bluuebunny/crossref_metadata_2025 huggingface dataset:
A diagnostic dilemma: a man with culture sterile cavitating lung lesions

Authors: Cheema Ranvir S P , Kler Prabhjoyt K , Madu Alpha , Macve Joanna , MacDuff Andrew
Published: October 2022

A 20-year-old male presented to the Emergency Department with pyrexia, dyspnoea, chest pain and haemoptysis. Cavitating lung lesions were noted on chest x-ray and the patient was admitted to the intensive care unit where he was intubated and ventilated. Routine investigations including serial cultures did not provide an aetiological diagnosis. As such, a lung biopsy was carried out and 16S rDNA PCR was undertaken on the sample. This identified Fusobacterium necrophorum as the causative organism. The patient was treated for Lemierre’s syndrome and successfully discharged from hospital. This case highlights how DNA tissue typing on a lung biopsy sample can be the key to successful diagnosis in an atypical pneumonia and raises the question as to whether this infrequently used approach should be added to forthcoming BTS community acquired pneumonia guidelines.
MEASUREMENT EFFICIENCY OF AN INSTRUMENTED MOUTHGUARD UNDER A LARGE RANGE OF HEAD ACCELERATIONS AND THE EFFECTS OF FILTERING
Authors: Jones Christopher M. , Austin Kieran , Augustus Simon , Nicholas Kieran Jai , Yu Xiancheng , Baker Claire , Loosemore Mike , Ghajari Mazdak
Published: October 2022

Instrumented mouthguards (iMG) measure head kinematics in sport, but their measurements have not been validated at high levels of accelerations observed in those sports like rugby. In addition, the effects of filter cut-off frequency on the measured kinematics are still unknown. To address these questions, a drop testing helmeted head-form of an anthropometric testing device (ATD) was used to produce a range of accelerations and accurately control them. Peak linear acceleration (PLA), rotational velocity (PRV), rotational acceleration (PRA) and maximum principal strain (MPS) values were computed. The influence of filter cut-off frequency on peak kinematics was also calculated. Comparison of the peak values across ATD and iMG indicated high levels of agreement, with a total concordance correlation coefficient of 0.97 and intraclass correlation coefficients of 0.990 for PLA, 0.970 for PRV, 0.945 for PRA, and 0.970 for MPS. Cut-off frequencies of 100-300Hz did not significantly attenuate peak kinematics, but frequencies lower than 100Hz did. This is the first study to test an iMG under impact conditions seen in sport. The method presented can be used for in-lab validation of iMGs under head accelerations seen in sport. Furthermore, these results can contribute towards defining standards for filtering iMG data.
Cortico-striatal beta-oscillations as a marker of learned reward value
Authors: Koloski M.F. , Hulyalkar S. , Tang T. , Wu X. , Fakhraei L. , Barnes S.A. , Mishra J. , Ramanathan D.S.
Published: October 2022

Single neuron correlates of reward value have been observed in brain regions along the cortico-striatal pathway including ventral striatum, orbital, and medial prefrontal cortex. Brain imaging studies in humans further validate these findings and suggest that value is represented in a network of brain regions opposed to a particular area. Neural activity oscillates at periodic frequencies to coordinate long-range communication in widespread, dynamic networks. To explore how oscillatory dynamics across brain regions may represent reward value, we measured local field potentials of male Long-Evans rats during three distinct behavioral tasks, each probing a different aspect of reward processing. Our goal was to use a data-driven approach to identify a common electrophysiology property associated with reward value. We found that reward-locked oscillations at beta frequencies, in both single units and local field potentials, were markers of positive reward valence. More importantly, Reward-locked beta-oscillations scaled with expected reward value on specific trial types and in a behaviorally relevant way across tasks. Oscillatory signatures of reward processing were observed throughout the cortico-striatal network including electrodes placed in orbitofrontal cortex, anterior insula, medial prefrontal cortex, ventral striatum, and amygdala. These data suggests that beta-oscillations reflect learned reward value in a distributed network, and this may serve as a stable and robust bio-marker for future studies.
The causal role of the inferior temporal cortex in visual perception
Authors: Shahbazi Elia , Ma Timothy , Pernuš Martin , Scheirer Walter , Afraz Arash
Published: October 2022

Neurons in the inferotemporal (IT) cortex respond selectively to complex visual features, implying their role in object perception. However, perception is subjective and cannot be read out from neural responses; thus, bridging the causal gap between neural activity and perception demands independent characterization of perception. Historically though, the complexity of the perceptual alterations induced by artificial stimulation of IT cortex has rendered them impossible to quantify. Here we addressed this old problem by combining machine learning with high-throughput behavioral optogenetics in macaque monkeys. In closed-loop experiments, we generated complex and highly specific images that the animal could not discriminate from the state of being cortically stimulated. These images, named “perceptograms” for the first time, reveal and depict the contents of the complex hallucinatory percepts induced by local neural perturbation in IT cortex. Furthermore, we found that the nature and magnitude of these hallucinations highly depend on concurrent visual input, stimulation location, and intensity. Objective characterization of stimulation-induced perceptual events opens the door to developing a mechanistic theory of visual perception. Further, it enables us to make better visual prosthetic devices and gain a greater understanding of visual hallucinations in mental disorders.

