bluuebunny/crossref_metadata_2025 huggingface dataset:
A young age of subspecific divergence in the desert locustSchistocerca gregaria, inferred by ABC Random Forest
Authors: Chapuis Marie-Pierre , Raynal Louis , Plantamp Christophe , Meynard Christine N. , Blondin Laurence , Marin Jean-Michel , Estoup Arnaud
Published: June 2019

Abstract

Dating population divergence within species from molecular data and relating such dating to climatic and biogeographic changes is not trivial. Yet it can help formulating evolutionary hypotheses regarding local adaptation and future responses to changing environments. Key issues include statistical selection of a demographic and historical scenario among a set of possible scenarios, and estimation of the parameter(s) of interest under the chosen scenario. Such inferences greatly benefit from new statistical approaches including approximate Bayesian computation - Random Forest (ABC-RF), the latter providing reliable inference at a low computational cost, with the possibility to take into account prior knowledge on both biogeographical history and genetic markers. Here, we used ABC-RF, including independent information on evolutionary rate and pattern at microsatellite markers, to decipher the evolutionary history of the African arid-adapted pest locust,Schistocerca gregaria. We found that the evolutionary processes that have shaped the present geographical distribution of the species in two disjoint northern and southern regions of Africa were recent, dating back 2.6 Ky (90% CI: 0.9 – 6.6 Ky). ABC-RF inferences also supported a southern colonization of Africa from a low number of founders of northern origin. The inferred divergence history is better explained by the peculiar biology ofS. gregaria, which involves a density-dependent swarming phase with some exceptional spectacular migrations, rather than a continuous colonization resulting from the continental expansion of open vegetation habitats during more ancient Quaternary glacial climatic episodes.
TrkB-expressing paraventricular hypothalamic neurons suppress appetite through multiple neurocircuits
Authors: An Juan Ji , Kinney Clint E. , Liao Guey-Ying , Kremer Eric J. , Xu Baoji
Published: June 2019

The TrkB receptor is critical for the control of energy balance, as mutations in its gene (NTRK2) lead to hyperphagia and severe obesity in humans and mice. The main neural substrate mediating the appetite-suppressing activity of TrkB, however, remains unknown. Here, we demonstrate that selective Ntrk2 deletion within the paraventricular hypothalamus (PVH) leads to severe hyperphagic obesity. Furthermore, chemogenetic activation or inhibition of TrkB-expressing PVH (PVHTrkB) neurons suppresses or increases food intake, respectively. PVHTrkB neurons project to multiple brain regions, including the ventromedial hypothalamus (VMH) and the lateral parabrachial nucleus (LPBN). We found that PVHTrkB neurons projecting to LPBN are distinct from those projecting to VMH, yet Ntrk2 deletion in PVH neurons projecting to either VMH or LPBN results in hyperphagia and obesity. Therefore, TrkB signaling is a key regulator of a previously uncharacterized and heterogenous neuronal population within the PVH that impinges upon multiple circuits to govern appetite.
Preferential phosphatidylinositol 5-phosphate binding contributes to a destabilization of the VHS domain structure of Tom1
Authors: Xiong Wen , Tang Tuo-Xian , Littleton Evan , Karcini Arba , Lazar Iulia M. , Capelluto Daniel G. S.
Published: June 2019

Tom1 transports endosomal ubiquitinated proteins that are targeted for degradation in the lysosomal pathway. Infection of eukaryotic cells byShigella flexneriboosts oxygen consumption and promotes the synthesis of phosphatidylinositol-5-phosphate [PtdIns5P], which triggers Tom1 translocation to signaling endosomes. Removing Tom1 from its cargo trafficking function hinders protein degradation in the host and, simultaneously, enables bacterial survival. Tom1 preferentially binds PtdIns5Pviaits VHS domain, but the effects of a reducing environment as well as PtdIns5P on the domain structure and function are unknown. Thermal denaturation studies demonstrate that, under reducing conditions, the monomeric Tom1 VHS domain switches from a three-state to a two-state transition behavior. PtdIns5P reduced thermostability, interhelical contacts, and conformational compaction of Tom1 VHS, suggesting that the phosphoinositide destabilizes the protein domain. Destabilization of Tom1 VHS structure was also observed with other phospholipids. Isothermal calorimetry data analysis indicates that, unlike ubiquitin, Tom1 VHS endothermically binds to PtdIns5P through two noncooperative binding sites, with its acyl chains playing a relevant role in the interaction. Altogether, these findings provide mechanistic insights about the recognition of PtdIns5P by the VHS domain that may explain how Tom1, when in a different VHS domain conformational state, interacts with downstream effectors underS. flexneriinfection.
Inferring the collective dynamics of neuronal populations from single-trial spike trains using mechanistic models
Authors: Donner Christian , Opper Manfred , Ladenbauer Josef
Published: June 2019

