ≈10 kAU, partly because I use 2σ outlier rejection to clean their sample first. None the less, the uncertainties are small enough that existing WB data are nearly sufficient to distinguish Newtonian dynamics from Modified Newtonian Dynamics. I estimate that ≈1000 WB systems will be required for this purpose if using only line velocities. In addition to a larger sample, it will also be important to control for systematics like undetected companions and moving groups. This could be done statistically. The contamination can be minimized by considering a narrow theoretically motivated range of parameters and focusing on how different theories predict different proportions of WBs in this region.
On the flux of high-energy cosmogenic neutrinos and the influence of the extragalactic magnetic field
Authors: Wittkowski David , Kampert Karl-Heinz
Published: June 2019

Cosmogenic neutrinos originate from interactions of cosmic rays propagating through the universe with cosmic background photons. Since both high-energy cosmic rays and cosmic background photons exist, the existence of high-energy cosmogenic neutrinos is certain. However, their flux has not been measured so far. Therefore, we calculated the flux of high-energy cosmogenic neutrinos arriving at the Earth on the basis of elaborate 4D simulations that take into account three spatial degrees of freedom and the cosmological time-evolution of the universe. Our predictions for this neutrino flux are consistent with the recent upper limits obtained from large-scale cosmic-ray experiments. We also show that the extragalactic magnetic field has a strong influence on the neutrino flux. The results of this work are important for the design of future neutrino observatories, since they allow to assess the detector volume and observation time that are necessary to detect high-energy cosmogenic neutrinos in the near future. An observation of such neutrinos would push multimessenger astronomy to hitherto unachieved energy scales.
Molossops temminckii (Chiroptera: Molossidae)
Authors: Gamboa Alurralde Santiago , Díaz M Mónica
Published: June 2019

The dwarf dog-faced bat, Molossops temminckii (Burmeister, 1854), is a small molossid bat that occurs from Colombia, Venezuela, and Guyana, southwestward through Ecuador, Peru, Bolivia, Paraguay, Brazil, Uruguay, and Argentina. It is one of two species in the genus Molossops and usually roosts in man-made structures, rock crevices, and hollow trees. The species is insectivorous, inhabits a variety of habitats, and is typically found in low altitude zones. Diagnostic characters include triangular ears separated by a wide space, one lower incisor in each ramus, and a last upper molar with three clearly marked commissures. Molossops temminckii is listed as “Least Concern” by the International Union for Conservation of Nature and Natural Resources.
Extreme divergence between one-to-one orthologs: the structure of N15 Cro bound to operator DNA and its relationship to the λ Cro complex
Authors: Hall Branwen M , Roberts Sue A , Cordes Matthew H J
Published: June 2019

The gene cro promotes lytic growth of phages through binding of Cro protein dimers to regulatory DNA sites. Most Cro proteins are one-to-one orthologs, yet their sequence, structure and binding site sequences are quite divergent across lambdoid phages. We report the cocrystal structure of bacteriophage N15 Cro with a symmetric consensus site. We contrast this complex with an orthologous structure from phage λ, which has a dissimilar binding site sequence and a Cro protein that is highly divergent in sequence, dimerization interface and protein fold. The N15 Cro complex has less DNA bending and smaller DNA-induced changes in protein structure. N15 Cro makes fewer direct contacts and hydrogen bonds to bases, relying mostly on water-mediated and Van der Waals contacts to recognize the sequence. The recognition helices of N15 Cro and λ Cro make mostly nonhomologous and nonanalogous contacts. Interface alignment scores show that half-site binding geometries of N15 Cro and λ Cro are less similar to each other than to distantly related CI repressors. Despite this divergence, the Cro family shows several code-like protein–DNA sequence covariations. In some cases, orthologous genes can achieve a similar biological function using very different specific molecular interactions.
Retrosigmoid Transtentorial Resection of a Petroclival Meningioma: 2-Dimensional Operative Video
Authors: Eser Ocak Pinar , Yilmazlar Selcuk
Published: June 2019

In this video, we aimed to demonstrate retrosigmoid-transtentorial resection of a 4.5 × 4 × 4.5 cm3 left-sided petroclival meningioma compressing the brainstem in a 62-yr-old male who presented with decreased hearing on the left and imbalance.

