bluuebunny/crossref_metadata_2025 huggingface dataset:
The P2RX7B splice variant modulates osteosarcoma cell behaviour and metastatic properties
Authors: Tattersall Luke , Shah Karan M. , Lath Darren L. , Singh Archana , Down Jennifer M. , De Marchi Elena , Williamson Alex , Di Virgilio Francesco , Heymann Dominique , Adinolfi Elena , Fraser William D. , Green Darrell , Lawson Michelle A. , Gartland Alison
Published: May 2021

Osteosarcoma (OS) is the most common type of primary bone cancer affecting children and adolescents. OS has a high propensity to spread, meaning the disease is often incurable and fatal. There have been no improvements in survival rates for decades. This highlights an urgent need for development of novel therapeutic strategies. In this study, we have producedin vitroandin vivodata that demonstrates the role of purinergic signalling, specifically, the B isoform of the purinergic receptor P2RX7 (herein termed “ P2RX7B”), in OS progression and metastasis. Our data shows that P2RX7B expression confers a survival advantage in TE85+P2RX7B and MNNG-HOS+ P2RX7B human OS cell linesin vitrothat is minimised following treatment with A740003, a specific P2RX7 antagonist. P2RX7B expression reduced cell adhesion and P2RX7B activation promoted invasion and migrationin vitro, suggesting a probable metastatic phenotype. Using anin vivoOS xenograft model, MNNG-HOS+P2RX7B tumours exhibited ectopic bone formation that was abrogated with A740003 treatment. An increased metastatic phenotype was further demonstratedin vivoas expression of P2RX7B in primary tumour cells increased the propensity of the tumour to metastasise to the lungs. RNA-seq identified a novel gene axis,FN1/LOX/PDGFB/IGFBP3/BMP4, downregulated in response to A740003 treatment. In conclusion, our data indicates for the first time a role for P2RX7B in OS tumour growth, progression and metastasis. We show that P2RX7B is a potential therapeutic target in human OS.

Novelty and Impact

We provide evidence for the pro-tumorigenic role of the B isoform of the P2RX7 purinergic receptor in osteosarcoma (OS). In addition to increasing proliferation, P2RX7B increases the cancerous properties of OS cells, reducing adhesion and increasing migration and invasion.In vivo, P2RX7B does not affect primary tumour growth, but does lead to an increased propensity to metastasize. RNA-seq revealed a new axis of oncogenic genes inhibited by the P2RX7 antagonist and this data could potentially lead to new targets for OS treatment.
Embeddings of genomic region sets capture rich biological associations in lower dimensions
Authors: Gharavi Erfaneh , Gu Aaron , Zheng Guangtao , Smith Jason P. , Zhang Aidong , Brown Donald E. , Sheffield Nathan C.
Published: May 2021

Motivation

Genomic region sets summarize functional genomics data and define locations of interest in the genome such as regulatory regions or transcription factor binding sites. The number of publicly available region sets has increased dramatically, leading to challenges in data analysis.

Results

We propose a new method to represent genomic region sets as vectors, or embeddings, using an adapted word2vec approach. We compared our approach to two simpler methods based on interval unions or term frequency-inverse document frequency and evaluated the methods in three ways: First, by classifying the cell line, antibody, or tissue type of the region set; second, by assessing whether similarity among embeddings can reflect simulated random perturbations of genomic regions; and third, by testing robustness of the proposed representations to different signal thresholds for calling peaks. Our word2vec-based region set embeddings reduce dimensionality from more than a hundred thousand to 100 without significant loss in classification performance. The vector representation could identify cell line, antibody, and tissue type with over 90% accuracy. We also found that the vectors could quantitatively summarize simulated random perturbations to region sets and are more robust to subsampling the data derived from different peak calling thresholds. Our evaluations demonstrate that the vectors retain useful biological information in relatively lower-dimensional spaces. We propose that vector representation of region sets is a promising approach for efficient analysis of genomic region data.