Multi-neuronal spike-train data recorded in vivo often exhibit rich dynamics as well as considerable variability across cells and repetitions of identical experimental conditions (trials). Efforts to characterize and predict the population dynamics and the contributions of individual neurons require model-based tools. Abstract statistical models allow for principled parameter estimation and model selection, but possess only limited interpretive power because they typically do not incorporate prior biophysical constraints. Here we present a statistically principled approach based on a population of doubly-stochastic integrate-and-fire neurons, taking into account basic biophysics. This model class comprises an idealized description for the dynamics of the neuronal membrane voltage in response to fast independent and slower shared input fluctuations. To efficiently estimate the model parameters and compare different model variants we compute the likelihood of observed single-trail spike trains by leveraging analytical methods for spiking neuron models combined with inference techniques for hidden Markov models. This allows us to reconstruct the shared input variations, classify their dynamics, obtain precise spike rate estimates, and quantify how individual neurons couple to the low-dimensional overall population dynamics, all from a single trial. Extensive evaluations based on simulated data show that our method correctly identifies the dynamics of the shared input process and accurately estimates the model parameters. Validations on ground truth recordings of neurons in vitro demonstrate that our approach successfully reconstructs the dynamics of hidden inputs and yields improved fits compared to a typical phenomenological model. Finally, we apply the method to a neuronal population recorded in vivo, for which we assess the contributions of individual neurons to the overall spiking dynamics. Altogether, our work provides statistical inference tools for a class of reasonably constrained, mechanistic models and demonstrates the benefits of this approach to analyze measured spike train data.
Probabilistic representation in human visual cortex reflects uncertainty in serial decisions
Authors: van Bergen R.S. , Jehee J.F.M.
Published: June 2019

How does the brain represent the reliability of its sensory evidence? Here, we test whether sensory uncertainty is encoded in cortical population activity as the width of a probability distribution – a hypothesis that lies at the heart of Bayesian models of neural coding. We probe the neural representation of uncertainty by capitalizing on a well-known behavioral bias called serial dependence. Human observers of either sex reported the orientation of stimuli presented in sequence, while activity in visual cortex was measured with fMRI. We decoded probability distributions from population-level activity and found that serial dependence effects in behavior are consistent with a statistically advantageous sensory integration strategy, in which uncertain sensory information is given less weight. More fundamentally, our results suggest that probability distributions decoded from human visual cortex reflect the sensory uncertainty that observers rely on in their decisions, providing critical evidence for Bayesian theories of perception.
Archaeal ribosomal proteins possess nuclear localization signal-type motifs: implications for the origin of the cell nucleus
Authors: Melnikov Sergey , Kwok Hui-Si , Manakongtreecheep Kasidet , van den Elzen Antonia , Thoreen Carson C. , Söll Dieter
Published: June 2019

Abstract

Eukaryotic cells are divided into the nucleus and the cytosol, and, to enter the nucleus, proteins typically possess short signal sequences, known as nuclear localization signals (NLSs). Although NLSs have long been considered as features unique to eukaryotic proteins, we show here that similar or identical protein segments are present in ribosomal proteins from the Archaea. Specifically, the ribosomal proteins uL3, uL15, uL18, and uS12 possess NLS-type motifs that are conserved across all major branches of the Archaea, including the most ancient groups Microarchaeota and Diapherotrites, pointing to the ancient origin of NLS-type motifs in the Archaea. Furthermore, by using fluorescence microscopy, we show that the archaeal NLS-type motifs can functionally substitute eukaryotic NLSs and direct the transport of ribosomal proteins into the nuclei of human cells. Collectively, these findings illustrate that the origin of NLSs preceded the origin of the cell nucleus, suggesting that the initial function of NLSs was not related to intracellular trafficking. Overall, our study reveals rare evolutionary intermediates among archaeal cells that can help elucidate the sequence of events that led to the origin of the eukaryotic cell.
Magnetic-alignment of polymer macro-nanodiscs enable residual dipolar couplings based high-resolution structural studies by NMR
Authors: Ravula Thirupathi , Ramamoorthy Ayyalusamy
Published: June 2019

Residual dipolar couplings (RDCs) have been shown to be valuable for the structural studies of systems ranging from small molecules to large proteins. Here we demonstrate the lyotropic liquid crystal behavior of polymer macro-nanodiscs (> 20 nm in diameter) and enable the measurement of RDCs using high resolution NMR.
Reversal learning performance in the XY* mouse model of Klinefelter and Turner Syndromes
Authors: Aarde Shawn M. , Hrncir Haley , Arnold Arthur P. , Jentsch J. David
Published: June 2019

Klinefelter syndrome (KS; 47, XXY) and Turner syndrome (TS; 45, XO) are caused by two relatively common sex chromosome aneuploidies. These conditions are associated with an increased odds of neuropsychiatric disorders, including attention deficit/hyperactivity disorder (ADHD), as well as impairments in cognition that include learning delays, attentional dysfunction and impulsivity. We studied cognitive functions in the XY* mouse model, which allows comparison of XXY to XY males (KS model), and XO to XX females (TS model). We evaluated adult mice with and without gonads, using a version of an operant reversal-learning task (RLT) that can be used to measure various facets of learning, impulsivity and attention. In the KS model, only one measure related to impulsivity – perseverative responding under reversal conditions – reliably discriminated gonadally intact XXY and XY mice. In contrast, a fundamental learning impairment (more trials to criterion in acquisition phase) in XXY mice, as compared to XY, was observed in gonadectomized subjects. No other task measures showed differences consistent with KS. In the TS mouse model, XO mice did not show a pattern of results consistent with TS, similar to past observations. Thus, the application of this RLT to these XY* models reveals only limited behavioral impairments relevant to KS.
A neurally plausible model for online recognition and postdiction in a dynamical environment
Authors: Wenliang Li Kevin , Sahani Maneesh
Published: June 2019