 The patient was placed in park-bench position and a left-sided suboccipital craniotomy was performed. The mass was severely compressing the brainstem as well as the cranial nerves V, VI, VII, and VIII while IV was encased by the tumor. The circumferential dissection of the tumor was facilitated while the surgical corridor and exposure were enlarged by incising the tentorium. Uneventfully, the meningioma was resected in piecemeal fashion as it was not coming out easily with the ultrasonic aspirator. All relevant cranial nerves and adjacent vascular structures were protected. Early postoperative CT scan demonstrated changes due to the surgery and resolution of the compression on the brainstem. The patient made excellent recovery and he was discharged home on postoperative day 4 safely.

 Petroclival meningiomas are one of the most challenging tumors for neurosurgeons due to their close proximity to the vascular structures, cranial nerves as well as the brainstem. The retrosigmoid approach provides a direct route during microsurgical resection of these tumors. By incising the tentorium, the corridor can be widened while addressing the supratentorial portion of the tumor with relative ease.
A possible solution to the Hubble constant discrepancy: Cosmology where the local volume expansion is driven by the domain average density
Authors: Kasai Masumi , Futamase Toshifumi
Published: June 2019

The Hubble constant problem is the discrepancy between different measurements of the Hubble constant on different scales. We show that this problem can be resolved within the general relativistic framework of the perturbation theory in the inhomogeneous universe, with the help of a spatial averaging procedure over a finite local domain in the $t={\rm{const.}}$ hypersurface. The idea presented in this paper is unique in the sense that it has all of the following properties. a) It is based on the general relativistic perturbation theory, with ordinary dust matter only. No strange matter nor energy components are required. b) The employment of the spatially invariant averaging procedure on the finite domain is essential. c) The key is the first-order effect of the inhomogeneities in the linear perturbation theory. No nonlinear effects are required.
Recognizing and Effectively Managing Hypermobility-Related Conditions
Authors: Russek Leslie N , Stott Patricia , Simmonds Jane
Published: June 2019

Hypermobility spectrum disorder (HSD) and hypermobile Ehlers-Danlos syndrome (hEDS) can cause widespread or chronic pain, fatigue, and proprioceptive and coordination deficits resulting in functional restrictions. These conditions are common and often unrecognized, and patients are likely to present in physical therapy for musculoskeletal injuries, pain, or coordination deficits. Although physical therapy is considered central to managing these conditions, many patients report pain and iatrogenic injuries due to inappropriate interventions. The diagnostic classification for these conditions was revised in 2017 to supersede previous diagnostic categories of Joint Hypermobility Syndrome and Ehlers-Danlos Syndrome—hypermobility type/type III. It is now known that these conditions affect multiple body systems and not just joints and that patients require a holistic approach. This Perspective article will describe the 2017 diagnostic classification system, clinical presentation, examination, evaluation, and management of patients with HSD/hEDS. Both adult and pediatric cases are presented to illustrate the patient management concepts discussed. This knowledge can lead to more effective management of this patient population.
The Central Role of Protein Kinase C Epsilon in Cyanide Cardiotoxicity and Its Treatment
Authors: Cheung Joseph Y , Merali Salim , Wang JuFang , Zhang Xue-Qian , Song Jianliang , Merali Carmen , Tomar Dhanendra , You Hanning , Judenherc-Haouzi Annick , Haouzi Philippe
Published: June 2019

In adult mouse myocytes, brief exposure to sodium cyanide (CN) in the presence of glucose does not decrease ATP levels, yet produces profound reduction in contractility, intracellular Ca2+ concentration ([Ca2+]i) transient and L-type Ca2+ current (ICa) amplitudes. We analyzed proteomes from myocytes exposed to CN, focusing on ionic currents associated with excitation-contraction coupling. CN induced phosphorylation of α1c subunit of L-type Ca2+ channel and α2 subunit of Na+-K+-ATPase. Methylene blue (MB), a CN antidote that we previously reported to ameliorate CN-induced reduction in contraction, [Ca2+]i transient and ICa amplitudes, was able to reverse this phosphorylation. CN decreased Na+-K+-ATPase current contributed by α2 but not α1 subunit, an effect that was also counteracted by MB. Peptide consensus sequences suggested CN-induced phosphorylation was mediated by protein kinase C epsilon (PKCε). Indeed, CN stimulated PKC kinase activity and induced PKCε membrane translocation, effects that were prevented by MB. Pretreatment with myristoylated PKCε translocation activator or inhibitor peptides mimicked and inhibited the effects of CN on ICa and myocyte contraction, respectively. We conclude that CN activates PKCε, which phosphorylates L-type Ca2+ channel and Na+-K+-ATPase, resulting in depressed cardiac contractility. We hypothesize that this inhibition of ion fluxes represents a novel mechanism by which the cardiomyocyte reduces its ATP demand (decreased ion fluxes and contractility), diminishes ATP turnover and preserves cell viability. However, this cellular protective effect translates into life-threatening cardiogenic shock in vivo, thereby creating a profound disconnect between survival mechanisms at the cardiomyocyte level from those at the level of the whole organism.
Aggressive interactions affect foraging and use of space in a drift foraging salmonid, Salvelinus malma (Salmoniformes: Salmonidae)
Authors: Cullen Jeffrey L , Grossman Gary D
Published: June 2019

