bluuebunny/crossref_metadata_2025 huggingface dataset:
Narratology and the Soundtrack
Authors: Buhler James
Published: November 2018

Chapter 6 focuses on narrative theories of film. It opens with a discussion of film narratology in general. The second section then covers narratological theories of the soundtrack, especially music, which was one of the first subsystems of film to have its theory rewritten in explicitly narratological terms. It considers contributions by Claudia Gorbman, Michel Chion, Sarah Kozoloff, Giorgi Biancorosso, Robynn Stilwell, Jeff Smith, and Ben Winters and traces how the basic conceptual distinction of diegetic and nondiegetic music has evolved. The next section examines the important narratological concept of focalization as it applies to music in film, drawing on the work of Guido Heldt and concludes with a brief discussion of focalization in Casablanca.
Confinement, Mendicancy, and the Making of the Street Musician
Authors: Llano Samuel
Published: November 2018

This chapter analyzes the social, historical, and legal context in which the San Bernardino workhouse and band were created, and in which their activity developed. San Bernardino was founded in 1834 to confine the poor, who were seen as a source of public shame and contamination, and who were blamed for the rise of cholera epidemics in Madrid. The system of confinement relied on the distinction between deserving and undeserving poor and aimed to make them productive. The harsh discipline and deficient hygiene of workhouses, however, acted as deterrents and forced the authorities to resort to violence in order to force reluctant beggars into the workhouse. The increasingly tolerated presence on the streets of blind buskers, who were of no practical use in workhouses, gave rise to new legislation on disability and changed the composition of Madrid’s soundscape.
A Limited Leviathan
Authors: Vanderschraaf Peter
Published: November 2018

The state social contract relationship between rulers and the ruled in civil society is fruitfully understood as a governing convention. This relationship is modeled with an indefinitely repeated Humean Sovereignty game, where subjects and their sovereign maintain a governing convention by respectively obeying and providing adequate government. The ruled and their rulers maintain an implicit contract that is self-enforcing rather than an explicit contract requiring third-party enforcement. This model is motivated by the Trust problem in game theory and dynamic programming models of employment search. The governing convention idea has roots in Hume’s discussions of government. The closely allied Leadership Selection problem has roots in Hobbes’ account of commonwealth by institution. Hobbes’ original analysis fails, but his general strategy of justifying government by identifying an isomorphism between an actual regime and the regime of hypothetical choice motivates justifying democratic government via the salience of a democratic leadership convention.
Antigen recognition in autoimmune diabetes: a novel pathway underlying disease initiation
Authors: Wan Xiaoxiao , Unanue Emil R
Published: November 2018

Development of human autoimmune disorders results from complex interplay among genetic, environmental, and immunological risk factors. Despite much heterogeneity in environmental triggers, the leading genes that give the propensity for tissue-specific autoimmune diseases, such as type 1 diabetes, are those associated with particular class II major histocompatibility complex alleles. Such genetic predisposition precipitates presentation of tissue antigens to MHC-II-restricted CD4 T cells. When properly activated, these self-reactive CD4 T cells migrate to the target tissue and trigger the initial immune attack. Using the non-obese diabetic mouse model of spontaneous autoimmune diabetes, much insight has been gained in understanding how presentation of physiological levels of self-antigens translates into pathological outcomes. In this review, we summarize recent advances illustrating the features of the antigen presenting cells, the sites of the antigen recognition, and the nature of the consequent T cell responses. We emphasize emerging evidence that highlights the importance of systemic presentation of catabolized tissue antigens in mobilization of pathogenic T cells. The implication of these studies in therapeutic perspectives is also discussed.
Discriminative Validity of the Pain Attitudes and Beliefs Scale for Physical Therapists
Authors: Eland Nicolaas D , Kvåle Alice , Ostelo Raymond W J G , de Vet Henrica C W , Strand Liv I
Published: November 2018

Background

The Pain Attitudes and Beliefs Scale (PABS) for Physical Therapists aims to measure clinicians’ biomedical and biopsychosocial treatment orientations regarding nonspecific low back pain.

Objective

The objective of this study was to assess whether the PABS can differentiate between subgroups of physical therapists hypothesized to differ in treatment orientations.

Design

This study was a cross-sectional survey.

Methods

The PABS was completed by 662 Norwegian physical therapists with a diversity of professional backgrounds. Twenty-four a priori hypotheses on expected differences in PABS scores were formulated. Sufficient discriminative ability was defined as a minimum of 75% confirmed hypotheses. Hypotheses on differences in scores were tested for the biomedical and biopsychosocial subscales separately as well as for combinations of the 2 subscales, representing responders with high biomedical and low biopsychosocial PABS scores and vice versa.

Results

Of the 24 hypotheses, only 15 (62.5%) were confirmed. Between-group differences concerning the separate subscales were small, varying from −0.63 to 1.70 scale points, representing values up to 6.0% of the total subscale ranges. Between-group differences were larger when combined subscales were used, varying from 1.80 to 6.70 points, representing values up to 25.1% of the total subscale ranges. Despite little spread in scores, 24% of respondents demonstrated extreme attitudes.

