bluuebunny/crossref_metadata_2025 huggingface dataset:
Prior expectations of motion direction modulate early sensory processing
Authors: Aitken Fraser , Turner Georgia , Kok Peter
Published: March 2020

Perception is a process of inference, integrating sensory inputs with prior expectations. However, little is known regarding the temporal dynamics of this integration. It has been proposed that expectation plays a role early in the perceptual process, by biasing early sensory processing. Alternatively, others suggest that expectations are integrated only at later, post-perceptual decision-making stages. The current study aimed to dissociate between these hypotheses. We exposed male and female human participants (N=24) to auditory cues predicting the likely direction of upcoming noisy moving dot patterns, while recording millisecond-resolved neural activity using magnetoencephalography (MEG). First, we found that participants’ reports of the moving dot directions were biased towards the direction predicted by the auditory cues. To investigate when expectations affected sensory representations, we used inverted encoding models to decode the direction represented in early sensory signals. Strikingly, the auditory cues modulated the direction represented in the MEG signal as early as 150ms after visual stimulus onset. This early neural modulation was related to perceptual effects of expectation: participants with a stronger perceptual bias towards the predicted direction also revealed a stronger reflection of the predicted direction in the MEG signal. For participants with this perceptual bias, a trial-by-trial correlation between decoded and perceived direction already emerged prior to visual stimulus onset (∼-150ms), suggesting that the pre-stimulus state of the visual cortex influences sensory processing. Together, these results suggest that prior expectations can influence perception by biasing early sensory processing, making expectation a fundamental component of the neural computations underlying perception.

Significance statement

Perception can be thought of as an inferential process in which our brains integrate sensory inputs with prior expectations to make sense of the world. This study investigated whether this integration occurs early or late in the process of perception. We exposed human participants to auditory cues which predicted the likely direction of visual moving dots, while recording neural activity with millisecond resolution using magnetoencephalography (MEG). Participants’ perceptual reports of the direction of the moving dots were biased towards the predicted direction. Additionally, the predicted direction modulated the neural representation of the moving dots just 150 ms after they appeared. This suggests that prior expectations affected sensory processing at very early stages, playing an integral role in the perceptual process.
Immunogenicity, safety and efficacy of sequential immunizations with an SIV-based IDLV expressing CH505 Envs
Authors: Maria Blasi , Donatella Negri , Kevin Saunders O , Erich Baker J , Hannah Stadtler , Celia LaBranche , Benjamin Mildenberg , Georgeanna Morton , Andrew Ciarla , Xiaoying Shen , Yunfei Wang , Wes Rountree , Bala Balakumaran , Sampa Santra , Barton Haynes F , Anthony Moody M , Andrea Cara , Mary Klotman E
Published: March 2020

A preventative HIV-1 vaccine is an essential intervention needed to halt the HIV-1 pandemic. Neutralizing antibodies protect against HIV-1 infection in animal models, and thus an approach toward a protective HIV-1 vaccine is to induce broadly cross-reactive neutralizing antibodies (bnAbs). One strategy to achieve this goal is to define envelope (Env) evolution that drives bnAb development in infection and to recreate those events by vaccination. In this study we report the immunogenicity, safety and efficacy in rhesus macaques of an SIV-based integrase defective lentiviral vector (IDLV) expressing sequential gp140 Env immunogens derived from the CH505 HIV-1-infected individual who made the CH103 and CH235 bnAb lineages. Immunization with IDLV expressing sequential CH505 Env induced higher magnitude and more durable binding and neutralizing antibody responses compared to protein or DNA+/-protein immunizations using the same sequential envelopes. Compared to monkeys immunized with vector expressing Envs alone, those immunized with the combination of IDLV expressing Env and CH505 Env protein demonstrated improved durability of antibody responses at six month after the last immunization as well as lower peak viremia and better virus control following autologous SHIV-CH505 challenge. There was no evidence of vector mobilization or recombination in the immunized and challenged monkeys. Our results show that while IDLV proved safe and successful at inducing higher titer and more durable immune responses compared to other vaccine platforms, the use of non-stabilized sequential envelope trimers did not induce broadly neutralizing antibody responses.
PIP3 depletion rescues myoblast fusion defects in human rhabdomyosarcoma cells
Authors: Lian Yen-Ling , Chen Kuan-Wei , Chou Yu-Ting , Ke Ting-Ling , Chen Bi-Chang , Lin Yu-Chun , Chen Linyi
Published: March 2020

Myoblast fusion is required for myotube formation during myogenesis, and defects in myoblast differentiation and fusion have been implicated in a number of diseases, including human rhabdomyosarcoma. While the transcriptional regulation of the myogenic program has been studied extensively, the mechanisms controlling myoblast fusion remain largely unknown. This study identified and characterized the dynamics of a distinct class of blebs, termed bubbling blebs, which are smaller than those that participate in migration. The formation of these bubbling blebs occurred during differentiation and decreased alongside a decline in phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) at the plasma membrane before myoblast fusion. In a human rhabdomyosarcoma-derived (RD) cell line that exhibits strong blebbing dynamics and myoblast fusion defects, PIP3 was constitutively abundant on the membrane during myogenesis. Targeting phosphatase and tensin homolog (PTEN) to the plasma membrane reduced PIP3 levels, inhibited bubbling blebs, and rescued myoblast fusion defects in RD cells. These findings highlight the differential distribution and crucial role of PIP3 during myoblast fusion and reveal a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma.