Although intraspecific interactions likely affect habitat choice and foraging behaviour in animals, our knowledge regarding how these factors interact is frequently limited to either lab or field studies, but not both. We observed pairs of dominant and subordinate drift-foraging Dolly Varden char (Salvelinus malma) in an Alaskan stream, and quantified intraspecific interactions and foraging behaviour. Dominant individuals had higher foraging rates, occupied slower holding velocities and were displaced shorter distances during bouts compared to subordinate individuals. Individuals initiated bouts more frequently from the downstream position, than from lateral or upstream positions. Dominant individuals were more likely to occupy the upstream position after a bout than subordinates, which ensures that dominants have the first opportunity to capture drifting prey.
Taxonomic and phylogenetic review of Necrosuchus ionensis (Alligatoroidea: Caimaninae) and the early evolution and radiation of caimanines
Authors: Cidade Giovanne M , Fortier Daniel , Hsiou Annie S
Published: June 2019

Alligatoroidea is the most species-rich crocodylomorph clade of the Cenozoic of South America, with nearly all species belonging to the Caimaninae clade. However, the earliest records of Caimaninae in South America, which are from the Palaeocene, are based mostly on incomplete specimens, which increases the importance of detailed taxonomic and phylogenetic studies on these taxa. This paper offers a taxonomic and phylogenetic review of Necrosuchus ionensis, a caimanine species from the Salamanca Formation of the Palaeocene of Argentina. Necrosuchus ionensis is considered a valid species, albeit with a different diagnosis from that proposed by previous authors. The phylogenetic analysis shows, for the first time, that N. ionensis belongs to the derived Caimaninae clade Jacarea. However, a better understanding of the Jacarea clade is needed, and alternative placements for N. ionensis might be considered. Nevertheless, the placement of N. ionensis as a derived caimanine raises interesting perspectives on the early evolution and radiation of caimanines, which are thoroughly discussed in this paper together with other results obtained in this study, such as the recovery of the North American caimanines Bottosaurus and Tsoabichi as a clade.
CRISPR/CAS9 mutagenesis of a single
r-opsin
gene blocks phototaxis in a marine larva
Authors: Neal S. , de Jong D. M. , Seaver E. C.
Published: June 2019

Many marine animals depend upon a larval phase of their life cycle to locate suitable habitat, and larvae use light detection to influence swimming behaviour and dispersal. Light detection is mediated by the
opsin
genes, which encode light-sensitive transmembrane proteins. Previous studies suggest that
r-opsins
in the eyes mediate locomotory behaviour in marine protostomes, but few have provided direct evidence through gene mutagenesis. Larvae of the marine annelid
Capitella teleta
have simple eyespots and are positively phototactic, although the molecular components that mediate this behaviour are unknown. Here, we characterize the spatio-temporal expression of the rhabdomeric
opsin
genes in
C. teleta
and show that a single rhabdomeric
opsin
gene,
Ct-r-opsin1
, is expressed in the larval photoreceptor cells. To investigate its function,
Ct-r-opsin1
was disrupted using CRISPR/CAS9 mutagenesis. Polymerase chain reaction amplification and DNA sequencing demonstrated efficient editing of the
Ct-r-opsin1
locus. In addition, the pattern of
Ct-r-opsin1
expression in photoreceptor cells was altered. Notably, there was a significant decrease in larval phototaxis, although the eyespot photoreceptor cell and associated pigment cell formed normally and persisted in
Ct-r-opsin1
-mutant animals. The loss of phototaxis owing to mutations in
Ct-r-opsin1
is similar to that observed when the entire photoreceptor and pigment cell are deleted, demonstrating that a single
r-opsin
gene is sufficient to mediate phototaxis in
C. teleta
. These results establish the feasibility of gene editing in animals like
C. teleta
, and extend previous work on the development, evolution and function of the
C. teleta
visual system
.
Our study represents one example of disruption of animal behaviour by gene editing through CRISPR/CAS9 mutagenesis, and has broad implications for performing genome editing studies in a wide variety of other understudied animals.
Symbolic representation of numerosity by honeybees (
Apis mellifera
): matching characters to small quantities
Authors: Howard Scarlett R. , Avarguès-Weber Aurore , Garcia Jair E. , Greentree Andrew D. , Dyer Adrian G.
Published: June 2019

