Contributors:Tom Ferrante, Dana Braff, Melina Fan, Lee Gehrke, James J. Collins, Alexander A. Green, Dawn M. Dudley, Nina Donghia, David H. O’Connor, Melissa K. Takahashi, Irene Bosch, Guillaume Lambert, Jeong Wook Lee, Nichole M. Daringer, Keith Pardee, Duo Ma
The recent Zika virus outbreak highlights the need for low-cost diagnostics that can be rapidly developed for distribution and use in pandemic regions. Here, we report a pipeline for the rapid design, assembly, and validation of cell-free, paper-based sensors for the detection of the Zika virus RNA genome. By linking isothermal RNA amplification to toehold switch RNA sensors, we detect clinically relevant concentrations of Zika virus sequences and demonstrate specificity against closely related Dengue virus sequences. When coupled with a novel CRISPR/Cas9-based module, our sensors can discriminate between viral strains with single-base resolution. We successfully demonstrate a simple, field-ready sample-processing workflow and detect Zika virus from the plasma of a viremic macaque. Our freeze-dried biomolecular platform resolves important practical limitations to the deployment of molecular diagnostics in the field and demonstrates how synthetic biology can be used to develop diagnostic tools for confronting global health crises.
Contributors:Tyler Jacks, Paolo Sassone-Corsi, Pierre Baldi, Marlene Cervantes, Kenichiro Kinouchi, Selma Masri, Thales Papagiannakopoulos, Yu Liu
The circadian clock controls metabolic and physiological processes through finely tuned molecular mechanisms. The clock is remarkably plastic and adapts to exogenous “zeitgebers,” such as light and nutrition. How a pathological condition in a given tissue influences systemic circadian homeostasis in other tissues remains an unanswered question of conceptual and biomedical importance. Here, we show that lung adenocarcinoma operates as an endogenous reorganizer of circadian metabolism. High-throughput transcriptomics and metabolomics revealed unique signatures of transcripts and metabolites cycling exclusively in livers of tumor-bearing mice. Remarkably, lung cancer has no effect on the core clock but rather reprograms hepatic metabolism through altered pro-inflammatory response via the STAT3-Socs3 pathway. This results in disruption of AKT, AMPK, and SREBP signaling, leading to altered insulin, glucose, and lipid metabolism. Thus, lung adenocarcinoma functions as a potent endogenous circadian organizer (ECO), which rewires the pathophysiological dimension of a distal tissue such as the liver.
Contributors:Miguel Carvalho, Rui Silva, José Antunes, Vincent Debut, Elin Figueiredo
The bell from the church of S. Pedro de Coruche is one rare surviving example of early bells, cast during the 13th century in Europe, which was exhumed from a crypt-ossuary in an archaeological excavation carried out near Lisbon in Portugal. Of particular significance, it is believed to belong to a time period during which bell's profile has evolved noticeably, leading to bells with fine musical qualities and a well-defined sense of pitch. If the bell from Coruche was a tangible piece of evidence for tracing the history of bell casting in Europe, it had however lost all trace of its original sound: indeed the bell was found broken and incomplete and even if it has undergone a restoration process since the archaeological discovery, the use of an adhesive during the reassembly has changed somehow the vibrational properties of the bell structure. To bring back to life the sound of this broken musical artefact, a methodology combining experimental and numerical techniques from materials science and music acoustics is described in this paper. The general approach comprises material characterisation, geometrical measurements, modal analysis and physics-based sound synthesis techniques. By coupling a physical dynamical model of a bell impacted by a clapper with the modal properties of the original bell computed by Finite Element Analysis, realistic time-domain simulations of the Coruche bell dynamics were performed and realistic synthetic sounds were produced. As the original clapper has not survived, parametric computations have been performed to illustrate the changes in bell sounds associated with clappers of different mechanical properties. The overall approach provides insight into the tuning of this medieval bell which can be compared to the modern-type tuning, and reproduce the sound that the bell from Coruche might have had. The strategy developed can be easily adapted to other musical instruments in poor/variable states of preservation, therefore benefiting the importance of such non-renewable cultural resources.
Contributors:Juan J. Sendra, Rafael Suárez, Alicia Alonso
Some major historical heritage which has disappeared over time can currently be recovered in part thanks to computer modeling tools and virtual reality technologies. Incorporating sensory experience using immaterial reconstruction constitutes a new form of knowledge and a major methodological change in the field of cultural heritage. Archaeoacoustics are used to introduce phenomenology as a new method for the analysis of historical heritage, allowing evaluation of the sound quality of a space based on subjective perception by using auralization techniques which allow cognitive and physical elements to be reproduced and combined. This study assess and recover the acoustics of a now extinct major religious space: the Maior Ecclesia in Cluny, recognised as European heritage. Its long reverberation times produced a grandiose acoustic experience of Gregorian chant, heightening spirituality. Its extensive choir served as a place of spatial reference, because of its location in the temple and its major role in the liturgy. It could be defined as an ecclesiola in ecclesia with an identity of its own. The sound of the Gregorian chant of the monks was perceived clearly and powerfully within this space. However, the high reverberance perceived in the rest of the spaces of the church transformed the chant into an unintelligible, inaudible signal.