Limitations

The lack of convincing scientific evidence from previous research on differences in attitudes and beliefs between physical therapists was a limitation for the formulation of hypotheses.

Conclusions

Discriminative validity of separate subscales of the PABS was not supported. Combining the 2 subscales into global treatment attitudes enabled better discrimination. Little spread in biomedical and biopsychosocial orientations explains why more than one-third of the hypotheses were not confirmed. Either Norwegian physical therapists are basically similar in their treatment orientation or the PABS is not able to detect any differences between them.
Percutaneous low-energy osteotomy in treatment of pathological coronal knee deformities in pediatrics
Authors: Emara Khaled M. , Mahmoud Shady A. , Diab Ramy A. , Elshobaky Mahmoud A. , Emara Ahmed K.
Published: November 2018

The aim of this study was to assess the safety and efficacy of percutaneous low-energy osteotomy and casting in treatment of pathological coronal knee deformities in children equal or younger than 6 years. A prospective nonrandomized case series study was conducted. A total of 62 (109 limbs) patients with pathological coronal knee deformities were treated by percutaneous low-energy osteotomy and casting and observed over 3–10 years. The pathological nature was variable (rickets, Blount disease, dysplasia, after trauma, or after infection). The average age at the time of surgery was 4.5 years (range: 3–6 years). Clinical and radiological outcomes were evaluated annually and at the end of follow-up period. There was a statistically significant improvement of the clinical appearance and the radiological parameters regarding mechanical axis deviation and tibiofemoral angle at the end of follow-up period. The total complication rate was 6.4%, with only four limbs with overcorrection and three limbs with recurrence. Percutaneous osteotomy is a simple, safe, and effective option in the treatment of children with coronal knee deformities equal or younger than 6 years.
A Case Report of a Complete Penile and Scrotum Skin Degloving Injury
Authors: Li Dongyu , Chen Fang , Hu Chenghao , Zhang Jianhua , Wu Jiani , Dongye Yuhui , Li Huibin
Published: November 2018

Male genital injuries are rare and only few of them are total penoscrotal degloving injuries. Though this kind of injury is not life-threatening, it could be psychologically devastating to patients if not treated appropriately. This report presents a case of total male genitalia degloving injury treated by sliding flap and skin graft, assisted by Vacuum Sealing Drainage. Via this therapeutic approach, the injured area was completely healed. Three months after surgery, there were still no scars that affected normal function of male genitalia.This approach, which has never been reported before, yields a satisfactory result for both aesthetic appearance and sexual functions.
UDI2Claims: Planning a Pilot Project to Transmit Identifiers for Implanted Devices to the Insurance Claim
Authors: Zerhouni Yasmin A. , Krupka Dan C. , Graham Jove , Landman Adam , Li Angela , Bhatt Deepak L. , Nguyen Louis L. , Capatch Kevin , Concheri Kevin , Reich Amanda J. , Wilson Natalia , Weissman Joel S.
Published: November 2018

Background

In response to problems with the current postmarket surveillance of medical devices, the U.S. Food and Drug Administration mandated device labelers to include a unique device identifier (UDI), composed of a device identifier (DI) and production identifier. Including the DI in insurance claims could be a potent method to monitor implanted devices, yet implementation has lagged because of questions of benefit and operational concerns.

Methods

To illustrate the potential benefit of including DIs in claims, rates of 90-day adverse events after implantation using an electronic health record (EHR) were compared with the EHR plus claims, which capture utilization outside that EHR’s health system. To explore operations, we planned a pilot project to transmit the DI of implanted devices from the point of care to the claim at two provider/payer pairs.

Results

By querying claims plus EHR, estimated rates of patients with potential adverse events were as much as 3.75 times higher. For our pilot, our multistakeholder team identified and resolved the following five challenges: (1) capturing the DI at the point of care; (2) selecting a location for the DI on the claim form; (3) transmitting the DI to the claim form; (4) analyzing the claim forms received by the payer; and (5) verifying the quality of the transmitted information.

Conclusions

Including DIs on claims could allow more complete data capture of adverse events for implanted devices than the EHR data. We overcame challenges in transmitting the DI to the claim with attention to planning and multistakeholder involvement.
Reactivation of latent Histoplasma and disseminated cytomegalovirus in a returning traveller with ulcerative colitis
Authors: Lucey Olivia , Carroll Iain , Bjorn Thomas , Millar Michael
Published: November 2018

Introduction. We describe a case of progressive disseminated histoplasmosis (PDH) and disseminated cytomegalovirus (CMV) with development of haemophagocytic lymphohistiocytosis in a 62-year-old man of Bangladeshi origin living in the UK.

Case presentation. The patient had a background of ulcerative colitis for which he took prednisolone and azathioprine. He presented with fever, lethargy, cough, weight loss and skin redness, and was initially treated for bacterial cellulitis and investigated for underlying malignancy. He developed multiple progressive erythematous skin lesions, sepsis and colitis requiring management on intensive care. A skin biopsy showed yeasts in the dermis and sub-cutaneous fat, which were confirmed as Histoplasma capsulatum by PCR. Disseminated CMV with evidence of end organ gastrointestinal disease was also diagnosed. Despite anti-viral and anti-fungal treatment, the patient deteriorated with evidence of bone marrow suppression and a diagnosis of haemophagocytic lymphohistiocytosis was made.