The assignment of a symbolic representation to a specific numerosity is a fundamental requirement for humans solving complex mathematical calculations used in diverse applications such as algebra, accounting, physics and everyday commerce. Here we show that honeybees are able to learn to match a sign to a numerosity, or a numerosity to a sign, and subsequently transfer this knowledge to novel numerosity stimuli changed in colour properties, shape and configuration. While honeybees learned the associations between two quantities (two; three) and two signs (N-shape; inverted T-shape), they failed at reversing their specific task of sign-to-numerosity matching to numerosity-to-sign matching and vice versa (i.e. a honeybee that learned to match a sign to a number of elements was not able to invert this learning to match the numerosity of elements to a sign). Thus, while bees could learn the association between a symbol and numerosity, it was linked to the specific task and bees could not spontaneously extrapolate the association to a novel, reversed task. Our study therefore reveals that the basic requirement for numerical symbolic representation can be fulfilled by an insect brain, suggesting that the absence of its spontaneous emergence in animals is not due to cognitive limitation.
Geographical and host species barriers differentially affect generalist and specialist parasite community structure in a tropical sky-island archipelago
Authors: Gupta Pooja , Vishnudas C. K. , Ramakrishnan Uma , Robin V. V. , Dharmarajan Guha
Published: June 2019

Understanding why some parasites emerge in novel host communities while others do not has broad implications for human and wildlife health. In the case of haemosporidian blood parasites, epidemic wild bird mortalities on oceanic islands have been linked to
Plasmodium
spp., but not genera like
Haemoproteus
. Indeed,
Haemoproteus
is absent from many oceanic islands. By contrast, birds on continental islands share long coevolutionary histories with both
Plasmodium
and
Haemoproteus
, and are thus ideal model systems to elucidate eco-evolutionary endpoints associated with these parasites in oceanic islands. Here, we examine eco-evolutionary dynamics of avian haemosporidian in the Shola sky-island archipelago of the Western Ghats, India. Our analyses reveal that compared to
Plasmodium
,
Haemoproteus
lineages were highly host-specific and diversified via co-speciation with their hosts. We show that community structure of host-generalist
Plasmodium
was primarily driven by geographical factors (e.g. biogeographic barriers), while that of host-specialist
Haemoproteus
was driven by host species barriers (e.g. phylogenetic distance). Consequently, a few host species can harbour a high diversity of
Plasmodium
lineages which, in turn, are capable of infecting multiple host species. These two mechanisms can act in concert to increase the risk of introduction, establishment, and emergence of novel
Plasmodium
lineages in island systems.
Environmental heterogeneity decreases reproductive success via effects on foraging behaviour
Authors: Trevail Alice M. , Green Jonathan A. , Sharples Jonathan , Polton Jeff A. , Miller Peter I. , Daunt Francis , Owen Ellie , Bolton Mark , Colhoun Kendrew , Newton Stephen , Robertson Gail , Patrick Samantha C.
Published: June 2019