Summary Statement

This study reveals a novel mechanism underlying myogenesis defects in human rhabdomyosarcoma cells involving PIP3, whose depletion with PTEN rescues myoblast fusion defects.
Acute and long-term circuit-level effects in the auditory cortex after sound trauma
Authors: Jeschke Marcus , Happel Max F.K. , Tziridis Konstantin , Krauss Patrick , Schilling Achim , Schulze Holger , Ohl Frank W.
Published: March 2020

Harmful environmental sounds are a prevailing source for chronic hearing impairments, including noise induced hearing loss, hyperacusis, or tinnitus. How these symptoms are related to pathophysiological damage to the sensory receptor epithelia and its effects along the auditory pathway, such as functional reorganizations in the auditory cortex (ACx), have been documented in numerous studies. An open question concerns the temporal evolution of maladaptive changes after damage and their manifestation in the balance between afferent thalamocortical input and corticocortical input to the ACx.

To address this, we investigated the loci of plastic reorganizations across the tonotopic axis of the auditory cortex of male Mongolian gerbils (Meriones unguiculatus) acutely after a sound trauma and after several weeks. We used a laminar residual current-source density analysis to dissociate adaptations of intracolumnar input and horizontally relayed corticocortical input to synaptic populations across cortical layers in ACx. A pure tone-based sound trauma caused acute changes of subcortical inputs and corticocortical inputs at all tonotopic regions, particularly showing a broad elimination of tone-evoked inputs at tonotopic regions with a pre-trauma best frequency between 2-8 kHz. At other cortical sites, the overall columnar activity acutely decreased, while relative contributions of lateral corticocortical inputs increased. After 4-6 weeks, cortical activity to the altered sensory inputs showed a general increase of local thalamocortical input reaching levels higher than before the trauma. Hence, our results suggest a detailed mechanism for overcompensation of altered frequency input in the auditory cortex that relies on a changing balancing of thalamocortical and intracortical input and is confined to the spectral neighborhood of the trauma frequency.

Significance statement

Harmful noise exposure is a major anthropogenic cause of hearing disorders and is becoming an ever-increasing burden for human health and society. Damage to the sensory epithelia elicited by harmful sounds can subsequently lead to chronic hearing loss, hyperacusis or tinnitus. We still lack an understanding of the pathophysiological plastic processes and their evolution, particularly at the circuit level of the auditory cortex (ACx), which is fundamentally involved in auditory perception. We demonstrate that plastic changes in ACx after noise induced hearing loss (NIHL) occur over several weeks, and that changes in intracortical functional connectivity compensate the acute effects in the deafferentiated subcortical inputs. Such long-term changes may underlie the temporal evolution of hearing impairments or phantom sounds after NIHL.
Genotyping of Russian isolates of fungal pathogenTrichophyton rubrum, based on simple sequence repeat and single nucleotide polymorphism
Authors: Pchelin Ivan M. , Mochalov Yuri V. , Azarov Daniil V. , Romanyuk Sofya A. , Chilina Galina A. , Vybornova Irina V. , Bogdanova Tatiyana V. , Zlatogursky Vasily V. , Apalko Svetlana V. , Vasilyeva Natalia V. , Taraskina Anastasia E.
Published: March 2020

Background

TheTrichophyton rubrumspecies group consists of prevalent causative agents of human skin, nail and hair infections, includingT. rubrum sensu strictoandT. violaceum, as well as other less well established or debatable taxa likeT. soudanense,T. kuryangeiandT. megninii. Our previous study provided limited evidence in favour of the existence of two genetic lineages in the RussianT. rubrum sensu strictopopulation.

Objectives

We aimed to study the genetic structure of the Russian population ofT. rubrum, and to identify factors shaping this structure.

Methods

We analysed the polymorphism of 12 simple sequence repeat (SSR, or microsatellite) markers and single-nucleotide polymorphism in the TERG_02941 protein-coding gene in 70T. rubrumisolates and performed a phylogenomic reconstruction.

Results

All three types of data provided conclusive evidence that the population consists of two genetic lineages. Clustering, performed by means of microsatellite length polymorphism analysis, was strongly dependent on the number of nucleotide repeats in the 5’-area of the fructose-1,6-bisphosphate aldolase gene. Analysis of molecular variance (AMOVA) on the basis of SSR typing data indicated that 22–48% of the variability was among groups withinT. rubrum. There was no clear connection of population structure with types of infection, places of geographic origin, aldolase gene expression or urease activity.