Humans and other animals are frequently near-optimal in their ability to integrate noisy and ambiguous sensory data to form robust percepts, which are informed both by sensory evidence and by prior experience about the causal structure of the environment. It is hypothesized that the brain establishes these structures using an internal model of how the observed patterns can be generated from relevant but unobserved causes. In dynamic environments, such integration often takes the form of postdiction, wherein later sensory evidence affects inferences about earlier percepts. As the brain must operate in current time, without the luxury of acausal propagation of information, how does such postdictive inference come about? Here, we propose a general framework for neural probabilistic inference in dynamic models based on the distributed distributional code (DDC) representation of uncertainty, naturally extending the underlying encoding to incorporate implicit probabilistic beliefs about both present and past. We show that, as in other uses of the DDC, an inferential model can be learned efficiently using samples from an internal model of the world. Applied to stimuli used in the context of psychophysics experiments, the framework provides an online and plausible mechanism for inference, including postdictive effects.
Challenging the boundaries of the physical self: purely distal cues in the environment impact body ownership
Authors: Grechuta Klaudia , De La Torre Javier , Ballester Belén Rubio , Verschure Paul F.M.J.
Published: June 2019

The unique ability to identify one’s own body and experience it as one’s own is fundamental in goal-oriented behavior and survival. However, the mechanisms underlying the so-called body ownership are yet not fully understood. The plasticity of body ownership has been studied using two experimental methods or their variations. Specifically, the Rubber Hand Illusion (RHI), where the tactile stimuli are externally generated, or the moving RHI which implies self-initiated movements. Grounded in these paradigms, evidence has demonstrated that body ownership is a product of bottom-up reception of self- and externally-generated multisensory information and top-down comparison between the predicted and the actual sensory stimuli. Crucially, provided the design of the current paradigms, where one of the manipulated cues always involves the processing of a proximal modality sensing the body or its surface (e.g., touch), the contribution of sensory signals which pertain to the environment remain elusive. Here we propose that, as any robust percept, body ownership depends on the integration and prediction of all the sensory stimuli, and therefore it will depend on the consistency of purely distal sensory signals pertaining to the environment. To test our hypothesis, we create an embodied goal-oriented task and manipulate the predictability of the surrounding environment by changing the congruency of purely distal multisensory cues while preserving bodily and action-driven signals entirely predictable. Our results empirically reveal that the way we represent our body is contingent upon all the sensory stimuli including purely distal and action-independent signals which pertain to the environment.
Nitrogen Fertilisers Shape the Composition and Predicted Functions of the Microbiota of Field-Grown Tomato Plants
Authors: Caradonia Federica , Ronga Domenico , Catellani Marcello , Azevedo Cleber Vinícius Giaretta , Terrazas Rodrigo Alegria , Robertson-Albertyn Senga , Francia Enrico , Bulgarelli Davide
Published: June 2019

The microbial communities thriving at the root-soil interface have the potential to improve plant growth and sustainable crop production. Yet, how agricultural practices, such as the application of either mineral or organic nitrogen fertilisers, impact on the composition and functions of these communities remains to be fully elucidated. By deploying a two-pronged 16S rRNA gene sequencing and predictive metagenomics approach we demonstrated that the bacterial microbiota of field-grown tomato (Solanum lycopersicum) plants is the product of a selective process that progressively differentiates between rhizosphere and root microhabitats. This process initiates as early as plants are in a nursery stage and it is then more marked at late developmental stages, in particular at harvest. This selection acts on both the bacterial relative abundances and phylogenetic assignments, with a bias for the enrichment of members of the phylum Actinobacteria in the root compartment. Digestate-based and mineral-based nitrogen fertilisers trigger a distinct bacterial enrichment in both rhizosphere and root microhabitats. This compositional diversification mirrors a predicted functional diversification of the root-inhabiting communities, manifested predominantly by the differential enrichment of genes associated to ABC transporters and the two-component system. Together, our data suggest that the microbiota thriving at the tomato root-soil interface is modulated by and in responses to the type of nitrogen fertiliser applied to the field.
Impact of narrow spectrum Penicillin V on the oral and fecal resistome in a young child treated for otitis media
Authors: Sturød Kjersti , Dhariwal Achal , Dahle Ulf R , Vestrheim Didrik F , Petersen Fernanda C
Published: June 2019

Background

Antibiotic overuse has led to a global emergence of resistant bacteria, and children are among the frequent users. Most studies with broad-spectrum antibiotics show severe impact on the resistome development of patients. Although narrow-spectrum antibiotics are believed to have less side-effects, their impact on the microbiome and resistome is mostly unknown. The aim of this study was to investigate the impact of the narrow-spectrum antibiotic phenoxymethylpenicillin (Penicillin V) on the microbiome and resistome of a child treated for acute otitis media (OM).