Environmental heterogeneity shapes the uneven distribution of resources available to foragers, and is ubiquitous in nature. Optimal foraging theory predicts that an animal's ability to exploit resource patches is key to foraging success. However, the potential fitness costs and benefits of foraging in a heterogeneous environment are difficult to measure empirically. Heterogeneity may provide higher-quality foraging opportunities, or alternatively could increase the cost of resource acquisition because of reduced patch density or increased competition. Here, we study the influence of physical environmental heterogeneity on behaviour and reproductive success of black-legged kittiwakes,
Rissa tridactyla
. From GPS tracking data at 15 colonies throughout their British and Irish range, we found that environments that were physically more heterogeneous were associated with longer trip duration, more time spent foraging while away from the colony, increased overlap of foraging areas between individuals and lower breeding success. These results suggest that there is greater competition between individuals for finite resources in more heterogeneous environments, which comes at a cost to reproduction. Resource hotspots are often considered beneficial, as individuals can learn to exploit them if sufficiently predictable. However, we demonstrate here that such fitness gains can be countered by greater competition in more heterogeneous environments.
The broad-spectrum antiviral drug arbidol inhibits foot-and-mouth disease virus genome replication
Authors: Herod Morgan R. , Adeyemi Oluwapelumi O. , Ward Joseph , Bentley Kirsten , Harris Mark , Stonehouse Nicola J. , Polyak Stephen J.
Published: June 2019

Arbidol (ARB, also known as umifenovir) is used clinically in several countries as an anti-influenza virus drug. ARB inhibits multiple enveloped viruses in vitro and the primary mode of action is inhibition of virus entry and/or fusion of viral membranes with intracellular endosomal membranes. ARB is also an effective inhibitor of non-enveloped poliovirus types 1 and 3. In the current report, we evaluate the antiviral potential of ARB against another picornavirus, foot-and-mouth disease virus (FMDV), a member of the genus Aphthovirus and an important veterinary pathogen. ARB inhibits the replication of FMDV RNA sub-genomic replicons. ARB inhibition of FMDV RNA replication is not a result of generalized inhibition of cellular uptake of cargo, such as transfected DNA, and ARB can be added to cells up to 3 h post-transfection of FMDV RNA replicons and still inhibit FMDV replication. ARB prevents the recovery of FMDV replication upon withdrawal of the replication inhibitor guanidine hydrochloride (GuHCl). Although restoration of FMDV replication is known to require de novo protein synthesis upon GuHCl removal, ARB does not suppress cellular translation or FMDV internal ribosome entry site (IRES)-driven translation. ARB also inhibits infection with the related Aphthovirus, equine rhinitis A virus (ERAV). Collectively, the data demonstrate that ARB can inhibit some non-enveloped picornaviruses. The data are consistent with inhibition of picornavirus genome replication, possibly via the disruption of intracellular membranes on which replication complexes are located.
Polycomb contraction differentially regulates terminal human hematopoietic differentiation programs
Authors: Lorzadeh A. , Hammond C. , Wang F. , Knapp D.J.H.F. , Wong J.CH. , Zhu J.Y.A , Cao Q. , Heravi-Moussavi A. , Carles A. , Wong M. , Sharafian Z. , Moksa M. , Bilenky M. , Lavoie P.M. , Eaves C.J. , Hirst M.
Published: June 2019

Lifelong production of the many types of mature blood cells from less differentiated progenitors is a hierarchically ordered process that spans multiple cell divisions. The nature and timing of the molecular events required to integrate the environmental signals, transcription factor activity, epigenetic modifications, and changes in gene expression involved are thus complex and still poorly understood. We now show that the more primitive types of human cells in this system display a unique repressive H3K27me3 signature that is retained by mature lymphoid cells but is lost in terminally differentiated monocytes and erythroblasts. Additional intervention data implicate that control of this chromatin state change is a requisite part of the process, whereby normal human hematopoietic progenitor cells make lymphoid and myeloid fate decisions.
Not just BLAST nt: WGS database joins the party
Authors: Martí Jose Manuel , Garay Carlos P.
Published: June 2019

Since its introduction in 1990 and with over 50k citations, the NCBI BLAST family has been an essential tool of in silico molecular biology. The BLAST nt database, based on the traditional divisions of GenBank, has been the default and most comprehensive database for nucleotide BLAST searches and for taxonomic classification software in metagenomics. Here we argue that this is no longer the case. Currently, the NCBI WGS database contains one billion reads (almost five times more than GenBank), and with 4.4 trillion nucleotides, WGS has about 14 times more nucleotides than GenBank. This ratio is growing with time. We advocate a change in the database paradigm in taxonomic classification by systematically combining the nt and WGS databases in order to boost taxonomic classifiers sensitivity. We present here a case in which, by adding WGS data, we obtained over five times more classified reads and with a higher confidence score. To facilitate the adoption of this approach, we provide the draftGenomes script.