Conclusion

Our results suggest that the Russian population ofT. rubrumconsists of two cosmopolitan genetic lineages.
Distinct Neuronal Populations Contribute to Trace Conditioning and Extinction Learning in the Hippocampal CA1
Authors: Mount Rebecca A. , Hansen Kyle R. , Sridhar Sudiksha , Mohammed Ali I. , Abdulkerim Moona , Kessel Robb , Nazer Bobak , Gritton Howard J. , Han Xue
Published: March 2020

Trace conditioning and extinction learning depend on the hippocampus, but it remains unclear how ongoing neural activities in the hippocampus are modulated during different learning processes. To explore this question, we performed calcium imaging in a large number of individual CA1 neurons during both trace eye-blink conditioning and subsequent extinction learning in mice. Using trial-averaged calcium fluorescence analysis, we found direct evidence that in real time, as learning emerges, distinct populations of CA1 cells contribute to trace conditioned learning versus extinction learning. Furthermore, we examined network connectivity by calculating co-activity between CA1 neuron pairs, and found that CA1 network connectivity is different between conditioning and extinction and between correct versus incorrect behavioral responses during trace conditioned learning. However, the overall connectivity density remains constant across these behavioral conditions. Together, our results demonstrate that distinct populations of CA1 neurons, forming different sub-networks with unique connectivity patterns, encode different aspects of learning.
A transcriptomic census reveals that Rbfox contributes to a broad but selective recapitulation of peripheral tissue splicing patterns in the thymus
Authors: Jansen Kathrin , Shikama-Dorn Noriko , Attar Moustafa , Maio Stefano , Lopopolo Maria , Buck David , Holländer Georg A. , Sansom Stephen N.
Published: March 2020

Thymic epithelial cells (TEC) control the selection of a T-cell repertoire reactive to pathogens but tolerant of self. While this process is known to involve the promiscuous expression of virtually the entire protein-coding gene repertoire the extent to which TEC recapitulate peripheral isoforms, and the mechanisms by which they do so, have remained largely unknown. We performed the first assembly-based transcriptomic census of transcript structures and splicing factor (SF) expression in mouse medullary TEC (mTEC) and 21 peripheral tissues. Mature mTEC expressed 60.1% of all protein-coding transcripts, more than was detected in any of the peripheral tissues. However, for genes with tissue-restricted expression, we found that mTEC produced fewer isoforms than did the relevant peripheral tissues. Analysis of exon inclusion revealed an absence of brain-specific micro-exons in mTEC. We did not find unusual numbers of novel transcripts in TEC and show thatAire, the facilitator of promiscuous gene expression, promotes usage of long transcripts but has only a limited impact on alternative splicing in mTEC. Comprehensive assessment of SF expression in mTEC identified a small set of non-promiscuously expressed SF genes amongst which we confirmed RBFOX to be present with AIRE in mTEC nuclei. Using a conditional loss of function approach, we show thatRbfox2promotes mTEC development and regulates the alternative splicing of promiscuously expressed genes. These data indicate that TEC recommission a small number of peripheral SFs, including members of the Rbfox family, to generate a broad but selective representation of the peripheral splice isoform repertoire.
Is male dimorphism under sexual selection in humans? A meta-analysis
Authors: Lidborg L. H. , Cross C. P. , Boothroyd L. G.
Published: March 2020

Humans are sexually dimorphic: men and women differ in body build and composition, craniofacial structure, and voice pitch, likely mediated in part by developmental testosterone. Sexual selection hypotheses posit that, ancestrally, more ‘masculine’ men may have acquired more mates and/or sired more viable offspring. Thus far, however, evidence for either association is unclear. Here, we meta-analyze the relationships between six masculine traits and mating/reproductive outcomes (96 studies, 474 effects,N= 177,044). Voice pitch, height, and testosterone all predicted mating; however, strength/muscularity was the strongest and only consistent predictor of both mating and reproduction. Facial masculinity and digit ratios did not significantly predict either. There was no clear evidence for any effects of masculinity on offspring viability. Our findings support arguments that strength/muscularity can be considered sexually selected in humans, but raise concerns over other forms of masculinity and highlight the need to increase tests of evolutionary hypotheses outside of industrialized populations.
Positioning of nucleosomes containing γ-H2AX precedes active DNA demethylation and transcription initiation
Authors: Dobersch Stephanie , Rubio Karla , Singh Indrabahadur , Günther Stefan , Graumann Johannes , Cordero Julio , Castillo-Negrete Rafael , Huynh Minh Bao , Mehta Aditi , Braubach Peter , Cabrera-Fuentes Hector , Bernhagen Jürgen , Chao Cho-Ming , Bellusci Saverio , Günther Andreas , Preissner Klaus T , Dobreva Gergana , Wygrecka Malgorzata , Braun Thomas , Papy-Garcia Dulce , Barreto Guillermo
Published: March 2020

In addition to nucleosomes, chromatin contains non-histone chromatin-associated proteins, of which the high-mobility group (HMG) proteins are the most abundant. Chromatin-mediated regulation of transcription involves DNA methylation and histone modifications. However, the order of events and the precise function of HMG proteins during transcription initiation remain unclear. Here we show that HMG AT-hook 2 protein (HMGA2) induces DNA nicks at the transcription start site, which are required by the histone chaperone FACT (facilitates chromatin transcription) complex to incorporate nucleosomes containing the histone variant H2A.X. Further, phosphorylation of H2A.X at S139 (γ-H2AX) is required for repair-mediated DNA demethylation and transcription activation. The relevance of these findings is demonstrated within the context of TGFB1 signaling and idiopathic pulmonary fibrosis, suggesting therapies against this lethal disease. Our data support that chromatin opening during transcriptional initiation involves intermediates with DNA breaks that subsequently require DNA repair mechanisms to ensure the integrity of the genome.
A numerical study about the flight of the dragonfly: 2D gliding and 3D hovering regimes
Authors: Benedetti Lorenzo , Bianchi Giovanni , Cinquemani Simone , Belloli Marco
Published: March 2020