Conclusion. PDH is classically seen in patients with significant immunosuppression, e.g. those with human immunodeficiency virus (HIV) or on anti-TNF therapy; however, we present a case of reactivation of Histoplasma in a non-HIV patient. We consider the importance of contemplating reactivation of endemic mycoses and CMV in critically unwell and deteriorating patients.
Thermodynamic integration for dynamic causal models
Authors: Aponte Eduardo A. , Raman Sudhir , Frässle Stefan , Heinzle Jakob , Penny Will D. , Stephan Klaas E.
Published: November 2018

In generative modeling of neuroimaging data, such as dynamic causal modeling (DCM), one typically considers several alternative models, either to determine the most plausible explanation for observed data (Bayesian model selection) or to account for model uncertainty (Bayesian model averaging). Both procedures rest on estimates of the model evidence, a principled trade-off between model accuracy and complexity. In DCM, the log evidence is usually approximated using variational Bayes (VB) under the Laplace approximation (VBL). Although this approach is highly efficient, it makes distributional assumptions and can be vulnerable to local extrema. An alternative to VBL is Markov Chain Monte Carlo (MCMC) sampling, which is asymptotically exact but orders of magnitude slower than VB. This has so far prevented its routine use for DCM.

This paper makes four contributions. First, we introduce a powerful MCMC scheme – thermodynamic integration (TI) – to neuroimaging and present a derivation that establishes a theoretical link to VB. Second, this derivation is based on a tutorial-like introduction to concepts of free energy in physics and statistics. Third, we present an implementation of TI for DCM that rests on population MCMC. Fourth, using simulations and empirical functional magnetic resonance imaging (fMRI) data, we compare log evidence estimates obtained by TI, VBL, and other MCMC-based estimators (prior arithmetic mean and posterior harmonic mean). We find that model comparison based on VBL gives reliable results in most cases, justifying its use in standard DCM for fMRI. Furthermore, we demonstrate that for complex and/or nonlinear models, TI may provide more robust estimates of the log evidence. Importantly, accurate estimates of the model evidence can be obtained with TI in acceptable computation time. This paves the way for using DCM in scenarios where the robustness of single-subject inference and model selection becomes paramount, such as differential diagnosis in clinical applications.
TCF7L1 and TCF7 differentially regulate specific mouse ES cell genes in response to GSK-3 inhibition
Authors: Moreira Steven , Seo Caleb , Polena Enio , Mahendram Sujeivan , Mercier Eloi , Blais Alexandre , Doble Bradley W.
Published: November 2018

The genome-wide chromatin occupancy of the TCF/LEF factors and its modulation by Wnt pathway activation remain poorly defined. Here, we describe mouse ES cell (mESC) lines expressing a single copy knock-in of the 3xFLAG epitope at the N-terminus of TCF7L1 and TCF7, the two most-highly expressed TCF/LEF factors in mESCs. TCF7L1 protein levels, detected by immunoblotting with a FLAG antibody, were much higher than TCF7 in mESCs maintained in standard serum- and LIF-supplemented medium, even in the presence of the GSK-3 inhibitor, CHIR99021 (CHIR). We used FLAG antibody-mediated ChIP-seq to determine TCF7 and TCF7L1 chromatin occupancy in mESCs cultured in standard medium with or without CHIR for 14 hours. TCF7 and TCF7L1 displayed very few overlapping ChIP peaks across the genome, with TCF7L1 binding significantly more genes than TCF7 in both culture conditions. Despite a reduction in total TCF7L1 protein after CHIR treatment, the TCF7L1 ChIP peak profiles were not uniformly attenuated. Our data demonstrate that TCF7L1 chromatin occupancy upon short-term CHIR treatment is modulated in a target-specific manner. Our findings also suggest that Wnt target genes in mESCs are not regulated by TCF/LEF switching, and TCF7L1, although often called a constitutive repressor, may serve as a transcriptional activator of certain target genes in CHIR-treated mESCs.

Highlights

ChIP and cytometry data suggest that TCF7L1 does not directly regulate mESC Nanog expression.

TCF7L1 remains associated with β-catenin in the presence of CHIR99021.

TCF7 and TCF7L1 display different chromatin occupancies in mESCs.

TCF7L1 binding at specific genomic sites is variably altered by CHIR99021.
Waving goodbye to contrast: Self-generated hand movements attenuate visual sensitivity
Authors: Vasser Madis , Vuillaume Laurène , Cleeremans Axel , Aru Jaan
Published: November 2018

It is well known that the human brain continuously predicts the sensory consequences of its own body movements, which typically results in sensory attenuation. Yet, the extent and exact mechanisms underlying sensory attenuation are still debated. To explore this issue, we asked participants to decide which of two visual stimuli was of higher contrast in a virtual reality situation where one of the stimuli could appear behind the participants’ invisible moving hand or not. Over two experiments, we measured the effects of such “virtual occlusion” on first-order sensitivity and on metacognitive monitoring. Our findings show that self-generated hand movements reduced the apparent contrast of the stimulus. This result can be explained by the active inference theory. Moreover, sensory attenuation seemed to affect only first-order sensitivity and not (second-order) metacognitive judgments of confidence.
Crown defoliation decreases reproduction and wood growth in a marginal European beech population
Authors: Oddou-Muratorio Sylvie , Petit-Cailleux Cathleen , Journé Valentin , Lingrand Matthieu , Magdalou Jean-André , Hurson Christophe , Garrigue Joseph , Davi Hendrik , Magnanou Elodie
Published: November 2018