Author summary

Culture-independent methods are revolutionizing biology. The NIH/NCBI Basic Local Alignment Search Tool (BLAST) is one of the most widely used methods in computational biology. The BLAST nt database has become a de facto standard for taxonomic classifiers in metagenomics. We believe that it is time for a change in the database paradigm for such a classification. We advocate the systematic combination of the BLAST nt database with genomes of the massive NCBI Whole-Genome Shotgun (WGS) database. We make draftGenomes available, a script that eases the adoption of this approach. Current developments and technologies make it feasible now. Our recent results in several metagenomic projects indicate that this strategy boosts the sensitivity in taxonomic classifications.
HER2 Cancer Protrusion Growth Signaling Regulated by Unhindered, Localized Filopodial Dynamics
Authors: Lam Wai Yan , Wang Yi , Mostofian Barmak , Jorgens Danielle , Kwon Sunjong , Chin Koei , Carpenter M. Alexandra , Jacob Thomas , Heiser Katie , Agrawal Anurag , Wang Jing , Nan Xiaolin , Chang Young Hwan , Zuckerman Daniel M. , Gray Joe , Bruchez Marcel , Lidke Keith A. , Vu Tania Q.
Published: June 2019

Protrusions are plasma membrane extensions that are found in almost every cell in the human body. Cancer cell filopodial and lamellipodial protrusions play key roles in the integral processes of cell motility and signaling underlying tumor invasion and metastasis. HER2 (ErbB-2) is overexpressed in diverse types of tumors and regulates PI3K-pathway-mediated protrusion growth. It is known that HER2 resides at breast cancer cell protrusions, but how protrusion-based HER2 spatiotemporal dynamics shape cancer signaling is unclear. Here, we study how HER2 location and motion regulate protrusion signaling and growth using quantitative spatio-temporal molecular imaging approaches. Our data highlight morphologically-segregated features of filopodial and lamellipodial protrusions, in in vitro 2D breast cancer cells and in vivo intact breast tumor. Functional-segregation parallels morphological-segregation, as HER2 and its activated downstream pAKT-PI3K signaling remain spatially-localized at protrusions, provoking new protrusion growth proximal to sites of HER2 activation. HER2 in SKBR3 breast cancer cell filopodia exhibits fast, linearly-directed motion that is distinct from lamellipodia and non-protrusion subcellular regions (∼3-4 times greater diffusion constant, rapid speeds of 2-3 um2/s). Surprisingly, filopodial HER2 motion is passive, requiring no active energy sources. Moreover, while HER2 motion in lamellipodia and non-protrusion regions show hindered diffusion typical of membrane proteins, HER2 diffuses freely within filopodia. We conclude that HER2 activation, propagation, and functional protrusion growth is a local process in which filopodia have evolved to exploit Brownian thermal fluctuations within a barrier-free nanostructure to transduce rapid signaling. These results support the importance of developing filopodia and other protrusion-targeted strategies for cancer.
Pharmacological enrichment of polygenic risk for precision medicine in complex disorders
Authors: Reay William R. , Atkins Joshua R. , Carr Vaughan J. , Green Melissa J. , Cairns Murray J.
Published: June 2019

Individuals with complex disorders typically have a heritable burden of common variation that can be expressed as a polygenic risk score (PRS). While PRS has some predictive utility, it lacks the molecular specificity to be directly informative for clinical interventions. We therefore sought to develop a framework to quantify an individual’s common variant enrichment in clinically actionable systems responsive to existing drugs. This was achieved with a metric designated the pharmagenic enrichment score (PES), which we demonstrate for individual SNP profiles in a cohort of cases with schizophrenia. A large proportion of these had elevated PES in one or more of eight clinically actionable gene-sets enriched with schizophrenia associated common variation. Notable candidates targeting these pathways included vitamins, insulin modulating agents, and protein kinase inhibitors with putative neuroprotective properties. Interestingly, elevated PES was also observed in individuals with otherwise low common variant burden. The biological saliency of PES profiles were observed directly through their impact on gene expression in a subset of the cohort with matched transcriptomic data, supporting our assertion that this framework can integrate an individual’s common variant risk to inform personalised interventions, including drug repositioning, for complex disorders such as schizophrenia.
Mesenchymal-Epithelial Transition Regulates Initiation of Pluripotency Exit before Gastrulation
Authors: Hamidi Sofiane , Nakaya Yukiko , Nagai Hiroki , Alev Cantas , Kasukawa Takeya , Chhabra Sapna , Lee Ruda , Niwa Hitoshi , Warmflash Aryeh , Shibata Tatsuo , Sheng Guojun
Published: June 2019