One-Sentence Summary

Combining state-of-the-art AI with high-throughput closed-loop brain stimulation experiments, for the first time, we took “pictures” of the complex and subjective visual hallucinations induced by local stimulation in the inferior temporal cortex, a cortical area associated with object recognition.
Adversarial Attacks on Protein Language Models
Authors: Carbone Ginevra , Cuturello Francesca , Bortolussi Luca , Cazzaniga Alberto
Published: October 2022

Deep Learning models for protein structure prediction, such as AlphaFold2, leverage Transformer architectures and their attention mechanism to capture structural and functional properties of amino acid sequences. Despite the high accuracy of predictions, biologically insignificant perturbations of the input sequences, or even single point mutations, can lead to substantially different 3d structures. On the other hand, protein language models are often insensitive to biologically relevant mutations that induce misfolding or dysfunction (e.g. missense mutations). Precisely, predictions of the 3d coordinates do not reveal the structure-disruptive effect of these mutations. Therefore, there is an evident inconsistency between the biological importance of mutations and the resulting change in structural prediction. Inspired by this problem, we introduce the concept of adversarial perturbation of protein sequences in continuous embedding spaces of protein language models. Our method relies on attention scores to detect the most vulnerable amino acid positions in the input sequences.Adversarial mutationsare biologically diverse from their references and are able to significantly alter the resulting 3d structures.
Complex social behaviour during an extended period of time in a valproic acid animal model of autism spectrum disorder
Authors: Maisterrena Alexandre , de Chaumont Fabrice , Longueville Jean-Emmanuel , Balado Eric , Ey Elodie , Jaber Mohamed
Published: October 2022

Autism Spectrum Disorder (ASD) is a progressive neurodevelopmental disorder characterized mainly by deficits in social communication and stereotyped and restricted interests. Deficits in social interactions in ASD animal models are generally analysed using the three chamber’s test paradigm that is simple to implement and use but fails to detect subtle social deficits or complex social behavior on an extended period of time within a group of mice. Here, we set up a novel procedure entitled the Live Mouse Tracker (LMT) that detects a great number of complex social behaviours that we recorded continuously for up to three days in groups of 4 mice. This was performed in the valproic acid (VPA) mouse model where VPA (450 mg/kg) was injected to pregnant females at E12.5. Studies were performed with a special focus on females given that ASD is 3-4 times more diagnosed in males than in females and that several ASD models failed to detect major social deficits in females, contrary to males. Comparisons were made within groups of 4 female animals with same treatment or within groups of different treatments (saline versus VPA). We report that VPA females show several types of social deficits and that are different in nature and magnitude in relation with time (from 1 hour to 3 days). These deficits were also different when VPA mice were tested together compared to when they were mixed with saline treated mice. Indeed, while social behavior was improved in VPA mice with the presence of saline mice that of saline mice was negatively affected by the presence of VPA mice.

This study indicates that female VPA mice show several social deficits, contrary to the common knowledge. It further implies that ASD related behavior alters normal behavior in a mixed group of mice.
Neural dynamics underlying self-control in the primate subthalamic nucleus
Authors: Pasquereau Benjamin , Turner Robert S.
Published: October 2022

The subthalamic nucleus (STN) is hypothesized to play a central role in neural processes that regulate self-control. Still uncertain, however, is how that brain structure participates in the dynamically evolving representation of value that underlies the ability to delay gratification and wait patiently for a gain. To address that gap in knowledge, we studied the spiking activity of neurons in the STN of monkeys during a task in which animals were required to remain motionless for varying periods of time in order to obtain food reward. At the single-neuron and population levels, we found a cost-benefit integration between the desirability of the expected reward and the imposed delay to reward delivery, with STN signals that dynamically combined both attributes of the reward to form a single integrated estimate of value. This neural representation of subjective value evolved dynamically across the waiting period that intervened between instruction cue and reward delivery. Moreover, this representation was gradually distributed along the antero-posterior axis of the STN such that the most posterior-placed neurons represented the temporal discounting of value most strongly. These findings highlight the selective involvement of the posterior STN in a dynamic internal process that dynamically estimates the ongoing cost-benefit balance of the current context. Such a process is essential for self-control, promoting goal pursuit and the willingness to bear the costs of time delays.
Comprehensive integration of single-cell transcriptomic data illuminates the regulatory network architecture of plant cell fate specification
Authors: Cao Shanni , He Chao , Zhao Xue , Yu Ranran , Li Yuqi , Fang Wen , Zhang Chen-Yu , Yan Wenhao , Chen Dijun
Published: October 2022

Plant morphogenesis relies on precise gene expression programs at the proper time and position which is orchestrated by transcription factors (TFs) in intricate regulatory networks at a cell-type specific manner. Here we presented a reference single-cell transcriptomic atlas ofArabidopsisseedlings by integration of 40 published scRNA-seq datasets from representative tissues as well as the entire under- and above-ground parts. We identified 34 distinct cell types or states, largely expanding our current view of plant cell compositions. We then mapped the developmental trajectory of root-shoot lineage separation and identified differential gene expression programs that may regulate the cell fate determination of under- and above-ground organs. Lastly, we systematically constructed cell-type specific gene regulatory networks and uncovered key regulators that act in a coordination manner to control cell-type specific gene expression. Taken together, our study not only offers a valuable resource plant cell atlas exploration but also provides molecular insights into gene-regulatory programs that determines organ specify, particularly the differentiation between root and shoot.
Transcriptome analyses using regulon, functional category, and operon information with GINtool
Authors: Wang Biwen , van der Kloet Frans , Kes Mariah B.M.J. , Luirink Joen , Hamoen Leendert W.
Published: October 2022