Abiotic and biotic stresses related to climate change have been associated to increased crown defoliation, decreased growth and a higher risk of mortality in many forest tree species, but the impact of stresses on tree reproduction and forest regeneration remains understudied. At dry, warm margin of species distributions, flowering, pollination and seed maturation processes are expected to be affected by drought, late frost and other stresses, eventually resulting in reproduction failure. Moreover, inter-individual variations in reproductive performances versus other performances (growth, survival) could have important consequences on population’s dynamics.

We investigated the relationships between individual crown defoliation, growth and reproduction in a drought-prone population of European beech, Fagus sylvatica. We used a spatially explicit mating model and marker-based parentage analyses to estimate effective female and male fecundities of 432 reproductive trees, which were also monitored for basal area increment and crown defoliation over nine years.

Female and male fecundities markedly varied among individuals, more than did growth. Both female fecundity and growth decreased with increasing crown defoliation and competition and increased with size. Male fecundity only responded to competition, and decreased with increasing competition. Moreover, the negative effect of defoliation on female fecundity was size-dependent, with a slower decline in female fecundity with increasing defoliation for the large individuals. Finally, a trade-off between growth and female fecundity was observed in response to defoliation: some large trees maintained significant female fecundity at the expense of reduced growth in response to defoliation, while some other defoliated trees rather maintained high growth at the expense of reduced female fecundity.

Synthesis. Our results suggest that while decreasing their growth, some large defoliated trees still contribute to reproduction through seed production and pollination. This non-coordinated decline of growth and fecundity at individual-level in response to stress may compromise the evolution of stress-resistance traits at population level, and increase forest tree vulnerability.
Neurovascular coupling preserved in a chronic mouse model of Alzheimer’s disease: Methodology is critical
Authors: Sharp Paul S , Ameen-Ali Kam , Boorman Luke , Harris Sam , Wharton Stephen , Howarth Clare , Redgrave Peter , Berwick Jason
Published: November 2018

Neurovascular coupling is the process by which neural activity causes localised changes in cerebral blood flow. Impaired neurovascular coupling has been suggested as an early pathogenic factor in Alzheimer’s disease (AD), and if so, could serve as an early biomarker of cerebral pathology. We have established an anaesthetic regime in which evoked hemodynamic responses are comparable to those in awake mice. This protocol was adapted to allow repeated measurements of neurovascular function over three months in the hAPP-J20 mouse model of AD (J20-AD) and wild-type (WT) controls. Animals were 9-12 months old at the start of the experiment, which is when deficits due to the disease condition would be expected. Mice were chronically prepared with a cranial window through which optical imaging spectroscopy (OIS) was used to generate functional maps of the cerebral blood volume and saturation changes evoked by whisker stimulation and vascular reactivity challenges. Unexpectedly, the hemodynamic responses were largely preserved in the J20-AD group. This result failed to confirm previous investigations using the J20-AD model. However, a final acute electrophysiology and OIS experiment was performed to measure both neural and hemodynamic responses concurrently. In this experiment, previously reported deficits in neurovascular coupling in the J20-AD model were observed. This suggests that J20-AD mice may be more susceptible to the physiologically stressing conditions of an acute experimental procedure compared to WT animals. These results therefore highlight the importance of experimental procedure when determining the characteristics of animal models of human disease.

Significance Statement

Using a chronic anaesthetised preparation, we measured hemodynamic responses evoked by sensory stimulation and respiratory gases in the J20-AD mouse model of Alzheimer’s Disease over a period of 3 months. We showed that neurovascular responses were preserved compared to age matched wildtype controls. These results failed to confirm previous investigations reporting a marked reduction of neurovascular coupling in the J20-AD mouse model. However, when our procedure involved acute surgical procedures, previously reported neurovascular deficits were observed. The effects of acute electrode implantation were caused by disturbances to baseline physiology rather than a consequence of the disease condition. These results highlight the importance of experimental procedure when determining the characteristics of animal models of human disease.
On estimating evolutionary probabilities of population variants
Authors: Patel Ravi , Kumar Sudhir
Published: November 2018

Background

The evolutionary probability (EP) of an allele in a DNA or protein sequence predicts evolutionarily permissible (ePerm; EP ≥ 0.05) and forbidden (eForb; EP < 0.05) variants. EP of an allele represents an independent evolutionary expectation of observing an allele in a population based solely on the long-term substitution patterns captured in a multiple sequence alignment. In the neutral theory, EP and population frequencies can be compared to identify neutral and non-neutral alleles. This approach has been used to discover candidate adaptive polymorphisms in humans, which are eForbs segregating with high frequencies. The original method to compute EP requires the evolutionary relationships and divergence times of species in the sequence alignment (a timetree), which are not known with certainty for most datasets. This requirement impedes a general use of the original EP formulation. Here, we present an approach in which the phylogeny and times are inferred from the sequence alignment itself prior to the EP calculation. We evaluate if the modified EP approach produces results that are similar to those from the original method.