Availability

https://github.com/databio/regionset-embedding
The Impact of Control Interface on Features of Heart Rate Variability
Authors: Javaremi Mahdieh Nejati , Wu Di , Argall Brenna
Published: May 2021

Abstract

Shared human-robot control for assistive machines can improve the independence of individuals with motor impairments. Monitoring elevated levels of workload can enable the assistive autonomy to adjust the control-sharing in an assist-as-needed way, to achieve a balance between user fatigue, stress and independent control. In this work, we aim to investigate how heart-rate variability features can be utilized to monitor elevated levels of mental workload while operating a powered wheelchair, and how that utilization might vary under different control interfaces. To that end, we conducted a 22 person study with three commercial interfaces. Our results show that the validity and reliability of using the ultra-short-term heart-rate variability features as predictors for workload indeed are affected by the type of interface in use.
Multi-Modal Data Analysis for Alzheimer’s Disease Diagnosis: An Ensemble Model Using Imagery and Genetic Features
Authors: Ying Qi , Xing Xin , Liu Liangliang , Lin Ai-Ling , Jacobs Nathan , Liang Gongbo
Published: May 2021

Alzheimer’s disease (AD) is a devastating neurological disorder primarily affecting the elderly. An estimated 6.2 million Americans age 65 and older are suffering from Alzheimer’s dementia today. Brain magnetic resonance imaging (MRI) is widely used for the clinical diagnosis of AD. In the meanwhile, medical researchers have identified 40 risk locus using single-nucleotide polymorphisms (SNPs) information from Genome-wide association study (GWAS) in the past decades. However, existing studies usually treat MRI and GWAS separately. For instance, convolutional neural networks are often trained using MRI for AD diagnosis. GWAS and SNPs are frequently used to identify genomic traits. In this study, we propose a multi-modal AD diagnosis neural network that uses both MRIs and SNPs. The proposed method demonstrates a novel way to use GWAS findings by directly including SNPs in predictive models. We test the proposed methods on the Alzheimer’s Disease Neuroimaging Initiative dataset. The evaluation results show that the proposed method improves the model performance on AD diagnosis and achieves 93.5% AUC and 96.1% AP, respectively, when patients have both MRI and SNP data. We believe this work brings exciting new insights to GWAS applications and sheds light on future research directions.
The integrated role of resource memory and scent-based territoriality in the emergence of home-ranges
Authors: Theng Meryl , Prowse Thomas A. A. , Delean Steven , Cassey Phillip , Bracis Chloe
Published: May 2021

Despite decades of animal movement research, an integrated understanding of the processes underlying the emergence of home-ranges remains inadequate. We explored the effects of integrating two key processes of home-ranging arising from individual movement decisions: (i) memory-based resource use; and (ii) scent-based territoriality. Both mechanisms together led to the formation of exclusive, resource- and population density-dependent home-ranges, which were responsive to perturbations in the conspecific environment (i.e., removing individuals). Home-range patterns (size, size skewness and overlap) were primarily influenced by memory and scent decay rate parameters, demonstrating that home-ranging is ultimately a balance between an animal’s inherent exploratory tendency and its desire to avoid conspecifics. Model application to a population of feral cats demonstrated that general space use patterns could be approximated through simulation, and replication of finer-scale space use patterns is plausible with further model development. Our modelling framework provides a foundation for sophisticated theoretical models of space use in interacting animals.
Short-interval fires and vegetation change in southern California
Authors: Lucero Stephanie M. , Emery Nathan C. , D’Antonio Carla M.
Published: May 2021

Questions

In southern California, shortened fire return intervals may contribute to a decrease in native chaparral shrub presence and an increase in non-native annual grass presence. To test the hypothesis that short-fire return intervals promote a loss in shrub cover, we examined the contribution of single short-interval fires and abiotic conditions on the change of shrub cover within Ventura and Los Angeles counties. Through evaluating pre- and post-fire historical aerial images, we answered the following questions, 1) How has vegetation type cover changed after repeat fires? and 2) What landscape variables contribute the most to the observed change?

Location

Ventura County and Los Angeles County, California, USA.

Methods

We assessed the impact of a single short-interval fire by comparing vegetation recovery in adjacent once- and twice-burned fire burn polygons (long- and short-interval respectively). Pixel plots were examined within each polygon and vegetation cover was classified to vegetation type. We determined the best predictor of vegetation type cover with a linear mixed effects model comparison using Akaike Information Criterion.