When analysing transcriptome data, threshold values are chosen to decide whether the regulation of a gene is relevant or not, however this may result in the loss of valuable information. To overcome this problem it can be useful to analyse regulons instead of individual genes, to harness the statistical power of combining genes. Another advantage of a regulon-based analysis is that it provides direct insights into the activity of regulatory pathways, which is the essence of transcriptome analyses. We have developed a software tool called GINtool that can use regulon information to analyse transcriptome data. GINtool includes the option to take the activity mode of a regulator in account, which is important when a regulator can function both as an activator and repressor. GINtool also contains two novel graphical representations that greatly facilitate the visual inspection of regulon-based transcriptome analyses. Additional features of GINtool includes the evaluation of transcriptome data using functional categories, and the analysis of gene expression differences within operons. To ease the analyses and downstream processing of figures, GINtool has been developed as an add-in for Excel.
Cytoplasmic mRNA levels are regulated by a combination of chromatin retention and RNA stability
Authors: Henfrey Callum , Murphy Shona , Tellier Michael
Published: October 2022

Transcription and co-transcriptional processes, including pre-mRNA splicing and mRNA cleavage and polyadenylation, regulate the production of mature mRNAs. The carboxyl terminal domain (CTD) of RNA polymerase (pol) II, which comprises 52 repeats of the Tyr1Ser2Pro3Thr4Ser5Pro6Ser7 peptide, is involved in the coordination of transcription with co-transcriptional processes. The pol II CTD is dynamically modified by protein phosphorylation, which regulates recruitment of transcription and co-transcriptional factors. We have investigated whether cytoplasmic levels of mature mRNA from intron-containing protein-coding genes are related to pol II CTD phosphorylation, RNA stability, and pre-mRNA splicing and mRNA cleavage and polyadenylation efficiency. We find that genes that produce a low level of mature mRNA are associated with relatively high phosphorylation of the pol II CTD Tyr1 and Thr4 residues, poor RNA processing, increased chromatin retention, and shorter RNA half-life. While these poorly-processed transcripts are degraded by the nuclear RNA exosome, our results indicate that in addition to RNA half-life, chromatin retention due to a low RNA processing efficiency also plays an important role in the regulation of cytoplasmic mRNA levels.
A Robust, Compact and Diverse Population Code for Competing Sounds in Auditory Cortex
Authors: Nocon Jian Carlo , Witter Jake , Houghton Conor , Gritton Howard , Han Xue , Sen Kamal
Published: October 2022

Cortical circuits encoding sensory information consist of populations of neurons, yet how information aggregates via pooling individual cells remains poorly understood. Such pooling may be particularly important in noisy settings where single neuron encoding is degraded. One example is the cocktail party problem, with competing sounds from multiple spatial locations. How populations of neurons in auditory cortex (ACx) code competing sounds have not been previously investigated. Here, we apply a novel information theoretic approach to estimate information in populations of neurons in ACx about competing sounds from multiple spatial locations, including both summed population (SP) and labeled line (LL) codes. We find that a small subset of neurons is sufficient to nearly maximize mutual information over different spatial configurations, with the LL code outperforming the SP code, and approaching information levels attained without noise. Moreover, with a LL code, units with diverse spatial responses, including both regular and narrow-spiking units, constitute the best pool. Finally, information in the population increases with spatial separation between target and masker, in correspondence with behavioral results on spatial release from masking in human and animals. Taken together, our results reveal that a compact and diverse population of neurons in ACx provide a robust code for competing sounds from different spatial locations.
Cell Painting transfer increases screening hit rate
Authors: Cohen Ethan , Corbe Maxime , Franco Cláudio A. , Vasconcelos Francisca F. , Perez Franck , Nery Elaine Del , Bollot Guillaume , Genovesio Auguste
Published: October 2022

Drug discovery uses high throughput screening to identify compounds that interact with a molecular target or that alter a phenotype favorably. The cautious selection of molecules used for such a screening is instrumental, and is tightly related to the hit rate. In this work, we wondered if Cell Painting, a general purpose image-based assay, could be used as an efficient proxy for compound selection, thus increasing the success rate of a specific assay. To this end, we considered Cell Painting images with 30,000 molecules treatments, and selected compounds that produced a visual effect close to the positive control of an assay, by using the Frechet Inception Distance. We then compared the hit rates of such a preselection with what was actually obtained in real screening campaigns. As a result, Cell Painting would have permitted a significant increase in the success rate and, even for one of the assays, would have allowed to reach 80% of the hits with ten times fewer compounds to test. We conclude that images of a Cell Painting assay can be directly used for compound selection prior to screening, and we provide a simple quantitative approach in order to do so.
Spatially resolved human kidney multi-omics single cell atlas highlights the key role of the fibrotic microenvironment in kidney disease progression
Authors: Abedini Amin , Levinsohn Jonathan , Klötzer Konstantin A , Dumoulin Bernhard , Ma Ziyuan , Frederick Julia , Dhillon Poonam , Balzer Michael S , Shrestha Rojesh , Liu Hongbo , Vitale Steven , Devalaraja-Narashimha Kishor , Grandi Paola , Bhattacharyya Tanmoy , Hu Erding , Pullen Steven S. , Boustany-Kari Carine M , Guarnieri Paolo , Karihaloo Anil , Traum Daniel , Yan Hanying , Coleman Kyle , Palmer Matthew , Sarov-Blat Lea , Morton Lori , Hunter Christopher A. , Kaestner Klaus H , Li Mingyao , Susztak Katalin
Published: October 2022