The pluripotent epiblast gives rise to all tissues and organs in an adult body. Its differentiation starts at gastrulation when the epiblast generates mesoderm and endoderm germ layers through a process called epithelial-mesenchymal transition (EMT). Although gastrulation EMT coincides with loss of epiblast pluripotency, pluripotent cells in development and in vitro can adopt either mesenchymal or epithelial morphology. The relationship between epiblast’s cellular morphology and its pluripotency is not well understood. In this work, using chicken epiblast and mammalian pluripotency stem cell (PSC) models, we show that PSCs undergo a mesenchymal-epithelial transition (MET) prior to EMT-associated pluripotency loss. Epiblast MET and its subsequent EMT are two distinct processes. The former, a partial MET, is associated with reversible initiation of pluripotency exit; whereas the latter, a full EMT, is associated with complete and irreversible pluripotency loss. We provide evidence that integrin-mediated cell-matrix interaction is a key player in pluripotency exit regulation. We propose that epiblast partial MET is an evolutionarily conserved process among all amniotic vertebrates and its developmental function is to mediate planar symmetry-breaking within an epithelialized epiblast, taking place after epiblast MET but before gastrulation EMT.
Patch-DCA: Improved Protein Interface Prediction by utilizing Structural Information and Clustering DCA scores
Authors: Vajdi Amir , Zarringhalam Kourosh , Haspel Nurit
Published: June 2019

Over the past decade there have been impressive advances in determining the 3D structures of protein complexes. However, there are still many complexes with unknown structures, even when the structures of the individual proteins are known. The advent of protein sequence information provides an opportunity to leverage evolutionary information to enhance the accuracy of protein-protein interface prediction. To this end, several statistical and machine learning methods have been proposed. In particular, direct coupling analysis has recently emerged as a promising approach for identification of protein contact maps from sequential information. However, the ability of these methods to detect protein-protein inter-residue contacts remains relatively limited.

In this work, we propose a method to integrate sequential and co-evolution information with structural and functional information to increase the performance of protein-protein interface prediction. Further, we present a post-processing clustering method that improves the average relative F1 score by 70 % and 24 % and the precision by 80 % and 36 % in comparison with two state-of-the-art methods PSICOV and GREMLIN.
The influence of transcranial magnetic stimulation of the medial prefrontal cortex on emotional memory schemas
Authors: Bovy Leonore , Berkers Ruud M.W.J. , Pottkämper Julia , Varatheesvaran Rathiga , Fernández Guillén , Tendolkar Indira , Dresler Martin
Published: June 2019

Memory bias for negative information is a critical characteristic of major depression, but the underlying neural mechanisms are largely unknown. The recently revived concept of memory schemas may shed new light on memory bias in depression: negative schemas might enhance the encoding and consolidation of negative experiences, thereby contributing to the genesis and perpetuation of depressive pathology. To investigate this relationship, we aimed to transiently perturb processing in the medial prefrontal cortex (mPFC), a core region involved in schema memory, using neuronavigated transcranial magnetic stimulation (TMS) targeting the mPFC. Forty healthy volunteers first underwent a negative mood induction to activate negative schema processing after which they received either active inhibitory (N = 20) or control (N = 20) stimulation to the mPFC. Then, all participants performed the encoding of an emotional false memory task. Recall and recognition performance was tested the following morning. Polysomnographic data was recorded continuously during the night before and after encoding. Secondary measures included sleep and mood questionnaires. We observed a significantly lower number of false recognition of negative critical lures following mPFC perturbation compared to the control group, whereas no differences in veridical memory performance were observed. These findings were supported by reaction time data. No relation between REM sleep and (false) emotional memory performance was observed. These findings support previous causal evidence for a role of the mPFC in schema memory processing and further suggest a role of the mPFC in memory bias.