Results

Pre-fire and post-fire community type cover was highly correlated. Burn interval was the best predictor of tree cover change (lower cover in twice-burned pixel plots). Aspect was the best predictor of sage scrub cover change (greater cover on north-facing aspects). Years since fire was the best predictor of chaparral cover change (positive correlation) and sage scrub cover change (negative correlation). Conversion of chaparral to sage scrub cover was more likely to occur than conversion of chaparral to annual grass cover.

Conclusions

Our study did not find extensive evidence of a decrease in chaparral shrub cover due to a single short-interval fire. Instead, post-fire cover was highly correlated with pre-fire cover. Chaparral recovery, however, was dynamic suggesting that stand recovery may be strongly influenced by local scale conditions and processes.
A generalized kinetic model describes ion-permeation mechanisms in various ion channels
Authors: Wu Di
Published: May 2021

Ion channels conduct various ions across biological membranes to maintain the membrane potential, to transmit the electrical signals, and to elicit the subsequent cellular responses by the signaling ions. Ion channels differ in their capabilities to select and conduct ions, which can be studied by the patch-clamp recording method that compares the current traces responding to the test voltage elicited at different conditions. In these experiments, the current-voltage curves are usually fitted by a sigmoidal function containing the Boltzmann factor. This equation is quite successful in fitting the experimental data in many cases, but it also fails in several others. Regretfully, some useful information may be lost in these data, which otherwise can reveal the ion-permeation mechanisms. Here we present a generalized kinetic model that captures the essential features of the current-voltage relations and describes the simple mechanism of the ion permeation through different ion channels. We demonstrate that this model is capable to fit various types of the patch-clamp data and explain their ion-permeation mechanisms.
metID:A R package for automatable compound annotation for LC−MS-based data
Authors: Shen Xiaotao , Wu Si , Liang Liang , Chen Songjie , Contrepois Kévin , Zhu Zheng-Jiang , Snyder Michael
Published: May 2021

Accurate and efficient compound annotation is a long-standing challenge for LC−MS-based data (e.g. untargeted metabolomics and exposomics). Substantial efforts have been devoted to overcoming this obstacle, whereas current tools are limited by the sources of spectral information used (in-house and public databases) and are not automated and streamlined. Therefore, we developedmetID, an R package that combines information from all major databases for comprehensive and streamlined compound annotation.metIDis a flexible, simple, and powerful tool that can be installed on all platforms, allowing the compound annotation process to be fully automatic and reproducible. A detailed tutorial and a case study are provided in Supplementary Materials.

Availability and implementation

https://jaspershen.github.io/metID/.

Contact

jiangzhu@sioc.ac.cnandmpsnyder@stanford.edu
Knowledge production and translation of science between Academia and Industry: assessing the impact of R&D in India
Authors: US Vishal Rao , Ram Jenu Naga Durga , Arakeri Gururaj , Nayar Ravi C , Kumar Jitendra , Mendes Rui Amaral
Published: May 2021

India is at the 3rdposition worldwide in terms of publication of scientific literature. However, in terms of productivity, it has been consistently failing to transform the research knowledge into industrial output. This study compares India with the leading countries to understand its lacuna in terms of R&D policy and outputs. Although scientific publications are regarded as the output of basic research, patent applications serve as a better indicator of the applied research. This paper assesses the important determinants for patent filings of a nation. It also focuses on the role of academia and industry collaboration in R&D and the productivity of a nation. We found that the higher the GERD (total Gross Domestic Expenditure of R&D) and the R&D personnel in a nation, the higher the patent filings of the nation. Moreover, we show that academia-industrial collaboration plays a key role in transforming basic research into real-world applications, as we illustrate the government’s role in making necessary policies to make the collaboration successful. This paper highlights the significance of investing in R&D to improve the productivity of a nation, as also the need to design policies to strengthen the applied research environment by fostering solution-centric collaborations between academia and industry.
ARTIFICIAL INTELLIGENCE ACCURATELY DETECTS TRAUMATIC THORACOLUMBAR FRACTURES ON SAGITTAL RADIOGRAPHS
Authors: Rosenberg Guillermo Sanchez , Cina Andrea , Schirò Giuseppe Rosario , Giorgi Pietro Domenico , Gueorguiev Boyko , Alini Mauro , Varga Peter , Galbusera Fabio , Gallazzi Enrico
Published: May 2021

Background context

Traumatic thoracolumbar (TL) fractures are frequently encountered in emergency rooms. Sagittal and anteroposterior radiographs are the first step in the trauma routine imaging. Up to 30% of TL fractures are missed in this imaging modality, thus requiring a CT and/or MRI to confirm the diagnosis. A delay in treatment leads to increased morbidity, mortality, exposure to ionizing radiation and financial burden. Fracture detection with Machine Learning models has achieved expert level performance in previous studies. Reliably detecting vertebral fractures in simple radiographic projections would have a significant clinical and financial impact.