Kidneys possess one of the most intricate three-dimensional cellular structures in the body, yet the spatial and molecular principles of kidney health and disease remain inadequately understood. Here, we have generated high-quality datasets for 81 samples, including single cell (sc), single nuclear (sn), spot level (Visium) and single cell resolution (CosMx) spatial (sp)-RNA expression, and sn open chromatin, capturing cells from healthy, diabetic, and hypertensive diseased human kidneys. By combining the snRNA, snATAC and scRNA sequencing we identify cell types and map these cell types to their locations within the tissue. Unbiased deconvolution of the spatial data identifies 4 distinct spatial microenvironments: glomerular, immune, tubule and fibrotic. We describe the complex, heterogenous cellular and spatial organization of human microenvironments in health and disease. Further, we find that the fibrotic microenvironment spatial gene signature is not only able to molecularly classify human kidneys, but it also offers an improved prognosis prediction compared to traditional histopathological analysis. We provide a comprehensive spatially resolved molecular roadmap of the human kidney and the fibrotic process, demonstrating the clinical utility of spatial transcriptomics.
LARP4 Is an RNA-Binding Protein That Binds Nuclear-Encoded Mitochondrial mRNAs To Promote Mitochondrial Function
Authors: Lewis Benjamin M , Cho Chae Yun , Her Hsuan-Lin , Hunter Tony , Yeo Gene W
Published: October 2022

Mitochondrial associated RNA-binding proteins (RBPs) have emerged as key contributors to mitochondrial biogenesis and homeostasis. With few examples described, we set out to identify RBPs that regulate nuclear-encoded mitochondrial mRNAs (NEMmRNAs). Our systematic analysis of RNA-targets of 150 RBPs identified RBPs with a preference for binding NEMmRNAs, including LARP4, a La RBP family member. We show that LARP4’s targets are particularly enriched in mRNAs that encode respiratory chain complex proteins (RCCPs) and mitochondrial ribosome proteins (MRPs) across multiple human cell lines. Quantitative proteomics of cells lacking LARP4 show that protein levels of RCCPs and MRPs are significantly reduced. Furthermore, we show that LARP4 depletion reduces mitochondrial function, and that this phenotype is rescued by LARP4 re-expression. Our findings shed light onto a novel function for LARP4 as an RBP that binds to NEMmRNAs to promote mitochondrial respiratory function.

Highlights

Analysis of CLIP data reveals RBPs with a preference for mitochondrial mRNA targets

LARP4’s RNA-target set is enriched for OXPHOS and mitochondrial ribosomal proteins

Loss of LARP4 reduces protein levels of these two groups of mitochondrial proteins

LARP4 is required for normal proliferation, translation, and OXPHOS function
Immunogenicity of the BA.5 Bivalent mRNA Vaccine Boosters
Authors: Collier Ai-ris Y. , Miller Jessica , Hachmann Nicole P. , McMahan Katherine , Liu Jinyan , Bondzie Esther Apraku , Gallup Lydia , Rowe Marjorie , Schonberg Eleanor , Thai Siline , Barrett Julia , Borducchi Erica N. , Bouffard Emily , Jacob-Dolan Catherine , Mazurek Camille R. , Mutoni Audrey , Powers Olivia , Sciacca Michaela , Surve Nehalee , VanWyk Haley , Wu Cindy , Barouch Dan H.
Published: October 2022

Waning immunity following mRNA vaccination and the emergence of SARS-CoV-2 variants has led to reduced mRNA vaccine efficacy against both symptomatic infection and severe disease. Bivalent mRNA boosters expressing the Omicron BA.5 and ancestral WA1/2020 Spike proteins have been developed and approved, because BA.5 is currently the dominant SARS-CoV-2 variant and substantially evades neutralizing antibodies (NAbs). Our data show that BA.5 NAb titers were comparable following monovalent and bivalent mRNA boosters.
Impact of postnatal depression on neonatal outcomes: an exploratory study in Kisumu County, western Kenya
Authors: Gribbin Catherine , Achieng Florence , K’Oloo Alloys , Barsosio Hellen C. , Kwobah Edith , Kariuki Simon , Nabwera Helen M
Published: October 2022

Background

Previous Kenyan studies suggest postnatal depression (PND) may negatively impact infant growth. However these studies are limited to Nairobi and no research has explored the effects of PND in the neonatal period.

Aim

To explore the impact of PND on neonatal feeding practices, weight gain, illness episodes and identify key maternal caregiving challenges.