Methods

Oral and fecal samples were collected from a one-year child before (day 0) and after (day 5 and 30) receiving Penicillin V against OM. Metagenomic sequencing data was analysed to determine taxonomic profiling, using Kraken and Bracken software, and resistance profiling, using KMA in combination with the ResFinder database.

Results

In the oral samples, 11 antimicrobial resistance genes (ARGs), belonging to four classes, were identified at baseline. At day 5, the abundance of some ARGs was increased, some remained unchanged, while others disappeared. At day 30, most ARGs had returned to baseline levels, or lower. In the fecal samples we observed seven ARGs at baseline and five at day 5, with only one gene observed at day 5 being present at baseline. At day 30 the number of ARGs increased to 21 ARGs from 7 different classes.

Conclusions

Penicillin V had a remarkable impact on the fecal resistome indicating that even narrow-pectrum antibiotics may have important consequences in selecting for a more resistant microbiome.
Multiple conformations facilitate PilT function in the type IV pilus
Authors: McCallum Matthew , Benlekbir Samir , Nguyen Sheryl , Tammam Stephanie , Rubinstein John L. , Burrows Lori L. , Howell P. Lynne
Published: June 2019

Type IV pilus-like systems are protein complexes that polymerize a fibre of pilins. They are critical for virulence in many pathogens. Pilin polymerization and depolymerization are powered by motor PilT-like ATPases thought to possess C2 symmetry. However, most PilT-like ATPases crystallize with either C3 or C6 symmetry and the relevance of these conformations is unclear. Here we determined the X-ray structures of PilT in four unique conformations and used these structures to classify the conformation of available PilT-like ATPase structures. Single particle electron cryomicroscopy (cryoEM) structures of PilT revealed condition-dependent preferences for C2,C3, and C6 conformations. The physiologic importance of these conformations was validated by co-evolution analysis and functional studies of point mutants, identifying a rare gain-of-function mutation that favours the C2 conformation. With these data we propose a comprehensive model of PilT function with broad implications for PilT-like ATPases.
siQ-ChIP: A reverse-engineered quantitative framework for ChIP-sequencing
Authors: Dickson Bradley M , Tiedemann Rochelle L , Chomiak Alison A , Vaughan Robert M , Cornett Evan M , Rothbart Scott B
Published: June 2019

Chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) is a key technique for mapping the distribution and relative abundance of histone posttranslational modifications (PTMs) and chromatin-associated factors across genomes. There is a perceived challenge regarding the ability to quantitatively plot ChIP-seq data, and as such, approaches making use of exogenous additives, or “spike-ins” have recently been developed. Relying on the fact that the IP step of ChIP-seq is a competitive binding reaction, we present a quantitative framework for ChIP-seq analysis that circumvents the need to modify standard sample preparation pipelines with spike-in reagents. We also introduce a visualization technique that, when paired with our formal developments, produces a much more rich characterization of sequencing data.
Barcoding biological reactions with DNA-functionalized vesicles
Authors: Peruzzi Justin A. , Jacobs Miranda L. , Vu Timothy Q. , Kamat Neha P.
Published: June 2019

Targeted vesicle fusion is a promising approach to selectively control interactions between vesicle compartments and would enable the initiation of biological reactions in complex aqueous environments. Here, we explore how two features of vesicle membranes, DNA tethers and phase-segregated membranes, promote fusion between specific vesicle populations. We show that membrane phase-segregation provides an energetic driver for membrane fusion that increases the efficiency of DNA-mediated fusion events. Using this system, we show that orthogonality provided by DNA tethers allows us to direct fusion and delivery of DNA cargo to specific vesicle populations. We then demonstrate that vesicle fusion between DNA-tethered vesicles can be used to initiatein vitroprotein expression that leads to the synthesis of model soluble and membrane proteins. The ability to engineer orthogonal fusion events between DNA-tethered vesicles will provide a new strategy to control the spatio-temporal dynamics of cell-free reactions, expanding opportunities to engineer artificial cellular systems.
The structure of a calsequestrin filament reveals mechanisms of familial arrhythmia
Authors: Titus Erron W. , Deiter Frederick H. , Shi Chenxu , Wojciak Julianne , Scheinman Melvin , Jura Natalia , Deo Rahul C.
Published: June 2019

Mutations in the calcium-binding protein calsequestrin cause a highly lethal familial arrhythmia, catecholaminergic polymorphic ventricular tachycardia (CPVT). In vivo, calsequestrin multimerizes into filaments, but a compelling atomic-resolution structure of a calsequestrin filament is lacking. We report a crystal structure of a cardiac calsequestrin filament with supporting mutation analysis provided by anin vitrofomentation assay. We also report and characterize a novel disease-associated calsequestrin mutation, S173I, which localizes to the filament-forming interface. In addition, we show that a previously reported dominant disease mutation, K180R, maps to the same multimerization surface. Both mutations disrupt filamentation, suggesting that dominant disease arises from defects in multimer formation. A ytterbium-derivatized structure pinpoints multiple credible calcium sites at filament-forming interfaces, explaining the atomic basis of calsequestrin filamentation in the presence of calcium. This work advances our understanding of calsequestrin biochemistry and provides a unifying structure-function molecular mechanism by which dominant-acting calsequestrin mutations provoke lethal arrhythmias.
Topoisomerases modulate the timing of meiotic DNA breakage and chromosome morphogenesis inSaccharomyces cerevisiae
Authors: Heldrich Jonna , Sun Xiaoji , Vale-Silva Luis A. , Markowitz Tovah E. , Hochwagen Andreas
Published: June 2019