Purpose

To develop a deep learning model that detects traumatic fractures on sagittal radiographs of the TL spine.

Study design/setting

Retrospective Cohort study.

Methods

We collected sagittal radiographs, CT and MRI scans of the TL spine of 362 patients exhibiting traumatic vertebral fractures. Cases were excluded when CT and/or MRI where not available. The reference standard was set by an expert group of three spine surgeons who conjointly annotated the sagittal radiographs of 171 cases. CT and/or MRI were reviewed to confirm the presence and type of the fracture in all cases. 302 cropped vertebral images were labelled ‘fracture’ and 328 ‘no fracture’. After augmentation, this dataset was then used to train, validate, and test deep learning classifiers based on ResNet18 and VGG16 architectures. To ensure that the model’s prediction was based on the correct identification of the fracture zone, an Activation Map analysis was conducted.

Results

Vertebras T12 to L2 were the most frequently involved, accounting for 48% of the fractures. A4, A3 and A1 were the most frequent AO Spine fracture types. Accuracies of 88% and 84% were obtained with ResNet18 and VGG16 respectively. The sensitivity was 89% with both architectures but ResNet18 showed a higher specificity (88%) compared to VGG16 (79%). The fracture zone was precisely identified in 81% of the heatmaps.

Conclusions

Our AI model can accurately identify anomalies suggestive of vertebral fractures in sagittal radiographs by precisely identifying the fracture zone within the vertebral body.

Clinical significance

Clinical implementation of a diagnosis aid tool specifically trained for TL fracture identification is anticipated to reduce the rate of missed vertebral fractures in emergency rooms.
IMMUND: an Early Stage Diagnostic and Therapeutic Frame for Neurodegenerative Diseases and Multiple Sclerosis based on Immunological Markers
Authors: Sen Sagnik , Dey Ashmita , Sanyal Dwipanjan , Chattopadhyay Krishnananda , Maulik Ujjwal
Published: May 2021

For neurodegenerative diseases, the impact of immunological markers is one of the modern research areas. It has been observed that neuroinflammation increases the cellular precipitation of some of the key proteins associated with neurodegenerative diseases. Therefore, the possibility of functional loss can be enhanced due to neuroinflammation which leads to the initiation of any related diseases. In this regard, autoantibodies, which are known for their autophagy nature, can be considered as key elements for early diagnostic as well as early therapeutics. In this article, we have proposed a comprehensive framework to unveil the diagnostic as well as the therapeutic possibility of the autoantibodies which are largely associated with Mild-Moderate Alzheimer’s Disease, Early-Stage Parkinson’s Disease, and Multiple Sclerosis. Here, we have introduced a new concept of average p-value where multiple p-values of an autoantibody in a singular disease have been considered as a multi-occurrence of that sample in cellular systems. Also, multiple proteins from a single protein family under a differentially expressed range have been prioritized. As a result, the top ten autoantibodies have been selected for further study and also considered as diagnostic markers. Interestingly, most of the selected autoantibodies are either cytokines or immunoglobulins. Subsequently, we have performed an evolutionary sequence-structure space study to identify the druggable structural facet for the selected autoantibodies. To make the therapeutic perspective more robust, we have introduced the concept of protein moonlighting. Hence, it provides more robustness in therapeutic identification. Finally, two autoantibodies i.e., Q9NYV4 and P01602 are identified as a novel marker.
Stress-induced protein disaggregation in the Endoplasmic Reticulum catalysed by BiP
Authors: Melo Eduardo Pinho , Farace Ilaria , Konno Tasuku , Awadelkareem Mosab Ali , Skov Lise R. , Sancho Teresa P. , Paton Adrienne W. , Paton James C. , Fares Matthew , Paulo Pedro M. R. , Zang Xin , Avezov Edward
Published: May 2021