Methods

A mixed methods study of mothers and newborns <72 hours post-delivery from postnatal wards and clinics across 5 facilities in Kisumu County. At baseline, the Edinburgh Postnatal Depression Scale (EPDS) identified mothers with depressive features (EPDS ≥12) and infant feeding practices were assessed by questionnaire. 24 mothers were followed up 2 weeks later with a questionnaire and interview to further explore caregiving practices. Quantitative data was analysed using descriptive statistics. A thematic framework was used to identify and analyse emerging themes from the interviews.

Results

56 (37%) out of 150 mother-infant pairs screened at baseline had an EPDS score ≥12. These mothers practiced exclusive breastfeeding less frequently (76.9% vs 90.9% p = 0.6) and a smaller proportion of their infants gained weight at 2 weeks (23.1% vs 36.4% p = 0.75). Key stressors were financial insecurity and lack of social support. Mothers described the benefits of social support on their mood and caregiving abilities.

Conclusion

Adverse growth and feeding outcomes are already apparent in the first 2 weeks of life among infants of mothers with features of PND. Early screening and intervention through community support structures could mitigate against the impact of PND on maternal mood and caregiving ability.
Electrophysiological recording of human neuronal networks during suborbital spaceflight
Authors: Padilla Andie E. , Hovell Candice , Mares Jeremy , Reumers Veerle , Joddar Binata
Published: October 2022

The use of microfluidic tissue-on-a-chip devices in conjunction with electrophysiology (EPHYS) techniques has become prominent in recent years to study cell-cell interactions critical to the understanding of cellular function in extreme environments, including spaceflight and microgravity. Current techniques are confined to invasive whole-cell recording at intermittent time points during spaceflight, limiting data acquisition and overall reduced insight on cell behaviour. Currently, there exists no validated technology that offers continuous EPHYS recording and monitoring in physiological systems exposed to microgravity. In collaboration with imec and SpaceTango, we have developed an enclosed, automated research platform that enables continuous monitoring of electrically active human cell cultures during spaceflight. The Neuropixels probe system (imec) will be integrated for the first time within an engineered in-vitro neuronal tissue-on-a-chip model that facilitates the EPHYS recording of cells in response to extracellular electrical activity in the assembled neuronal tissue platform. Our goal is to study the EPHYS recordings and understand how exposure to microgravity affects cellular interaction within human tissue-on-a-chip systems in comparison to systems maintained under Earth’s gravity. Results may be useful for dissecting the complexity of signals obtained from other tissue systems, such as cardiac or gastrointestinal, when exposed to microgravity. This study will yield valuable knowledge regarding physiological changes in human tissue-on-a-chip models due to spaceflight, as well as validate the use of this type of platform for more advanced research critical in potential human endeavours to space.
Multi-Mode Fiber-Based Speckle Contrast Optical Spectroscopy: Analysis of Speckle Statistics
Authors: Lin Chen-Hao P. , Orukari Inema , Tracy Christopher , Frisk Lisa Kobayashi , Verma Manish , Chetia Sumana , Durduran Turgut , Trobaugh Jason W , Culver Joseph P.
Published: October 2022

Speckle contrast optical spectroscopy/tomography (SCOS/T) provides a real-time, non-invasive, and cost-efficient optical imaging approach to mapping of cerebral blood flow. By measuring many speckles (n>>10), SCOS/T has increased signal-to-noise ratio relative to diffuse correlation spectroscopy, which measures one or a few speckles. However, the current free-space SCOS/T designs are not ideal for large field-of-view imaging in humans because the curved head contour cannot be readily imaged with a single flat sensor and hair obstructs optical access. Herein we evaluate the feasibility of using cost-efficient multi-mode fiber (MMF) bundles for use in SCOS/T systems. One challenge with speckle contrast measurements is the potential for confounding noise sources (e.g., shot noise, readout noise) to contribute to the standard deviation measure and corrupt the speckle contrast measure that is central to the SCOS/T systems. However, for true speckle measurements, the histogram of pixel intensities from light interference follows a non-Gaussian distribution, specifically a gamma distribution with non-zero skew, whereas most noise sources have pixel intensity distributions that are Gaussian. By evaluating speckle data from static and dynamic targets imaged through MMF, we use histograms and statistical analysis of pixel histograms to evaluate whether the statistical properties of the speckles are retained. We show that flow-based speckle can be distinguished from static speckle and from sources of system noise through measures of skew in the pixel intensity histograms. Finally, we illustrate in humans that MMF bundles relay blood flow information. © 2022 Optica Publishing Group
Ultra-fast joint-genotyping with SparkGOR
Authors: Guðbjartsson Hákon , Þór Ísleifsson Hjalti , Ragnarsson Bergur , Guimaraes Raony , Wu Haiguo , Ólafsdóttir Hildur , Stefánsson Sigmar K.
Published: October 2022

Motivation

Our aim was to simplify and speedup joint-genotyping, from sequence based variation data of individual samples, while maintaining as high sensitivity and specificity as possible.