Contributors:Elena V. Volodina, Vera A. Matrosova, Hanna V. Rashevska, Olga N. Shekarova, Ludmila E. Savinetskaya, Ilya A. Volodin, Svetlana V. Proyavka, Mikhail Yu. Rusin
Alarm calls of ground squirrels are innate signals, showing substantial geographical variation across populations without the masking effects of sex and age- related variation. This makes them a convenient model for studying population genetic effects on the evolution of alarm communication. We compared data on the alarm call structure and the mitochondrial DNA (mtDNA) complete control region (C-region) (998–1002bp) polymorphism in the same 90 individual speckled ground squirrels (Spermophilus suslicus) across 6 populations (15 individuals per population), separated by distances from 12 to 1274km. We calculated acoustic distances between each pair of populations based on acoustic variables of alarm calls, averaged for each individual using Euclidean distances of population centroids, in the space of canonical axes of discriminant function analysis. Genetic distances ranged of 0–1.1% within populations and of 0.5–4.9% between populations. Prominent differences were found between eastern and western populations separated by the Dnieper River. Both genetic and acoustic distances showed a significant positive correlation with geographical among populations. Positive correlation between acoustic and genetic distances did not reach significance. These results support effects of ecological selection on the alarm call variables rather than the genetic drift hypothesis. In addition, these results support the current taxonomic separation between subspecies of speckled ground squirrels differing in diploid chromosome sets 2n=34 (Spermophilus suslicus guttatus) and 2n=36 (Spermophilus suslicus odessanus).
Contributors:Grega Repovš, Bruno Gingras, Anka Slana, W. Tecumseh Fitch
The context in which a stimulus is presented shapes the way it is processed. This effect has been studied extensively in the field of visual perception. Our understanding of how context affects the processing of auditory stimuli is, however, rather limited. Western music is primarily built on melodies (succession of pitches) typically accompanied by chords (harmonic context), which provides a natural template for the study of context effects in auditory processing. Here, we investigated whether pitch class equivalence judgments of tones are affected by the harmonic context within which the target tones are embedded. Nineteen musicians and 19 non-musicians completed a change detection task in which they were asked to determine whether two successively presented target tones, heard either in isolation or with a chordal accompaniment (same or different chords), belonged to the same pitch class. Both musicians and non-musicians were most accurate when the chords remained the same, less so in the absence of chordal accompaniment, and least when the chords differed between both target tones. Further analysis investigating possible mechanisms underpinning these effects of harmonic context on task performance revealed that both a change in gestalt (change in either chord or pitch class), as well as incongruency between change in target tone pitch class and change in chords, led to reduced accuracy and longer reaction times. Our results demonstrate that, similarly to visual processing, auditory processing is influenced by gestalt and congruency effects.
Contributors:Joyce Chua, Edward Menon, Jane Culpan
To evaluate the longer-term effects of electromechanical gait trainers (GTs) combined with conventional physiotherapy on health status, function, and ambulation in people with subacute stroke in comparison with conventional physiotherapy given alone.
Contributors:Derek Blankenship, Shaheen Kahn, Peter Acs, Jose Rossello-Urgell, Jacob Turner, Seunghee Hong, Romain Banchereau, Gerlinde Obermoser, Virginia Pascual, Esperanza Anguiano, Alma-Martina Cepika, Alisa Gotte, Nicole Baldwin, Marilynn Punaro, Yong-Jun Liu, Parvathi Vinod, Jeanine Baisch, Brandi Cantarel, Tracey Wright, Edward Wakeland, Jacques Banchereau, Lorien Nassi, Michelle Edens
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to nucleic acids and highly diverse clinical manifestations. To assess its molecular heterogeneity, we longitudinally profiled the blood transcriptome of 158 pediatric patients. Using mixed models accounting for repeated measurements, demographics, treatment, disease activity (DA), and nephritis class, we confirmed a prevalent IFN signature and identified a plasmablast signature as the most robust biomarker of DA. We detected gradual enrichment of neutrophil transcripts during progression to active nephritis and distinct signatures in response to treatment in different nephritis subclasses. Importantly, personalized immunomonitoring uncovered individual correlates of disease activity that enabled patient stratification into seven groups, supported by patient genotypes. Our study uncovers the molecular heterogeneity of SLE and provides an explanation for the failure of clinical trials. This approach may improve trial design and implementation of tailored therapies in genetically and clinically complex autoimmune diseases.