The dragonfly’s ability of gliding and performing dexterous maneuvers during flight attracts the interest of scientists and engineers who aim at replicating its performances in micro air vehicles. The great efficiency of its flight is achieved thanks to the vortices generated by wing movements and thanks to the corrugations on their surfaces. The high freedom of control of each wing has been proved to be the secret behind the dragonfly capability to carry out incredible flight manoeuvers. The study presented in this paper analyzes two of the most common flight regimes of the dragonfly. Firstly, some CFD simulations of gliding are performed and drag and lift coefficients have been calculated, showing a good match with experimental data found in literature. Then, hovering has been studied using a methodology inspired to the Blade Element Momentum (BEM) theory, which is usually applied in the context of wind turbines design. The lift force calculated with this simulation corresponds to the weight of dragonfly, suggesting the correctness of this analysis.
A fast and efficient smoothing approach to Lasso regression and an application in statistical genetics: polygenic risk scores for chronic obstructive pulmonary disease (COPD)
Authors: Hahn Georg , Lutz Sharon M. , Laha Nilanjana , Cho Michael H. , Silverman Edwin K. , Lange Christoph
Published: March 2020

High dimensional linear regression problems are often fitted using Lasso approaches. Although the Lasso objective function is convex, it is not differentiable everywhere, making the use of gradient descent methods for minimization not straightforward. To avoid this technical issue, we apply Nesterov smoothing to the original (unsmoothed) Lasso objective function. We introduce a closed-form smoothed Lasso which preserves the convexity of the Lasso function, is uniformly close to the unsmoothed Lasso, and allows us to obtain closed-form derivatives everywhere for efficient and fast minimization via gradient descent. Our simulation studies are focused on polygenic risk scores using genetic data from a genome-wide association study (GWAS) for chronic obstructive pulmonary disease (COPD). We compare accuracy and run-time of our approach to the current gold standard in the literature, the FISTA algorithm. Our results suggest that the proposed methodology provides estimates with equal or higher accuracy than the FISTA algorithm while having the same asymptotic runtime scaling. The proposed methodology is implemented in the R-packagesmoothedLasso, available on the Comprehensive R Archive Network (CRAN).
Auto-inhibitory regulation of DNA binding by the C-terminal tails of the mitochondrial transcription factors Mtf1 and TFB2M
Authors: Basu Urmimala , Mishra Nandini , Farooqui Mohammed , Shen Jiayu , Johnson Laura C. , Patel Smita S.
Published: March 2020

The structurally homologous Mtf1 and TFB2M proteins serve as transcription initiation factors of theSaccharomyces cerevisiaeand human mitochondrial RNA polymerases, respectively. These transcription factors directly interact with the non-template strand of the transcription bubble to drive promoter melting. Given the key roles of Mtf1 and TFB2M in promoter-specific transcription initiation, it is expected that the DNA binding activity of the mitochondrial transcription factors would be regulated to prevent DNA binding at inappropriate times. However, there is little information on how mitochondrial DNA transcription is regulated. While studying the C-tail deletion mutants of Mtf1 and TFB2M, we stumbled upon a new finding that suggested that the flexible C-tail region of these factors autoregulates their DNA binding activity. Quantitative DNA binding studies with fluorescence anisotropy-based titrations show that Mtf1 with an intact C-tail has no affinity for the DNA but the deletion of C-tail greatly increases the DNA binding affinity. Similar observations were made with TFB2M, although autoinhibition by the C-tail of TFB2M was not as absolute as in Mtf1. Analysis of available TFB2M structures show that the C-tail makes intramolecular interactions with the DNA binding groove in the free factor, which we propose masks the DNA binding activity. Further studies show that the RNA polymerase relieves autoinhibition by interacting with the C-tail and engaging it in complex formation. Thus, our biochemical and structural analysis identify previously unknown autoinhibitory and activation mechanisms of mitochondrial transcription factors that regulate the DNA binding activity and aid in specific assembly of the initiation complexes.
Embedding the de Bruijn graph, and applications to metagenomics
Authors: Menegaux Romain , Vert Jean-Philippe
Published: March 2020

Fast mapping of sequencing reads to taxonomic clades is a crucial step in metagenomics, which however raises computational challenges as the numbers of reads and of taxonomic clades increases. Besides alignment-based methods, which are accurate but computational costly, faster compositional approaches have recently been proposed to predict the taxonomic clade of a read based on the set ofk-mers it contains. Machine learning-based compositional approaches, in particular, have recently reached accuracies similar to alignment-based models, while being considerably faster. It has been observed that the accuracy of these models increases with the lengthkof thek-mers they use, however existing methods are limited to handlek-mers of lengths up tok= 12 or 13 because of their large memory footprint needed to store the model coefficients for each possiblek-mer. In order to explore the performance of machine learning-based compositional approaches for longerk-mers than currently possible, we propose to reduce the memory footprint of these methods by binning togetherk-mers that appear together in the sequencing reads used to train the models. We achieve this binning by learning a vector embedding for the vertices of a compacted de Bruijn graph, allowing us to embed any DNA sequence in a low-dimensional vector space where a machine learning system can be trained. The resulting method, which we callBrume, allows us to train compositional machine learning-based models withk-mers of length up tok= 31. We show on two metagenomics benchmark thatBrumereaches better performance than previously achieved, thanks to the use of longerk-mers.
Murine Radiation-Induced Stomach Pathology from Whole Thoracic Irradiation
Authors: McIlrath Daniel R. , Perez-Torres Carlos J.
Published: March 2020