During meiotic prophase, concurrent transcription, recombination, and chromosome synapsis, place substantial topological strain on chromosomal DNA, but the role of topoisomerases in this context remains poorly defined. Here, we analyzed the roles topoisomerases I and II (Top1 and Top2) during meiotic prophase inSaccharomyces cerevisiae. We show that both topoisomerases accumulate primarily in promoter-containing intergenic regions of actively transcribing genes. Enrichment partially overlaps meiotic double-strand break (DSB) hotspots, but disruption of either topoisomerase has different effects during meiotic recombination.TOP1disruption delays DSB induction and shortens the window of DSB accumulation by an unknown mechanism. By contrast, temperature-sensitivetop2-1mutants accumulate DSBs on synapsed chromosomes and exhibit a marked delay in meiotic chromosome remodeling. This defect results from a delay in recruiting the meiotic chromosome remodeler Pch2/TRIP13 but, unexpectedly, is not due to a loss of Top2 catalytic activity. Instead, mutant Top2-1 protein has reduced contact with chromatin but remains associated with meiotic chromosomes, and we provide evidence that this altered binding is responsible for the delay in chromosome remodeling. Our results imply independent roles for topoisomerases I and II in modulating meiotic recombination.
One-shot tagging during wake and cueing during sleep with spatiotemporal patterns of transcranial electrical stimulation can boost long-term metamemory of individual episodes in humans
Authors: Pilly Praveen K. , Skorheim Steven W. , Hubbard Ryan J. , Ketz Nicholas A. , Roach Shane M. , Jones Aaron P. , Robert Bradley , Bryant Natalie B. , Lerner Itamar , Hartholt Arno , Mullins Teagan S. , Choe Jaehoon , Clark Vincent P. , Howard Michael D.
Published: June 2019

Targeted memory reactivation (TMR) during slow-wave oscillations (SWOs) in non-rapid eye movement (NREM) sleep has been demonstrated with sensory cues to achieve about 5-12% improvement in post-nap memory performance on simple laboratory tasks. But prior work has neither addressed the one-shot aspect of episodic memory acquisition, nor dealt with the presence of interference from ambient environmental cues in real-world settings for the sensory cues. Moreover, TMR with sensory cues may not be scalable to the multitude of experiences over one’s lifetime. We designed a novel non-invasive paradigm that tags one-shot experiences of minute-long naturalistic episodes within immersive virtual reality (VR) with unique spatiotemporal amplitude-modulated patterns (STAMPs) of transcranial electrical stimulation (tES) and cues them during SWOs. In particular, we demonstrate that these STAMPs can be re-applied as brief pulses to temporally coincide with UP states of SWOs (0.4167 – 1 s) on two consecutive nights to achieve about 20% improvement in the metamemory of targeted episodes at 48 hours after the one-shot viewing, compared to the control episodes. Post-sleep metamemory of the targeted episodes was driven by an interaction between their pre-sleep metamemory and the number of STAMP applications for those episodes during sleep. Overnight metamemory improvements were mediated by spectral power increases from 6.18 to 6.7 s following the offset of STAMPs in the slow-spindle band (9-12 Hz) for left temporal areas in the scalp electroencephalography (EEG) during sleep. These results prescribe an optimal strategy to leverage STAMPs for boosting metamemory and suggest that real-world episodic memories can be modulated in a targeted manner even with coarser, non-invasive spatiotemporal stimulation.
DNA Punch Cards: Storing Data on Native DNA Sequences via Nicking
Authors: Tabatabaei S Kasra , Wang Boya , Athreya Nagendra Bala Murali , Enghiad Behnam , Hernandez Alvaro Gonzalo , Fields Christopher J. , Leburton Jean-Pierre , Soloveichik David , Zhao Huimin , Milenkovic Olgica
Published: June 2019

Synthetic DNA-based data storage systems have received significant attention due to the promise of ultrahigh storage density and long-term stability. However, all platforms proposed so far suffer from high cost, read-write latency and error-rates that render them noncompetitive with modern optical and magnetic storage devices. One means to avoid synthesizing DNA and to reduce the system error-rates is to use readily available native DNA. As the symbol/nucleotide content of native DNA is fixed, one may adopt an alternative recording strategy that modifies the DNA topology to encode desired information. Here, we report the first macromolecular storage paradigm in which data is written in the form of “nicks (punches)” at predetermined positions on the sugar-phosphate backbone of native dsDNA. The platform accommodates parallel nicking on multiple “orthogonal” genomic DNA fragments and paired nicking and disassociation for creating “toehold” regions that enable single-bit random access and strand displacement in-memory computations. As a proof of concept, we used the programmable restriction enzyme Pyrococcus furiosus Argonaute to punch two files into the PCR products of Escherichia coli genomic DNA. The encoded data is accurately reconstructed through high-throughput sequencing and read alignment.
Tissue-specific 3 prime-end adenylation of miR-125b mediates cell survival
Authors: Blahna Matthew T. , Neel Jean-Charles , Yu Ge , Louie Justin , Ghatpande Prajakta , Lagna Giorgio , Hata Akiko
Published: June 2019