Protein synthesis is supported by cellular machineries that ensure polypeptides fold to their native three-dimensional conformation with high fidelity whilst eliminating misfolded, aggregation-prone species. While protein aggregates can contribute to pathologies exemplified by Alzheimer’s and Parkinson’s diseases, their abundance is normally minimised by molecular chaperones such as HSP70/90, which promote native folding and drive the recycling of aberrantly folded species. Cytoplasmic chaperones (e.g. HSP70/40) can resolve insoluble protein aggregates should the preventive mechanisms falter. However, it is unknown whether an analogous disaggregation system is needed and exists in the Endoplasmic Reticulum (ER), where ∼30% of the proteome is synthesised. Here we show that the ER of a variety of mammalian cell types, including neurons, is endowed with the capability to resolve protein aggregates that accumulate upon expression of metastable proteins. Utilising a purpose-developed protein aggregation probing system with a sub-organellar resolution, we observed steady-state aggregate accumulation in the ER. Strikingly, pharmacological induction of ER stress did not augment aggregates but rather stimulated their clearance within hours. We found that this disaggregation activity was catalysed by the stress-responsive ER molecular chaperone – BiP. Its elimination abolished the disaggregation activity in cells. Further, we reconstructed the disaggregation-reactionin-vitroby a minimal system of ATP-fuelled BiP and its J-protein cofactor. These data reveal a hitherto unknown, non-redundant function of the ER stress response. Thus, our findings may facilitate the identification of aggregation-antagonising strategies and rationalising the age-dependent protein misfolding pathology.

ER stress induction activates a protein disaggregation machinery, powered by BiP – an abundant ER chaperone, revealed by a FLIM-based protein aggregation monitoring in live cells.
Disrupted microglial iron homeostasis in progressive multiple sclerosis
Authors: Proto Jonathan D. , Zhang Mindy , Ryan Sean , Yao Xinting , Huang Yinyin , Chang Yi-Chien , Dufault Michael R. , Christie Emilie , Chomyka Anthony , Saleh Jackie , Sancho Jose , Hammond Timothy , Trapp Bruce , Ofengeim Dimitry
Published: May 2021

Multiple Sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS). Despite therapies that reduce relapses, many patients eventually develop secondary progressive MS (SPMS), characterized by ongoing and irreversible neurodegeneration and worsening clinical symptoms. Microglia are the resident innate immune cells of the CNS. While the cellular and molecular determinants of disability progression in MS remain incompletely understood, they are thought to include non-resolving microglial activation and chronic oxidative injury. In this study, our aim was to better characterize microglia in SPMS tissues to identify disease-related changes at the single cell level. We performed single nucleus RNA-seq (snRNA-seq) on cryopreserved post-mortem brain cortex and identified disease associated changes in multiple cell types and in particular distinct SPMS-enriched microglia subsets. When compared to the cluster most enriched in healthy controls (i.e. homeostatic microglia), we found a number of SPMS-enriched clusters with transcriptional profiles reflecting increased oxidative stress and perturbed iron homeostasis. Using histology and RNA-scope, we confirmed the presence of iron accumulating, ferritin-light chain (FTL)-expressing microgliain situ. Among disease-enriched clusters, we found evidence for divergent responses to iron accumulation and identified the antioxidant enzyme GPX4 as a key fate determinant. These data help elucidate processes that occur in progressive MS brains, and highlight novel nodes for therapeutic intervention.
iPSC modeling shows uncompensated mitochondrial mediated oxidative stress underlies early heart failure in hypoplastic left heart syndrome
Authors: Xu Xinxiu , Jin Kang , Bais Abha S. , Zhu Wenjuan , Yagi Hisato , Feinstein Timothy N , Nguyen Phong , Criscione Joseph , Liu Xiaoqin , Beutner Gisela , Karunakaran Kalyani B. , Adams Phillip , Kuo Catherine K. , Kostka Dennis , Pryhuber Gloria S. , Shiva Sruti , Ganapathiraju Madhavi K. , Porter George A. , Lin Jiuann-Huey Ivy , Aronow Bruce , Lo Cecilia W.
Published: May 2021