Purpose

Radiation-induced lung injury is a common side effect in the treatment of lung and breast cancers. There is a large focus in the field on leveraging mouse models of radiation-induced lung injury to find novel treatments for the condition. While attempting to irradiate mouse lungs for purposes of creating a radiation-induced pulmonary fibrosis model, noticeable declines in health were observed at much earlier time points than recorded for lung pathology. This was later attributed to stomach pathology observed in CT images and ex vivo dissection.

Methods

For this study, we used longitudinal microCT to characterize male C57Bl/6 mice irradiated with a single dose of 20 Gy to the whole thoracic area delivered by an X-Rad cabinet irradiator. CT was performed with respiratory gating at 2 to 4 week timepoints to construct a timeline of pathology leading up to fibrosis and quantify severity of fibrosis afterwards. However, a mouse imaged at the 10 week timepoint showed evidence of stomach distention. These mice were sacrificed and their stomachs removed. Histology was performed on the stomachs using H&E staining.

Results

On the CT images, we observed a large, spherical volume of hypointense signal, caudal to the lungs (Figure 1). This correlated with a distended stomach caused by constipation and gas build-up within the stomach. Statistical analysis showed 81% of mice (n=105) died prematurely after irradiation and before significant development of pulmonary fibrosis. Mice sacrificed and dissected showed unpassed bolus as contents of the stomach, and histology showed cell necrosis of the stomach walls.

Conclusion

The histology indicated an inability for food to be digested and moved into the small intestine. This lead to a blockage and ensuing stomach distention. Given the severity of the pathology’s consequences, it lead to the mouse’s imminent mortality inhibiting the efficacy of the study. Future studies need to consider careful placement of shields or any beam contouring devices to ensure protection of the stomach given its higher radiosensitivity in contrast to the lungs.
Evidence accumulation and associated error-related brain activity as computationally-informed prospective predictors of substance use in emerging adulthood
Authors: Weigard Alexander S. , Brislin Sarah J. , Cope Lora M. , Hardee Jillian E. , Martz Meghan E. , Ly Alexander , Zucker Robert A. , Sripada Chandra , Heitzeg Mary M.
Published: March 2020

Rationale

Substance use peaks during the developmental period known as emerging adulthood (ages 18–25), but not every individual who uses substances during this period engages in frequent or problematic use. Although individual differences in neurocognition appear to predict use severity, mechanistic neurocognitive risk factors with clear links to both behavior and neural circuitry have yet to be identified. Here we aim to do so with an approach rooted in computational psychiatry, an emerging field in which formal models are used to identify candidate biobehavioral dimensions that confer risk for psychopathology.

Objectives

We test whether lower efficiency of evidence accumulation (EEA), a computationally-characterized individual difference variable that drives performance on the go/no-go and other neurocognitive tasks, is a risk factor for substance use in emerging adults.

Methods and Results

In an fMRI substudy within a sociobehavioral longitudinal study (n=106), we find that lower EEA and reductions in a robust neural-level correlate of EEA (error-related activations in salience network structures) measured at ages 18–21 are both prospectively related to greater substance use during ages 22–26, even after adjusting for other well-known risk factors. Results from Bayesian model comparisons corroborated inferences from conventional hypothesis testing and provided evidence that both EEA and its neuroimaging correlates contain unique predictive information about substance use involvement.

Conclusions

These findings highlight EEA as a computationally-characterized neurocognitive risk factor for substance use during a critical developmental period, with clear links to both neuroimaging measures and well-established formal theories of brain function.
Mantis shrimp navigate home using celestial and idiothetic path integration
Authors: Patel Rickesh N. , Cronin Thomas W.
Published: March 2020

Path integration is a robust mechanism that many animals employ to return to specific locations, typically their homes, during navigation. This efficient navigational strategy has never been demonstrated in a fully aquatic animal, where sensory cues used for orientation may differ dramatically from those available above the water’s surface. Here we report that the mantis shrimp,Neogonodactylus oerstedii, uses path integration informed by a hierarchical reliance on the sun, overhead polarization patterns, and idiothetic (internal) orientation cues to return home when foraging, making them the first fully aquatic path-integrating animals yet discovered. We show that mantis shrimp rely on navigational strategies closely resembling those used by insect navigators, opening a new avenue for the investigation of the neural basis of navigation behaviors and the evolution of these strategies in arthropods and potentially other animals as well.
locStra: Fast analysis of regional/global stratification in whole genome sequencing (WGS) studies
Authors: Hahn Georg , Lutz Sharon M. , Hecker Julian , Prokopenko Dmitry , Cho Michael H. , Silverman Edwin K. , Weiss Scott T. , Lange Christoph ,   the NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
Published: March 2020