Next-generation sequencing has uncovered microRNAs (miRNAs) that undergo sequence modifications, known as isomiRs. Their physiological significance, however, remains uncertain, partly because they generally comprise a small fraction of total miRNAs. Here we report that more than 60% of miR-125b, one of the most abundant miRNAs in vascular smooth muscle cells (vSMC), exists as an edited isoform containing a non-templated adenosine residue at the 3 prime-end (miR-125b+A). The properties of miR-125b+A, such as stability and subcellular localization, are similar to those of canonical miR-125b, but miR-125b+A more potently inhibits the expression of a subgroup of targets, including the apoptosis effector Caspase-6 (CASP6). In the CASP6 transcript, adenylated miR125b preferentially targets a conserved, atypical site, with an unusual 36 nucleotides loop between seed sequence and 3 prime-end supplementary site. PAP associated domain containing 2 (PAPD2) is responsible for monoadenylation of miR-125b. Downregulation of PAPD2 results in the conversion of miR-125b+A to miR-125b, derepression of CASP6, and sensitization of vSMC to apoptotic stimuli. Thus, atypical site recognition by a tissue-specific isomiR fulfills a pro-survival role.
Novel syngeneic animal model of tobacco-associated oral cancer reveals the activity of in situ anti-CTLA-4
Authors: Wang Zhiyong , Wu Victoria H. , Allevato Michael M. , Gilardi Mara , He Yudou , Callejas-Valera Juan Luis , Vitale-Cross Lynn , Martin Daniel , Amornphimoltham Panomwat , Mcdermott James , Goto Yusuke , Molinolo Alfredo A. , Sharabi Andrew B. , Cohen Ezra E. W. , Chen Qianming , Lyons J. Guy , Alexandrov Ludmil B. , Gutkind J. Silvio
Published: June 2019

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Tobacco use is the main risk factor for HNSCC, and tobacco-associated HNSCCs have poor prognosis and response to available treatments. Recently approved anti-PD-1 immune checkpoint inhibitors showed limited activity (≤20%) in HNSCC, highlighting the need to identify new therapeutic options. For this, mouse models that accurately reflect the complexity of the HNSCC mutational landscape and tumor immune environment are urgently needed. Here, we report the first mouse HNSCC model system that recapitulates the human tobacco-related HNSCC mutanome, in which tumors grow when implanted in the tongue of immunocompetent mice. These HNSCC lesions have similar immune infiltration and response rates to anti-PD-1 (≤20%) immunotherapy as human HNSCCs. Remarkably, we found that >70% of HNSCC lesions respond to intratumoral anti-CTLA-4. This syngeneic HNSCC mouse model provides a platform for the development of novel immunotherapeutic options for HNSCC.
Neural patterns reveal single-trial information on absolute pitch and relative pitch perception
Authors: Leipold Simon , Greber Marielle , Sele Silvano , Jäncke Lutz
Published: June 2019

Pitch is a fundamental attribute of sounds and yet is not perceived equally by all humans. Absolute pitch (AP) musicians perceive, recognize, and name pitches in absolute terms, whereas relative pitch (RP) musicians, representing the large majority of musicians, perceive pitches in relation to other pitches. In this study, we used electroencephalography (EEG) to investigate the neural representations underlying tone listening and tone labeling in a large sample of musicians (n = 105). Participants performed a pitch processing task with a listening and a labeling condition during EEG acquisition. Using a brain-decoding framework, we tested a prediction derived from both theoretical and empirical accounts of AP, namely that the representational similarity of listening and labeling is higher in AP musicians than in RP musicians. Consistent with the prediction, time-resolved single-trial EEG decoding revealed a higher representational similarity in AP musicians during late stages of pitch perception. Time-frequency-resolved EEG decoding further showed that the higher representational similarity was present in oscillations in the theta and beta frequency bands. Supplemental univariate analyses were less sensitive in detecting subtle group differences in the frequency domain. Taken together, the results suggest differences between AP and RP musicians in late pitch processing stages associated with cognition, rather than in early processing stages associated with perception.
Michael G. Rossmann (1930–2019), pioneer in macromolecular and virus crystallography: scientist, mentor and friend
Authors: Arnold Eddy , Wu Hao , Johnson John E.
Published: June 2019