Results

We compared EP estimates from the original and the modified approaches by using more than 18,000 protein sequence alignments containing orthologous sequences from 46 vertebrate species. For the original EP calculations, we used species relationships from UCSC and divergence times from TimeTree web resource, and the resulting EP estimates were considered to be the ground truth. We found that the modified approaches produced reasonable EP estimates for HGMD disease missense variant and 1000 Genomes Project missense variant datasets. Our results showed that reliable estimates of EP can be obtained without a priori knowledge of the sequence phylogeny and divergence times. We also found that, in order to obtain robust EP estimates, it is important to assemble a dataset with many sequences, sampling from a diversity of species groups.

Conclusion

We conclude that the modified EP approach will be generally applicable for alignments and enable the detection of potentially neutral, deleterious, and adaptive alleles in populations.
High-quality assembly of sweet basil genome
Authors: Dudai Nativ , Carp Marie-Jeanne , Milavski Renana , Chaimovitsh David , Shachter Alona , Baruch Kobi , Ronen Gil , Gonda Itay
Published: November 2018

Sweet basil, sometimes called the King of Herbs, is well known for its culinary uses, especially in the Italian sauce ‘Pesto’. It is also used in traditional medicine, as a source for essential oils and as an ornamental plant. So far, basil was bred by classical and traditional methods due to lack of a reference genome that will allow optimized application of the most up-to-date sequencing techniques. Here, we report on the first completion of the sweet basil genome of the cultivar ‘Perrie’, a fresh-cut Genovese-type basil, using several next generation sequencing platforms followed by genome assembly with NRGENE’s DeNovoMAGIC assembly tool. We determined that the genome size of sweet basil is 2.13 Gbp and assembled it into 12,212 scaffolds. The high-quality of the assembly is reflected in that more than 90% of the assembly size is composed of only 107 scaffolds. An independent analysis of single copy orthologues genes showed a 93% completeness which reveal also that 74% of them were duplicated, indicating that the sweet basil is a tetraploid organism. A reference genome of sweet basil will enable to develop precise molecular markers for various agricultural important traits such as disease resistance and tolerance to various environmental conditions. We will gain a better understanding of the underlying mechanisms of various metabolic processes such as aroma production and pigment accumulation. Finally, it will save time and money for basil breeders and scientists and ensure higher throughput and robustness in future studies.
Optimized fragmentation improves the identification of peptides cross-linked using MS-cleavable reagents
Authors: Stieger Christian E. , Doppler Philipp , Mechtler Karl
Published: November 2018

Cross-linking mass spectrometry (XLMS) is becoming increasingly popular, and current advances are widening the applicability of the technique so that it can be utilized by non-specialist laboratories. Specifically, the use of novel mass spectrometry-cleavable (MS-cleavable) reagents dramatically reduces complexity of the data by providing i) characteristic reporter ions and ii) the mass of the individual peptides, rather than that of the cross-linked moiety. However, optimum acquisition strategies to obtain the best quality data for such cross-linkers with higher energy C-trap dissociation (HCD) alone is yet to be achieved. Therefore, we have carefully investigated and optimized MS parameters to facilitate the identification of disuccinimidyl sulfoxide (DSSO)- based cross-links on HCD-equipped mass spectrometers. From the comparison of 9 different fragmentation energies we chose several stepped-HCD fragmentation methods that were evaluated on a variety of cross-linked proteins. The optimal stepped-HCD-method was then directly compared with previously described methods using an Orbitrap Fusion™ Lumos™ TribridTM instrument using a high-complexity sample. The final results indicate that our stepped-HCD method is able to identify more cross-links than other methods, mitigating the need for multistage MS (MSn) enabled instrumentation and alternative dissociation techniques.
Time-resolved systems analysis reveals a critical role of XCR1+ dendritic cells in the maintenance of effector T cells during chronic viral infection
Authors: Argilaguet Jordi , Pedragosa Mireia , Esteve-Codina Anna , Riera Graciela , Vidal Enric , Peligero-Cruz Cristina , Andreu David , Kaisho Tsuneyasu , Bocharov Gennady , Ludewig Burkhard , Heath Simon , Meyerhans Andreas
Published: November 2018

Upon a viral infection, the host immune system attempts to eradicate the virus. However, once the infection threat seems overwhelming, the infected host actively shuts down effector responses to reduce immunopathology. The price to pay for this is the establishment of a chronic infection that is only partially controlled by a lower level immune response. The genetic networks underlying this infection fate decision and the immune adaptation to the lower level response are not well understood. Here we used an integrated approach of gene coexpression network analysis of time-resolved splenic transcriptomes and immunological analysis to characterize the host response to acute and chronic lymphocytic choriomeningitis virus (LCMV) infections. We found first, an early attenuation of inflammatory monocyte/macrophage prior to the onset of T cell exhaustion and second, a critical role of the XCL1-XCR1 communication axis during the functional adaptation of the T cell response to the chronic infection state. These findings not only reveal an important feedback mechanism that couples T cell exhaustion with the maintenance of a lower level of effector T cell response but also suggest therapy options to better control virus levels during the chronic infection phase.