locStrais anR-package for the analysis of regional and global population stratification in whole genome sequencing studies, where regional stratification refers to the substructure defined by the loci in a particular region on the genome. Population substructure can be assessed based on the genetic covariance matrix, the genomic relationship matrix, and the unweighted/weighted genetic Jaccard similarity matrix. Using a sliding window approach, the regional similarity matrices are compared to the global ones, based on user-defined window sizes and metrics, e.g. the correlation between regional and global eigenvectors. An algorithm for the specification of the window size is provided. As the implementation fully exploits sparse matrix algebra and is written in C++, the analysis is highly efficient. Even on single cores, for realistic study sizes (several thousand subjects, several million RVs per subject), the runtime for the genome-wide computation of all regional similarity matrices does typically not exceed one hour, enabling an unprecedented investigation of regional stratification across the entire genome. The package is applied to three WGS studies, illustrating the varying patterns of regional substructure across the genome and its beneficial effects on association testing.
Intergenerational transmission of the patterns of functional and structural brain networks
Authors: Takagi Yu , Okada Naohiro , Ando Shuntaro , Yahata Noriaki , Morita Kentaro , Koshiyama Daisuke , Kawakami Shintaro , Sawada Kingo , Koike Shinsuke , Endo Kaori , Yamasaki Syudo , Nishida Atsushi , Kasai Kiyoto , Tanaka Saori C
Published: March 2020

There is clear evidence of intergenerational transmission of life values, cognitive traits, psychiatric disorders, and even aspects of daily decision making. To investigate biological substrates of this phenomenon, brain has received increasing attention as a measurable biomarker and potential target for intervention. However, no previous study has quantitatively and comprehensively investigated the effects of intergenerational transmission on functional and structural brain networks from parents to their children. Here, by employing an unusually large cohort dataset, we show that patterns of functional and structural brain networks are preserved over a generation. We also demonstrate that several demographic and behavioural phenotypes have effects on brain similarity. Collectively, our results provide a comprehensive picture of neurobiological substrates of parent-child similarity, and demonstrate the usability of our dataset for investigating the neurobiological substrates of intergenerational transmission.
An autoinhibitory clamp of actin assembly constrains and directs synaptic endocytosis
Authors: Del Signore Steven J. , Kelley Charlotte F. , Messelaar Emily M. , Lemos Tania , Marchan Michelle F. , Ermanoska Biljana , Mund Markus , Fai Thomas G. , Kaksonen Marko , Rodal Avital A
Published: March 2020

Synaptic membrane-remodeling events such as endocytosis require force-generating actin assembly. The endocytic machinery that regulates these actin and membrane dynamics localizes at high concentrations to large areas of the presynaptic membrane, but actin assembly and productive endocytosis are far more restricted in space and time. Here we describe a mechanism whereby autoinhibition clamps the presynaptic endocytic machinery to limit actin assembly to discrete functional events. We found that collective interactions between theDrosophilaendocytic proteins Nwk/FCHSD2, Dap160/Intersectin, and WASp relieve Nwk autoinhibition and promote robust membrane-coupled actin assemblyin vitro.Using automated particle tracking to quantify synaptic actin dynamicsin vivo, we discovered that Nwk-Dap160 interactions constrain spurious assembly of WASp-dependent actin structures. These interactions also promote synaptic endocytosis, suggesting that autoinhibition both clamps and primes the synaptic endocytic machinery, thereby constraining actin assembly to drive productive membrane remodeling in response to physiological cues.
Human-Genetic Ancestry Inference and False Positives in Forensic Familial Searching
Authors: Fortier Alyssa Lyn , Kim Jaehee , Rosenberg Noah A.
Published: March 2020

In forensic familial search methods, a query DNA profile is tested against a database to determine if the query profile represents a close relative of a database entrant. One challenge for familial search is that the calculations may require specification of allele frequencies for the unknown population from which the query profile has originated. Allele-frequency misspecification can substantially inflate false-positive rates compared to use of allele frequencies drawn from the same population as the query profile. Here, we use ancestry inference on the query profile to circumvent the high false-positive rates that result from highly misspecified allele frequencies. In particular, we perform ancestry inference on the query profile and make use of allele frequencies based on its inferred genetic ancestry. In a test for sibling matches on profiles that represent unrelated individuals, we demonstrate that false-positive rates for familial search with use of ancestry inference to specify the allele frequencies are similar to those seen when allele frequencies align with the population of origin of a profile. Because ancestry inference is possible to perform on query profiles, the extreme allele-frequency misspecifications that produce the highest false-positive rates can be avoided. We discuss the implications of the results in the context of concerns about the forensic use of familial searching.
Data Processing Pipeline for Multiband Diffusion-, T1- and Susceptibility Weighted MRI to Establish Structural Connectivity of the Human Basal Ganglia and Thalamus
Authors: Gilani Irtiza A. , Oguz Kader K. , Boyaci Huseyin , Doerschner Katja
Published: March 2020