Michael George Rossmann, who made monumental contributions to science, passed away peacefully in West Lafayette, Indiana on 14 May 2019 at the age of 88, following a courageous five-year battle with cancer. Michael was born in Frankfurt, Germany on 30 July 1930. As a young boy, he emigrated to England with his mother just as World War II ignited. Michael was a highly innovative and energetic person, well known for his intensity, persistence and focus in pursuing his research goals. Michael was a towering figure in crystallography as a highly distinguished faculty member at Purdue University for 55 years. Michael made many seminal contributions to crystallography in a career that spanned the entirety of structural biology, beginning in the 1950s at Cambridge where the first protein structures were determined in the laboratories of Max Perutz (hemoglobin, 1960) and John Kendrew (myoglobin, 1958). Michael's work was central in establishing and defining the field of structural biology, which amazingly has described the structures of a vast array of complex biological molecules and assemblies in atomic detail. Knowledge of three-dimensional biological structure has important biomedical significance including understanding the basis of health and disease at the molecular level, and facilitating the discovery of many drugs.
Simulation Analysis of Nonlinear Friction of Rod String in Sucker Rod Pumping System
Authors: Xing Mingming , Zhou Lili , Zhang Chengmao , Xue Kaifeng , Zhang Zhiyu
Published: June 2019

The nonlinear friction of rod string is an important foundation of dynamic simulation and efficiency optimization in sucker rod pumping system (SRPS). As we know, there are geometrical nonlinearity and contact nonlinearity of rod string in special oil well. Considering the earlier practical problems, a novel computational method of nonlinear friction of rod string is given. First, the simulation model of nonlinear friction is built. In the detail, the nonlinear friction of sucker rod string is made up of four parts: the viscous damping friction of rod surface, the viscous damping friction of rod coupling, liquid friction of centralizer, and the nonlinear Coulomb friction between rod and tube. Second, considering the rheology property of multiphase fluid in annular space, a simulation method of fluid pressure is proposed with software ansys. Based on earlier models, a numerical simulation model of nonlinear friction of rod string is built with visualbasic 6.0. Comparing experiment results with simulated results, good agreement is found, which shows the simulation model is feasible. The characteristics of fluid pressure and pressure gradient are analyzed. The instantaneous friction of rod string is simulated, and the sensitive factors of rod friction are analyzed. The novel simulation method solves the problem of environmental load calculation of large deformation rod. The analysis results have an important significance to guidance of optimization and design of SRPS.
Sensitivity Analysis for Hybrid Systems and Systems With Memory
Authors: Serban Radu , Recuero Antonio
Published: June 2019

We present an adjoint sensitivity method for hybrid discrete—continuous systems, extending previously published forward sensitivity methods (FSA). We treat ordinary differential equations (ODEs) and differential-algebraic equations (DAEs) of index up to two (Hessenberg) and provide sufficient solvability conditions for consistent initialization and state transfer at mode switching points, for both the sensitivity and adjoint systems. Furthermore, we extend the analysis to so-called hybrid systems with memory where the dynamics of any given mode depend explicitly on the states at the last mode transition point. We present and discuss several numerical examples, including a computational mechanics problem based on the so-called exponential model (EM) constitutive material law for steel reinforcement under cyclic loading.
On the Turbulence Modeling of Blood Flow in a Stenotic Vessel
Authors: Lui Mattia , Martino Savino , Salerno Mario , Quadrio Maurizio
Published: June 2019

Blood flow dynamics in a stenosed, subject-specific carotid bifurcation is numerically simulated using direct numerical simulation (DNS) and Reynolds-averaged Navier–Stokes (RANS) equations closed with turbulence models. DNS is meant to provide a term of comparison for the RANS calculations, which include classic two-equations models (k–ε and k–ω) as well as a transitional three-equations eddy-viscosity model (kT−kL−ω). Pulsatile inlet conditions based on in vivo ultrasound measurements of blood velocity are used. The blood is modeled as a Newtonian fluid, and the vessel walls are rigid. The main purpose of this work is to highlight the problems related to the use of classic RANS models in the numerical simulation of such flows. The time-averaged DNS results, interpreted in view of their finite-time averaging error, are used to demonstrate the superiority of the transitional RANS model, which is found to provide results closer to DNS than those of conventional models. The transitional model shows better predictive capabilities in terms of turbulence intensity, temporal evolution of the pressure along the cardiac cycle, and the oscillatory shear index (OSI). Indeed, DNS brings to light the locally transitional or weakly turbulent state of the blood flow, which presents velocity and pressure fluctuations only in the poststenotic region of the internal carotid artery during systole, while the flow is laminar during diastole.
Longitudinal Reinforcement of Acute Myocardial Infarcts Improves Function by Transmurally Redistributing Stretch and Stress
Authors: Estrada Ana Cristina , Yoshida Kyoko , Clarke Samantha A. , Holmes Jeffrey W.
Published: June 2019