Author Summary

The outcomes of viral infections are the result of dynamic interplays between infecting viruses and induced host responses. They can be categorized as either acute or chronic depending on temporal virus-host relationships. Chronic infections are associated with immune exhaustion, a partial shut-down of effector responses. The processes underlying infection fate decisions are incompletely understood. Here we analyzed, on a systems level, infection-fate–specific gene signatures and the resulting adaptive processes of the host. We used the well-established lymphocytic choriomeningitis virus infection mouse model which has been instrumental to detect many fundamental processes in the virus-immune system crosstalk that are also relevant in human infections. We show an early attenuation of macrophage-mediated inflammation and an involvement of cross-presenting dendritic cells in the maintenance of an antiviral cytotoxic T cell response and virus control in the chronic infection phase. Together our data demonstrate a delicate adaptation process towards a chronic virus infection with both immunosuppressive and immunostimulatory processes. We fill a knowledge gap regarding the mechanisms of effector T cell maintenance and provide a new rational for targeted therapeutic vaccination.
The impact of bilateral ongoing activity on evoked responses in mouse cortex
Authors: Shimaoka Daisuke , Steinmetz Nicholas A , Harris Kenneth D , Carandini Matteo
Published: November 2018

The ongoing activity of the left and right cortical hemispheres shows strong bilateral fluctuations. Here we show that these fluctuations are largely responsible for the variability observed in cortical responses to sensory stimuli. Using widefield imaging of voltage and calcium signals, we measured activity in the cortex of mice performing a visual detection task. Bilateral fluctuations invested all areas, particularly those closest to the midline. Activity was less bilateral in the monocular region of primary visual cortex and, especially during task engagement, in secondary motor cortex. Ongoing bilateral fluctuations dominated unilateral visual responses, and interacted additively with them, explaining much of the variance in trial-by-trial activity. Even though these fluctuations occurred in regions necessary for the task, they did not impact detection behavior. We conclude that bilateral ongoing activity continues during sensory stimulation and has a powerful additive impact on sensory processing.
C. elegans pathogenic learning confers multigenerational pathogen avoidance
Authors: Moore Rebecca S. , Kaletsky Rachel , Murphy Coleen T.
Published: November 2018

The ability to pass on learned information to progeny could present an evolutionary advantage for many generations. While apparently evolutionarily conserved1–12, transgenerational epigenetic inheritance (TEI) is not well understood at the molecular or behavioral levels. Here we describe our discovery that C. elegans can pass on a learned pathogenic avoidance behavior to their progeny for several generations through epigenetic mechanisms. Although worms are initially attracted to the gram-negative bacteria P. aeruginosa (PA14)13, they can learn to avoid this pathogen13. We found that prolonged PA14 exposure results in transmission of avoidance behavior to progeny that have themselves never been exposed to PA14, and this behavior persists through the fourth generation. This form of transgenerational inheritance of bacterial avoidance is specific to pathogenic P. aeruginosa, requires physical contact and infection, and is distinct from CREB-dependent long-term associative memory and larval imprinting. The TGF-β ligand daf-7, whose expression increases in the ASJ upon initial exposure to PA1414, is highly expressed in the ASI neurons of progeny of trained mothers until the fourth generation, correlating with transgenerational avoidance behavior. Mutants of histone modifiers and small RNA mediators display defects in naïve PA14 attraction and aversive learning. By contrast, the germline-expressed PRG-1/Piwi homolog15 is specifically required for transgenerational inheritance of avoidance behavior. Our results demonstrate a novel and natural paradigm of TEI that may optimize progeny decisions and subsequent survival in the face of changing environmental conditions.
Attraction to pheromones inCaenorhabditis eleganscan be reversed through associative learning
Authors: Bello M. Dal , Pérez-Escudero A. , Schroeder F. C. , Gore J.
Published: November 2018

Despite the ubiquity and importance of chemical signaling, we have only limited insight about the role of learning in the response to pheromones. Here, we demonstrate that responses to pheromones can be reprogrammed through associative learning. In particular, we show that attraction to ascaroside pheromones in the model nematodeCaenorhabditis eleganscan be reversed by training the animals to associate either a pheromone blend or single synthetic ascarosides with the lack of food. This behavioral plasticity alters worm preference for pheromones following consumption of a food patch, possibly improving foraging in natural environments. By bridging the gap between the current knowledge on the chemical language and the learning abilities ofC. elegans, we provide insight on the possible links between learning and chemical signaling in animals.
The sustained release of basic fibroblast growth factor accelerates angiogenesis and the survival of the inactivated dermis by high hydrostatic pressure
Authors: Le Tien Minh , Morimoto Naoki , Mitsui Toshihito , Notodihardjo Sharon Claudia , Munisso Maria Chiara , Kakudo Natsuko , Kusumoto Kenji
Published: November 2018