The basal ganglia and thalamus play an important role in cognition, procedural learning, eye movements, control of voluntary motor movements, emotional control, habit development, and are structures that are severely impacted by neurological disorders such as Parkinson’s disease, or Tourette syndrome. To understand the structural connectivity of cortical and subcortical circuits in the healthy human brain could thus be of pivotal importance for detecting changes in this circuitry and to start early intervention, to assess the progress of movement rehabilitation, or the effectiveness of therapeutic approaches in neuropsychiatry. While conventional clinical magnetic resonance imaging (MRI) is able to provide detailed information about connectivity at the macro level, the sensitivity and specificity of such structural imaging methods put limits on the amount of detail one can obtain when measuringin vivoconnectivity of human basal ganglia and thalamus at routine clinical magnetic field strengths. In contrast, the multiband diffusion echo planar imaging method, which acquires multiple slices simultaneously, enables high resolution imaging of these abovementioned brain structures with only short acquisition times at 3-Tesla and higher magnetic field strengths. To unleash the greater potential of information embedded in data acquired with this technique, complementary data processing pipelines are required. Here, we use a protocol composed of multiband diffusion-, T1- and susceptibility weighted data acquisition sequences and introduce an associated pipeline based on combined manual and automated processing. The design of this data processing pipeline allows us to generate comprehensivein vivoparticipant-specific probabilistic patterns and visualizations of the structural connections that exist within basal ganglia and thalamic nuclei. Moreover, we are able to map specific parcellations of these nuclei into sub-territories based on their connectivity with primary motor-, and somatosensory cortex. This data processing strategy enables detailed subcortical structural connectivity mapping which could benefit early intervention and therapy methods for human movement rehabilitation and for treating neuropsychiatric disorders.
Association Study based on Topological Constraints of Protein-Protein Interaction Networks
Authors: Guo Hao-Bo , Qin Hong
Published: March 2020

The non-random interaction pattern of a protein-protein interaction network (PIN) is biologically informative but its potentials have not been fully utilized in omics studies. Here, we propose a network-permutation-based association study (NetPAS) method that gauges the observed interactions between two sets of genes based on the comparison between permutation null models and the empirical networks. This enables NetPAS to evaluate relationships, constrained by network topology, between gene sets related to different phenotypes. We demonstrated the utility of NetPAS in 50 well-curated gene sets and comparison of association studies using Z-scores, p-values or overrepresentations. Using NetPAS, a weighted human disease network was generated from the association scores of 19 gene sets from OMIM. We also applied NetPAS in gene sets derived from gene ontology and pathway annotations and showed that NetPAS uncovered functional terms missed by DAVID and other network-based enrichment tools. Overall, we show that NetPAS can take topological constraints of molecular networks into account and offer new perspectives than existing methods.
Insights into chloroplast genome variation across Opuntioideae (Cactaceae)
Authors: Köhler Matias , Reginato Marcelo , Souza-Chies Tatiana T. , Majure Lucas C.
Published: March 2020

Chloroplast genomes (plastomes) are frequently treated as highly conserved among land plants. However, many lineages of vascular plants have experienced extensive structural rearrangements, including inversions and modifications to the size and content of genes. Cacti are one of these lineages, containing the smallest plastome known for an obligately photosynthetic angiosperm, including the loss of one copy of the inverted repeat (∼25 kb) and thendhgenes suite, but only a few cacti from the subfamily Cactoideae have been sufficiently characterized. Here, we investigated the variation of plastome sequences across the second-major lineage of the Cactaceae, the subfamily Opuntioideae, to address 1) how variable is the content and arrangement of chloroplast genome sequences across the subfamily, and 2) how phylogenetically informative are the plastome sequences for resolving major relationships among the clades of Opuntioideae. Ourde novoassembly of theOpuntia quimiloplastome recovered an organelle of 150,347 bp in length with both copies of the inverted repeats and the presence of all thendhgenes suite. An expansion of the large single copy unit and a reduction of the small single copy was observed, including translocations and inversion of genes as well as the putative pseudogenization of numerous loci. Comparative analyses among all clades within Opuntioideae suggested that plastome structure and content vary across taxa of this subfamily, with putative independent losses of thendhgene suite and pseudogenization of genes across disparate lineages, further demonstrating the dynamic nature of plastomes in Cactaceae. Our plastome dataset was robust in determining relationships among major clades and subclades within Opuntioideae, resolving three tribes with high support: Cylindropuntieae, Tephrocacteae and Opuntieae. A plastome-wide survey for highly informative phylogenetic markers revealed previously unused regions for future use in Sanger-based studies, presenting a valuable dataset with primers designed for continued evolutionary studies across Cactaceae. These results bring new insights into the evolution of plastomes in cacti, suggesting that further analyses should be carried out to address how ecological drivers, physiological constraints and morphological traits of cacti may be related with the common rearrangements in plastomes that have been reported across the family.
Differential RNA editing between epithelial and mesenchymal tumors impacts mRNA abundance in immune response pathways
Authors: Chan Tracey , Fu Ting , Bahn Jae Hoon , Jun Hyun-Ik , Lee Jae-Hyung , Quinones-Valdez Giovanni , Cheng Chonghui , Xiao Xinshu
Published: March 2020