A wide range of emerging therapies, from surgical restraint to biomaterial injection to tissue engineering, aim to improve heart function and limit adverse remodeling following myocardial infarction (MI). We previously showed that longitudinal surgical reinforcement of large anterior infarcts in dogs could significantly enhance systolic function without restricting diastolic function, but the underlying mechanisms for this improvement are poorly understood. The goal of this study was to construct a finite element model that could match our previously published data on changes in regional strains and left ventricular function following longitudinal surgical reinforcement, then use the model to explore potential mechanisms for the improvement in systolic function we observed. The model presented here, implemented in febio, matches all the key features of our experiments, including diastolic remodeling strains in the ischemic region, small shifts in the end-diastolic pressure–volume relationship (EDPVR), and large changes in the end-systolic pressure–volume relationship (ESPVR) in response to ischemia and to patch application. Detailed examination of model strains and stresses suggests that longitudinal reinforcement reduces peak diastolic fiber stretch and systolic fiber stress in the remote myocardium and shifts those peaks away from the endocardial surface by reshaping the left ventricle (LV). These findings could help to guide the development of novel therapies to improve post-MI function by providing specific design objectives.
The Effect of Articular Cartilage Focal Defect Size and Location in Whole Knee Biomechanics Models
Authors: Marchi Benjamin C. , Arruda Ellen M. , Coleman Rhima M.
Published: June 2019

Articular cartilage focal defects are common soft tissue injuries potentially linked to osteoarthritis (OA) development. Although several defect characteristics likely contribute to osteoarthritis, their relationship to local tissue deformation remains unclear. Using finite element models with various femoral cartilage geometries, we explore how defects change cartilage deformation and joint kinematics assuming loading representative of the maximum joint compression during the stance phase of gait. We show how defects, in combination with location-dependent cartilage mechanics, alter deformation in affected and opposing cartilages, as well as joint kinematics. Small and average sized defects increased maximum compressive strains by approximately 50% and 100%, respectively, compared to healthy cartilage. Shifts in the spatial locations of maximum compressive strains of defect containing models were also observed, resulting in loading of cartilage regions with reduced initial stiffnesses supporting the new, elevated loading environments. Simulated osteoarthritis (modeled as a global reduction in mean cartilage stiffness) did not significantly alter joint kinematics, but exacerbated tissue deformation. Femoral defects were also found to affect healthy tibial cartilage deformations. Lateral femoral defects increased tibial cartilage maximum compressive strains by 25%, while small and average sized medial defects exhibited decreases of 6% and 15%, respectively, compared to healthy cartilage. Femoral defects also affected the spatial distributions of deformation across the articular surfaces. These deviations are especially meaningful in the context of cartilage with location-dependent mechanics, leading to increases in peak contact stresses supported by the cartilage of between 11% and 34% over healthy cartilage.
A Reduced-Order Flow Model for Fluid–Structure Interaction Simulation of Vocal Fold Vibration
Authors: Li Zheng , Chen Ye , Chang Siyuan , Luo Haoxiang
Published: June 2019

We present a novel reduced-order glottal airflow model that can be coupled with the three-dimensional (3D) solid mechanics model of the vocal fold tissue to simulate the fluid–structure interaction (FSI) during voice production. This type of hybrid FSI models have potential applications in the estimation of the tissue properties that are unknown due to patient variations and/or neuromuscular activities. In this work, the flow is simplified to a one-dimensional (1D) momentum equation-based model incorporating the entrance effect and energy loss in the glottis. The performance of the flow model is assessed using a simplified yet 3D vocal fold configuration. We use the immersed-boundary method-based 3D FSI simulation as a benchmark to evaluate the momentum-based model as well as the Bernoulli-based 1D flow models. The results show that the new model has significantly better performance than the Bernoulli models in terms of prediction about the vocal fold vibration frequency, amplitude, and phase delay. Furthermore, the comparison results are consistent for different medial thicknesses of the vocal fold, subglottal pressures, and tissue material behaviors, indicating that the new model has better robustness than previous reduced-order models.
Subject-Specific Finite Element Models of the Tibia With Realistic Boundary Conditions Predict Bending Deformations Consistent With In Vivo Measurement
Authors: Haider Ifaz T. , Baggaley Michael , Brent Edwards W.
Published: June 2019

Understanding the structural response of bone during locomotion may help understand the etiology of stress fracture. This can be done in a subject-specific manner using finite element (FE) modeling, but care is needed to ensure that modeling assumptions reflect the in vivo environment. Here, we explored the influence of loading and boundary conditions (BC), and compared predictions to previous in vivo measurements. Data were collected from a female participant who walked/ran on an instrumented treadmill while motion data were captured. Inverse dynamics of the leg (foot, shank, and thigh segments) was combined with a musculoskeletal (MSK) model to estimate muscle and joint contact forces. These forces were applied to an FE model of the tibia, generated from computed tomography (CT). Eight conditions varying loading/BCs were investigated. We found that modeling the fibula was necessary to predict realistic tibia bending. Applying joint moments from the MSK model to the FE model was also needed to predict torsional deformation. During walking, the most complex model predicted deformation of 0.5 deg posterior, 0.8 deg medial, and 1.4 deg internal rotation, comparable to in vivo measurements of 0.5–1 deg, 0.15–0.7 deg, and 0.75–2.2 deg, respectively. During running, predicted deformations of 0.3 deg posterior, 0.3 deg medial, and 0.5 deg internal rotation somewhat underestimated in vivo measures of 0.85–1.9 deg, 0.3–0.9 deg, 0.65–1.72 deg, respectively. Overall, these models may be sufficiently realistic to be used in future investigations of tibial stress fracture.