Results

We have leveraged versatile GOR data structures to store biallelic representations of variants and sequence read coverage in a very efficient way, allowing for very fast joint-genotyping that is an order of magnitude faster than any joint-genotyping method published to date. Furthermore, it can be easily extended and executed much faster in an incremental fashion. Concordance analysis based on the Genome In A Bottle (GIAB) samples shows favorable results when compared with the de-facto standard approach, using gVCF files and GATK joint-calling. Additionally, we have developed variant quality classification using XGBoost and variant training sets derived from the GIAB samples. The entire business logic is implemented efficiently and concisely in SparkGOR.

Availability

SparkGOR is open-source and freely available athttps://github.com/gorpipe.

Contact

hakon@genuitysci.com
Fast and versatile sequence-independent protein docking for nanomaterials design using RPXDock
Authors: Sheffler William , Yang Erin C. , Dowling Quinton , Hsia Yang , Fries Chelsea N. , Stanislaw Jenna , Langowski Mark , Brandys Marisa , Khmelinskaia Alena , King Neil P. , Baker David
Published: October 2022

Computationally designed multi-subunit assemblies have shown considerable promise for a variety of applications, including a new generation of potent vaccines. One of the major routes to such materials is rigid body sequence-independent docking of cyclic oligomers into architectures with point group or lattice symmetries. Current methods for docking and designing such assemblies are tailored to specific classes of symmetry and are difficult to modify for novel applications. Here we describe RPXDock, a fast, flexible, and modular software package for sequence-independent rigid-body protein docking across a wide range of symmetric architectures that is easily customizable for further development. RPXDock uses an efficient hierarchical search and a residue-pair transform (RPX) scoring method to rapidly search through multidimensional docking space. We describe the structure of the software, provide practical guidelines for its use, and describe the available functionalities including a variety of score functions and filtering tools that can be used to guide and refine docking results towards desired configurations.

Author Summary

Protein design methodologies are now able to generate, through a stepwise approach, a wide variety of self-assembling protein structures that begin to rival the structural complexity of naturally occurring protein nanomachines. Efficient methods for docking oligomeric protein building blocks in user-defined target symmetries are central to these techniques. We developed RPXDock as a fast and versatile method to systematically dock pre-existing proteins together into a multitude of asymmetrical and symmetrical architectures. RPXdock is also readily extendable to future applications through the addition of new symmetries, score functions, and filtering criteria.
SurvivalML: an integrative platform for the discovery and exploration of prognostic models in multi-center cancer cohorts
Authors: Liu Zaoqu , Xu Hui , Liu Long , Weng Siyuan , Xing Zhe , Ren Yuqing , Ge Xiaoyong , Wang Libo , Guo Chunguang , Chen Shuang , Cheng Quan , Luo Peng , Zhang Jian , Han Xinwei
Published: October 2022

Advances in multi-omics and big-data technologies have led to numerous prognostic signatures aimed at improving current clinicopathological staging systems. Due to the lack of reproducibility and independent confirmation, few signatures have been translated into clinical routine. As high-quality datasets accumulate, identifying robust signatures across multiple independent cohorts becomes possible. Nonetheless, inaccurate data retrieval, different versions of genome annotations, disparate expression distributions, difficult data cleaning, inconsistent clinical information, algorithm selection, and parameter tuning have impeded model development and validation in multi-center datasets. Hence, for the first time, we introduced SurvivalML (https://rookieutopia.com/app_direct/SurvivalML/), a web application for helping develop and validate prognostic models across multi-center datasets. SurvivalML included 37,325 samples (253 eligible datasets) with both transcriptome data and survival information from 21 cancer types, which were renewedly and uniformly re-annotated, normalized, and cleaned. This application provided 10 survival machine-learning algorithms for flexibly training models via tuning essential parameters online and delivered four aspects for model evaluation, including Kaplan-Meier survival analysis, time-dependent ROC, calibration curve, and decision curve analysis. Overall, we believe that SurvivalML can serve as an attractive platform for model discovery from multi-center datasets.
MeCP2 represses the induction and maintenance of long-term synaptic plasticity
Authors: Liu Rong-Yu , Zhang Yili , Smolen Paul , Byrne John H.
Published: October 2022

Mechanisms of specific memory deficits associated with Rett syndrome are poorly understood, at least in part because mutations ofMECP2have confounding effects on nervous system development and basal synaptic transmission. To mitigate such empirical uncertainties, this study exploited technical advantages of theAplysiasensorimotor synapse to examine the potential role of MeCP2 in long-term synaptic plasticity. The results indicate MeCP2 may act as an inhibitory constraint on gene expression required for formation as well as maintenance of plasticity.
Gonadal Sex and Sex-Chromosome Complement Interact to Affect Ethanol Consumption in Adolescent Four Core Genotypes Mice
Authors: Aarde Shawn M. , Bagley Jared R. , Jentsch J. David
Published: October 2022

Background

Sex differences in ethanol consumption have been reported in both humans and laboratory rodents, but the independent/dependent contributions of genetic and hormonal sex◻biasing mechanisms to these phenotypes have not yet been fully explored.

Methods

To examine the contributions of sex-chromosome complement (SCC) and gonadal sex (GS) to ethanol consumption, we studied adolescent (28-32 days old) four core genotypes (FCG) mice (C57BL/6J background; FCG model allows for independent assortment of GS and SCC) using a modified drinking-in-the-dark (DID) procedure. Mice were offered concurrent access to 20%, 10% and 0% ethanol (in water) in four daily 2-hour sessions. Consumption at the level of individual bouts was recorded.