We developed a novel skin regeneration therapy combining nevus tissue inactivated by high hydrostatic pressure (HHP) in the reconstruction of the dermis with a cultured epidermal autograft (CEA). The issue with this treatment is the unstable survival of CEA on the inactivated dermis. In this study, we applied collagen/gelatin sponge (CGS), which can sustain the release of basic fibroblast growth factor (bFGF), to the inactivated skin in order to accelerate angiogenesis. Murine skin grafts from C57BL6J/Jcl mice (8 mm in diameter) were prepared, inactivated by HHP and cryopreserved. One month later, the grafts were transplanted subcutaneously onto the back of other mice and covered by CGS impregnated with saline or bFGF. Grafts were taken after one, two and eight weeks, at which point the survival was evaluated through the histology and angiogenesis-related gene expressions were determined by real-time polymerase chain reaction. Histological sections showed that the dermal cellular density and newly formed capillaries in the bFGF group were significantly higher than in the control group. The relative expression of FGF-2, PDGF-A and VEGF-A genes in the bFGF group was significantly higher than in the control group at Week 1. This study suggested that the angiogenesis into grafts was accelerated, which might improve the survival in combination with the sustained release of bFGF by CGSs.
The cost of being stable: Trade-offs between effort and stability across a landscape of redundant motor solutions
Authors: Sohn M. Hongchul , Ting Lena H.
Published: November 2018

Current musculoskeletal modeling approaches cannot account for variability in muscle activation patterns seen across individuals, who may differ in motor experience, motor training, or neurological health. While musculoskeletal simulations typically select muscle activation patterns that minimize muscular effort, and generate unstable limb dynamics, a few studies have shown that maximum-effort solutions can improve limb stability. Although humans and animals likely adopt solutions between these two extremes, we lack principled methods to explore how effort and stability shape how muscle activation patterns differ across individuals. Here we characterized trade-offs between muscular effort and limb stability in selecting muscle activation patterns for an isometric force generation task in a musculoskeletal model of the cat hindlimb. We define effort as the sum of squared activation across all muscles, and limb stability by the maximum real part of the eigenvalues of the linearized musculoskeletal system dynamics, with more negative values being more stable. Surprisingly, stability increased rapidly with only small increases in effort from the minimum-effort solution, suggesting that very small amounts of muscle coactivation are beneficial for postural stability. Further, effort beyond 40% of the maximum possible effort did not confer further increases in stability. We also found multiple muscle activation patterns with equivalent effort and stability, which could underlie variability observed across individuals with similar motor ability. Trade-off between muscle effort and limb stability could underlie diversity in muscle activation patterns observed across individuals, disease, learning, and rehabilitation.

Author summary

Current computational musculoskeletal models select muscle activation patterns that minimize the amount of muscle activity used to generate a movement, creating unstable limb dynamics. However, experimentally, muscle activation patterns with various level of co-activation are observed for performing the same task both within and across individuals that likely help to stabilize the limb. Here we show that a trade-off between muscular effort and limb stability across the wide range of possible muscle activation patterns for a motor task could explain the diversity of muscle activation patterns seen across individuals, disease, learning and rehabilitation. Increased muscle activity is necessary to stabilize the limb, but could also limit the ability to learn new muscle activation pattern, potentially providing a mechanism to explain individual-specific muscle coordination patterns in health and disease. Finally, we provide a straightforward method for improving the physiological relevance of muscle activation pattern and musculoskeletal stability in simulations.
Multilayered gene control drives timely exit from the stem cell state in uncommitted progenitors during Drosophila asymmetric neural stem cell division
Authors: Komori Hideyuki , Golden Krista L. , Kobayashi Taeko , Kageyama Ryoichiro , Lee Cheng-Yu
Published: November 2018

Self-renewal genes maintain stem cells in an undifferentiated state by preventing the commitment to differentiate. Robust inactivation of self-renewal gene activity following asymmetric stem cell division allows uncommitted stem cell progeny to exit from an undifferentiated state and initiate the commitment to differentiate. Nonetheless, how self-renewal gene activity at mRNA and protein levels becomes synchronously terminated in uncommitted stem cell progeny is unclear. We demonstrate that a multilayered gene regulation system terminates self-renewal gene activity at all levels in uncommitted stem cell progeny in the fly neural stem cell lineage. We found that the RNA-binding protein Brain tumor (Brat) targets the transcripts of a self-renewal gene, deadpan (dpn), for decay by recruiting the deadenylation machinery to the 3′ untranslated region (UTR). Furthermore, we identified a nuclear protein, Insensible, that complements Cullin-mediated proteolysis to robustly inactivate Dpn activity by limiting the level of active Dpn through protein sequestration. The synergy between post-transcriptional and transcriptional control of self-renewal genes drives timely exit from the stem cell state in uncommitted progenitors. Our proposed multilayered gene regulation system could be broadly applicable to the control of exit from stemness in all stem cell lineages.
In situdetection of a novel lysozyme monoclinic crystal form upon controlled relative humidity variation
Authors: Trampari S. , Valmas A. , Logotheti S. , Saslis S. , Fili S. , Spiliopoulou M. , Beckers D. , Degen T. , Nénert G. , Fitch A. N. , Calamiotou M. , Karavassili F. , Margiolaki I.
Published: November 2018