Recent studies revealed global shifts in RNA editing, the modification of RNA sequences, across many cancers. Besides a few sites implicated in tumorigenesis or metastasis, most tumor-associated sites, predominantly in noncoding regions, have unknown function. Here, we characterize editing profiles between epithelial (E) and mesenchymal (M) phenotypes in seven cancer types, as epithelial-mesenchymal transition (EMT) is a key paradigm for metastasis. We observe distinct editing patterns between E and M tumors and EMT induction upon loss of ADAR enzymes in cultured cells. E-M differential sites are highly enriched in genes involved in immune and viral processes, some of which regulate mRNA abundance of their respective genes. We identify a novel mechanism in which ILF3 preferentially stabilizes edited transcripts. Among editing-dependent ILF3 targets is the transcript encoding PKR, a crucial player in immune response. Our study demonstrates the broad impact of RNA editing in cancer and relevance of editing to cancer-related immune pathways.
Large scale analysis of smoking-induced changes in the tumor immune microenvironment
Authors: Alisoltani Arghavan , Qiu Xinru , Jaroszewski Lukasz , Sedova Mayya , Li Zhanwen , Godzik Adam
Published: March 2020

Tobacco smoke is a known carcinogen, mostly due to its genotoxicity, but its effects on the host immune system are also playing an important role. Here, we leveraged recent results on the immune landscape of cancer based on The Cancer Genomic Atlas (TCGA) data analysis and compared the proportions of major classes of tumor-infiltrating immune cells (TIICs) between smokers and never smokers in ten TCGA cancer types. We show that statistically significant changes can be identified in all ten cancers, with increased plasma cell populations and the modified ratio of activated to resting TIICs being the most consistent features distinguishing smokers and never-smokers across different cancers, with both being correlated with survival outcomes. Analysis of existing single-cell RNA-seq data further showed that smoking differentially affects the gene expression profile of cancer patients based on the immune cell type. The smoking-induced changes in the patterns of immune cells and their correlations to survival outcomes are stronger in female smokers.
Short-term exposure to intermittent hypoxia leads to changes in gene expression seen in chronic pulmonary disease
Authors: Wu Gang , Lee Yin Yeng , Gulla Evelyn M. , Potter Andrew , Kitzmiller Joseph , Ruben Marc D , Salomonis Nathan , Whitsett Jeffrey A. , Francey Lauren J , Hogenesch John B , Smith David F.
Published: March 2020

Obstructive sleep apnea (OSA) results from episodes of airway collapse and intermittent hypoxia and is associated with a host of health complications including dementia, diabetes, heart failure, and stroke. Although the lung is the first organ to sense changes in inspired oxygen levels, little is known about the consequences of IH to the lung hypoxia-inducible factor (HIF)-responsive pathways. Furthermore, cellular mechanisms causing disease progression across multiple systems in OSA are unknown. We hypothesized that exposure to IH would lead to up- and down-regulation of diverse expression pathways and that individual cell populations would show distinctive responses to IH. We identify changes in circadian and immune pathways in lungs from mice exposed to IH. Among all cell types, endothelial cells show the most prominent transcriptional changes. Interestingly, up-regulated genes in endothelial, fibroblast, and myofibroblast cells were enriched for genes associated with pulmonary fibrosis and pulmonary hypertension. These genes include targets of several drugs currently used to treat chronic pulmonary diseases. Our results reveal potential candidates for cell-targeted therapy seeking to minimize pulmonary effects of OSA. A better understanding of the pathophysiologic mechanisms underlying diseases associated with OSA could improve our therapeutic approaches, directing therapies to the most relevant cells and molecular pathways.
Increased FOXL2 Expression Alters Uterine Structures and Functions
Authors: Li Rong , Wu San-Pin , Zhou Lecong , Nicol Barbara , Lydon John P. , Yao Humphrey H-C , DeMayo Francesco J.
Published: March 2020

Transcription factor FOXL2 exhibits an increase in mRNA levels in eutopic endometrial biopsy in endometriosis patients. While FOXL2 is known of regulating sex differentiation and reproductive function, the impact of elevated FOXL2 expression on uterine physiology remains unknown. To answer this question, we generated mice with over expression of FOXL2 (FOXL2OE) in the female reproductive tract by crossingFoxl2LsL/+with thePgrcremodel. FOXL2OEuterus showed severe morphological abnormality including abnormal epithelial stratification, blunted adenogenesis, increased endometrial fibrosis and disrupted myometrial morphology. In contrast, increasing FOXL2 levels specifically in uterine epithelium by crossing theFoxl2LsL/+with theLtficremice resulted in the eFOXL2OEmice with uterine epithelial stratification but without defects in endometrial fibrosis and adenogenesis, demonstrating a role of the endometrial stroma in the uterine abnormalities of the FOXL2OEmice. Transcriptomic analysis of 12 weeks oldPgrcreand FOXL2OEuterus at diestrus stage showed a positive correlation of FOXL2OEuterine transcriptome with human endometrium of endometriosis patients. Furthermore, we found FOXL2OEmice were sterile. The infertility was caused in part by a disruption of the hypophyseal ovarian axis resulting in an anovulatory phenotype. The FOXL2OEmice failed to show decidual responses during artificial decidualization in ovariectomized mice which demonstrates the uterine contribution to the infertility phenotype. These data supported that aberrantly increased FOXL2 expressions in the female reproductive tract can disrupt ovarian and uterine functions, particularly, may be involved in the progressions of endometriosis.