Results

Although all four genotype groups preferred the 20% ethanol over 10% and 0%, and showed similar consumption of the 10% and 0% solutions, the group rankings for consumption of the 20% ethanol solution were XX+testes > XY+testes > XY+ovaries > XX+ovaries. Thus, an interaction was observed between SCC and GS for which the simple effect of SCC was greatest in mice with ovaries (XY > XX) and the simple effect of GS was greatest in XX mice (testes > ovaries). Moreover, these effects varied in magnitude across and within drinking sessions. The behavioral microstructure of ethanol consumption (i.e., parameterization of within-session discriminable drinking bouts) support the validity of our 3-bottle modification of the DID procedure as a model of binge-like consumption as: (1) the consumption rate of the 20% ethanol solution was ~80 g EtOH/kg/hwithin a bout(~12 s/bout, ~3 bouts/session), (2) most of this ethanol consumption was completed in a single bout and (3) within-session ethanol consumption was greater earlier than later, indicating “front loading.”

Conclusions

These results indicate that SCC and GS interact on ethanol consumption in adolescent FCG mice on a C57BL/6J background to affect binge-like consumption from the very initiation of access and that these effects are dynamic as they varied both across and within sessions.

Highlights

Gonadal sex and sex-chromosome complementinteracton ethanol consumption in adolescent four core genotypes mice

In adolescent four core genotypes mice, mice with testes drink more ethanol than mice with ovaries, particularly in the presence of an XX karyotype

In adolescent four core genotypes mice, XY mice drink more ethanol than XX mice, but only in mice with ovaries

The effects of sex-biasing biological factors on the patterns of ethanol consumption by adolescent four core genotypes mice that we observed in our 3-bottle Drinking-in-the-Dark procedure showed face validity with some of the sex/gender differences observed in human adolescents
A high-throughput 3D cantilever array to model airway smooth muscle hypercontractility in asthma
Authors: Beri Pranjali , Plunkett Christopher , Barbara Joshua , Shih Chien-Cheng , Barnes S. Whitney , Ross Olivia , Choconta Paula , Trinh Ton , Litvin Bella , Walker John , Qiu Minhua , Hammack Scott , Toyama Erin
Published: October 2022

Asthma is often characterized by tissue-level mechanical phenotypes that include remodeling of the airway and an increase in airway tightening driven by the underlying smooth muscle. Existing therapies only provide symptom relief and do not improve the baseline narrowing of the airway or halt progression of the disease. To investigate such targeted therapeutics, there is a need for models that can recapitulate the 3D environment present in this tissue, provide phenotypic readouts of contractility, and be easily integrated into existing assay plate designs and laboratory automation used in drug discovery campaigns. To address this, we have developed DEFLCT, a high-throughput plate insert that can be paired with standard labware to easily generate high volumes of microscale tissuesin vitrofor screening applications. Using this platform, we exposed primary human airway smooth muscle cell-derived microtissues to a panel of six of inflammatory cytokines present in the asthmatic niche, identifying TGF-β1 and IL-13 as strong contractile modulators. RNAseq analysis further demonstrated enrichment of contractile and remodeling-relevant pathways in TGF-β1 and IL-13 treated tissues as well as pathways generally associated with asthma. Taken together, these data establish a disease relevant, 3D tissue model for the asthmatic airway which combines niche specific inflammatory cues and complex mechanical readouts that can be utilized in drug discovery efforts.
JINXED: Just in time crystallization for easy structure determination of biological macromolecules
Authors: Henkel Alessandra , Galchenkova Marina , Maracke Julia , Yefanov Oleksandr , Hakanpää Johanna , Mesters Jeroen R. , Chapman Henry N. , Oberthür Dominik
Published: October 2022

Macromolecular crystallography is a well-established method in the field of structure biology and has led to the majority of known protein structures to date. After focusing on static structures, the method is now developing towards the investigation of protein dynamics through time-resolved methods. These experiments often require multiple handling steps of the sensitive protein crystals, e.g. for ligand soaking and cryo-protection. These handling steps can cause significant crystal damage, causing a decrease in data quality. Furthermore, in time-resolved experiments based on serial crystallography that use micron-sized crystals for short diffusion times of ligands, certain crystal morphologies with small solvent channels can prevent sufficient ligand diffusion. Described here is a method combining protein crystallization and data collection in a novel one-step-process. Corresponding experiments were successfully performed as a proof-of-principle using hen egg white lysozyme and crystallization times of only a few seconds. This method called JINXED (Justintimecrystallization foreasy structuredetermination) promises to result in high-quality data due the avoidance of crystal handling and has the potential to enable time-resolved experiments with crystals containing small solvent channels by adding potential ligands to the crystallization buffer, simulating traditional co-crystallization approaches.
Different extrapolation of moving object locations in perception, smooth pursuit and saccades
Authors: Lisi Matteo , Cavanagh Patrick
Published: October 2022