The effect of relative humidity (rH) on protein crystal structures, an area that has attracted high scientific interest during the past decade, is investigated in this study on hen egg-white lysozyme (HEWL) polycrystalline precipitatesvia in situlaboratory X-ray powder diffraction (XRPD) measurements. For this purpose, HEWL was crystallized at room temperature and pH 4.5, leading to a novel monoclinic HEWL phase which, to our knowledge, has not been reported before. Analysis of XRPD data collected upon rH variation revealed several structural modifications. These observations, on a well-studied molecule like HEWL, underline not only the high impact of humidity levels on biological crystal structures, but also the significance of in-house XRPD as an analytical tool in industrial drug development and its potential to provide information for enhancing manufacturing of pharmaceuticals.
Misfit dislocations between boron-doped homoepitaxial films and diamond substrates studied by X-ray diffraction topography
Authors: González-Mañas Marina , Vallejo Beatriz
Published: November 2018

Boron-doped diamond epilayers grown over diamond substrates have a different lattice parameter from the undoped diamond substrate, which introduces a lattice mismatch between substrates and epilayers. This can generate misfit dislocations at the interface when the epilayer reaches a certain critical thickness. For a boron concentration of about 1 × 1020 atoms cm−3, the calculated lattice mismatch is about 1.3 × 10−4 and the critical thickness is of the order of 0.2 µm. In the epilayers studied, grown over high-pressure high-temperature 1b (001) substrates, the lattice mismatch and the epilayer thickness are 1.3 × 10−4, 30 µm and 6.5 × 10−4, 4 µm. The epitaxial strain has been relaxed by the generation of two orthogonal misfit dislocation systems. These are edge dislocations parallel to the [100] and [010] directions with a Burgers vector making an angle of 45° with the (001) interface. Their lengths are 40–60 µm and their lineal densities 200–240 cm−1. They are heterogeneously nucleated, propagated in the form of half-loops along the slip planes (011) and (101), respectively, and related mainly to 〈111〉 threading dislocations emerging from octahedral growth sectors. Another kind of half-loop originates from the substrate growth sector boundaries. Limited X-ray topography has been demonstrated to be a very useful tool to discriminate between substrate and epilayer defects when their lattice mismatch is not sufficient to separate such defects in conventional Lang topography. X-ray section topography has confirmed the presence of [001] dislocations in the epilayers and the misfit half-loops related to threading dislocations propagating from the interface.
Live-pig-airway surface imaging and whole-pig CT at the Australian Synchrotron Imaging and Medical Beamline
Authors: Donnelley Martin , Morgan Kaye S. , Gradl Regine , Klein Mitzi , Hausermann Daniel , Hall Chris , Maksimenko Anton , Parsons David W.
Published: November 2018

The Australian Synchrotron Imaging and Medical Beamline (IMBL) was designed to be the world's widest synchrotron X-ray beam, partly to enable clinical imaging and therapeutic applications for humans, as well as for imaging large-animal models. Our group is currently interested in imaging the airways of newly developed cystic fibrosis (CF) animal models that display human-like lung disease, such as the CF pig. One key outcome measure for assessing the effectiveness of CF airway therapies is the ability of the lung to clear inhaled particulates by mucociliary transit (MCT). This study extends the ex vivo sheep and pig tracheal-tissue studies previously performed by the authors at the IMBL. In the present study, attempts were made to determine whether the design of the IMBL is suitable for imaging tracheal MCT in live pigs. The movement of 200 µm-diameter high-refractive-index (HRI) glass-bead marker particles deposited onto the tracheal airway surface of eight live piglets was tracked and quantified and the MCT response to aerosol delivery was examined. A high-resolution computed tomographic (CT) whole-animal post-mortem scan of one pig was also performed to verify the large sample CT capabilities of the IMBL. MCT tracking particles were visible in all animals, and the automated MCT tracking algorithms used were able to identify and track many particles, but accuracy was reduced when particles moved faster than ∼6 mm min−1 (50 pixels between exposures), or when the particles touched or overlapped. Renderings were successfully made from the CT data set. Technical issues prevented use of reliable shuttering and hence radiation doses were variable. Since dose must be carefully controlled in future studies, estimates of the minimum achievable radiation doses using this experiment design are shown. In summary, this study demonstrated the suitability of the IMBL for large-animal tracheal MCT imaging, and for whole-animal CT.
In situ semi-quantitative analysis of zinc dissolution within nanoporous silicon by X-ray absorption fine-structure spectroscopy employing an X-ray compatible cell
Authors: Muñoz-Noval Álvaro , Fukami Kazuhiro , Koyama Akira , Kuruma Takuya , Hayakawa Shinjiro
Published: November 2018

The in situ study of the discharge process in a zinc-based half-cell employing a porous electrode as a structural scaffold is reported. The in situ characterization has been performed by synchrotron X-ray absorption fine-structure spectroscopy and, for this purpose, an inexpensive, simple and versatile electrochemical cell compatible with X-ray experiments has been designed and described. The experimental results reported here have been employed to semi-quantify the dissolved and undissolved zinc species during the discharge, allowing the cell feasibility to be tested and to better understand the functioning of the zinc half-cell based on porous electrodes.