The ability to accurately perceive and track moving objects is crucial for many everyday activities. In this study, we use a “double-drift stimulus” Lisi and Cavanagh (2015); Shapiro et al. (2010); Tse and Hsieh (2006) to explore the processing of visual motion signals that underlie perception, pursuit, and saccade responses to a moving object. Participants were presented with peripheral moving apertures filled with noise that either drifted orthogonally to the aperture’s direction or had no net motion. Participants were asked to saccade to and track these targets with their gaze as soon as they appeared, and then to report their direction. In the trials with internal motion, the target disappeared at saccade onset so that the first 100 ms of the post-saccadic pursuit response was driven uniquely by peripheral information gathered before saccade onset. This provided independent measures of perceptual, pursuit, and saccadic responses to the double-drift stimulus on a trial-by-trial basis. Our analysis revealed systematic differences between saccadic responses on one hand and perceptual and pursuit responses on the other. These differences are unlikely to be caused by differences in the processing of motion signals because saccade and pursuit appear to use a common motion processing mechanism (e.g., Erkelens, 2006; Fleuriet and Goffart, 2012). We conclude that our results are instead due to a difference in how the processing mechanisms underlying perception, pursuit, and saccades combine motor signals with target position. These findings advance our understanding of the mechanisms underlying dissociation in visual processing between perception and eye movements.
A Numerical Method to Compute Brain Injury Associated with Concussion
Authors: Bastien C. , Scattina A. , Neal-Sturgess C. , Panno R. , Shrinivas V.
Published: October 2022

Concussion can result from various events in everyday life, including falls, sports collisions, and motor vehicle accidents, which could lead to the disruption of neuronal cell membranes and axonal stretching, leading to a neuro-metabolic cascade of molecular changes in the brain. There is currently no agreement on which computational method can assess such low-level injuries. This paper demonstrates for the first time that the Peak Virtual Power (PVP), based on the Clausius-Duhem inequality, assuming that the injury is represented by the irreversible work in a human body, could be a candidate to capture brain distortion related to concussion. The work is based on the evaluation of the PVP via reconstruction of three NFL helmet-to-helmet impacts by means of finite element analysis, using validated Biocore helmet models fitted with calibrated Hybrid III headforms against linear and angular acceleration impact corridors, which were defined as realistic impact conditions for each collision scenario. Once the exact impact parameters were defined, the Hybrid III headform was replaced with a validated THUMS 4.02 human head model in which the PVP was computed for each head at the corpus callosum and midbrain locations. The results indicate that mild and severe concussions could be prevented for lateral collisions and frontal impacts with PVP values lower than 0.928mW and 9.405mW, respectively, and no concussion would happen in the head vertical impact direction for a PVP value of less than 1.184mW. This innovative method proposes a new paradigm to improve helmet designs, assess sports injuries and improve people’s wellbeing.

Highlights

Peak Virtual Power method can capture brain distortion related to concussion

Concussion is extracted from corpus callosum and midbrain locations of THUMS4.02

Peak power in midbrain less than 1.184mW for a vertical impact leads to no concussion

Peak power in midbrain more than 0.928mW for a lateral impact leads to concussion

Peak power in midbrain more than 9.405mW for a front impact leads to concussion
Concurrent Contribution of Co-contraction to Error Reduction during Dynamic Adaptation of the Wrist
Authors: Farrens Andria J. , Schmidt Kristin , Cohen Hannah , Sergi Fabrizio
Published: October 2022

MRI-compatible robots provide a means of studying brain function involved in complex sensorimotor learning processes, such as adaptation. To properly interpret the neural correlates of behavior measured using MRI-compatible robots, it is critical to validate the measurements of motor performance obtained via such devices. Previously, we characterized adaptation of the wrist in response to a force field applied via an MRI-compatible robot, the MR-SoftWrist. Compared to arm reaching tasks, we observed lower end magnitude of adaptation, and reductions in trajectory errors beyond those explained by adaptation. Thus, we formed two hypotheses: that the observed differences were due to measurement errors of the MR-SoftWrist; or that impedance control plays a significant role in control of wrist movements during dynamic perturbations. To test both hypotheses, we performed a two-session counterbalanced study. In both sessions, participants performed wrist pointing in three force field conditions (zero force, constant, random). Participants used either the MR-SoftWrist or the UDiffWrist, a non-MRI-compatible wrist robot, for task execution in session one, and the other device in session two. To measure anticipatory co-contraction associated with impedance control, we collected surface EMG of four forearm muscles. We found no significant effect of device on behavior, validating the measurements of adaptation obtained with the MR-SoftWrist. EMG measures of co-contraction explained a significant portion of the variance in excess error reduction not attributable to adaptation. These results support the hypothesis that for the wrist, impedance control significantly contributes to reductions in trajectory errors in excess of those explained by adaptation.
Genome-Wide Mapping of 5’ Isoforms with 5’-Seq
Authors: Gvozdenov Zlata
Published: October 2022

Transcriptome of a genome is appreciated to be more complex than previously assumed. Same gene readouts can differ in terms of transcription start site, transcription end site and splicing. Growing evidence suggests functional importance of distinct transcript isoforms of the same gene. Obtaining these isoforms easily experimentally and processing data is crucial for prompt transcriptome functional characterizations. Here, I describe a quick protocol for generation of capped 5’ isoforms sequencing library and 5’ isoforms data analysis. The protocol relies on utilization of dephosphorylation-decapping method (oligo-capping), and it is a simplification of previously published 5’ isoform studies. The pipeline for data analysis suggests several isoform features to focus on.