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with 30% mortality from heart failure (HF) in the first year of life, but why only some patients suffer early-HF and its cause remain unknown. Modeling using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) showed early-HF patient iPSC-CM have increased apoptosis, redox stress, and failed antioxidant response. This was associated with mitochondrial permeability transition pore (mPTP) opening, mitochondrial hyperfusion and respiration defects. Whereas iPSC-CM from patients without early-HF had hyper-elevated antioxidant response with increased mitochondrial fission and mitophagy. Single cell transcriptomics showed dichotomization by HF outcome, with mitochondrial dysfunction and endoplasmic reticulum (ER) stress associated with early-HF. Importantly, oxidative stress and apoptosis associated with early HF were rescued by sildenafil inhibition of mPTP opening or TUDCA suppression of ER stress. Together these findings demonstrate a new paradigm for modeling clinical outcome in iPSC-CM, demonstrating uncompensated mitochondrial oxidative stress underlies early HF in HLHS.
xbx-4, a homolog of the Joubert syndrome gene FAM149B1, acts via the CCRK and MAK kinase cascade to regulate cilia morphology
Authors: Maurya Ashish K. , Sengupta Piali
Published: May 2021

Primary cilia are microtubule (MT)-based organelles that mediate sensory functions in multiple cell types. Disruption of cilia structure or function leads to a diverse collection of diseases termed ciliopathies (1–3). Mutations in the DUF3719 domain-containing protein FAM149B1 have recently been shown to elongate cilia via unknown mechanisms and result in the ciliopathy Joubert syndrome (4). The highly conserved CCRK and MAK/RCK kinases negatively regulate cilia length and structure inChlamydomonas, C. elegans, and mammalian cells (5–11). How the activity of this kinase cascade is tuned to precisely regulate cilia architecture is unclear. Here we identify XBX-4, a DUF3719 domain-containing protein related to human FAM149B1, as a novel regulator of the DYF-18 CCRK and DYF-5 MAK kinase pathway inC. elegans.As indyf-18anddyf-5mutants (11), sensory neuron cilia are elongated inxbx-4mutants and exhibit altered axonemal MT stability. XBX-4 promotes DYF-18 CCRK activity to regulate DYF-5 MAK function and localization. We find that Joubert syndrome-associated mutations in the XBX-4 DUF3719 domain also elongate cilia inC. elegans.Our results identify a new metazoan-specific regulator of this highly conserved kinase pathway, and suggest that FAM149B1 may similarly act via the CCRK/MAK kinase pathway to regulate ciliary homeostasis in humans.
Species variations in tenocytes’ response to inflammation require careful selection of animal models for tendon research
Authors: Oreff Gil Lola , Fenu Michele , Vogl Claus , Ribitsch Iris , Jenner Florien
Published: May 2021

For research on tendon injury, many different animal models are utilized; however, the extent to which these species simulate the clinical condition and disease pathophysiology has not yet been critically evaluated. Considering the importance of inflammation in tendon disease, this study compared the cellular and molecular features of inflammation in tenocytes of humans and four common model species (mouse, rat, sheep, and horse). While mouse and rat tenocytes most closely equalled human tenocytes’ low proliferation capacity and the negligible effect of inflammation on proliferation, the wound closure speed of humans was best approximated by rats and horses. The overall gene expression of human tenocytes was most similar to mice under healthy, to horses under transient and to sheep under constant inflammatory conditions. Humans were best matched by mice and horses in their tendon marker and collagen expression, by horses in extracellular matrix remodelling genes, and by rats in inflammatory mediators. As no single animal model perfectly replicates the clinical condition and sufficiently emulates human tenocytes, fit-for-purpose selection of the model species for each specific research question and combination of data from multiple species will be essential to optimize translational predictive validity.
Population Structure of Nation-wide Rice in Thailand
Authors: Vejchasarn Phanchita , Shearman Jeremy R. , Chaiprom Usawadee , Phansenee Yotwarit , Suthanthangjai Arissara , Jairin Jirapong , Chamarerk Varapong , Tulyananda Tatpong , Amornbunchornvej Chainarong
Published: May 2021

Background

Thailand is a country with large diversity in rice varieties due to its rich and diverse ecology. In this paper, 300 rice accessions from all across Thailand were sequenced to identify SNP variants allowing for the population structure to be explored.

Results

The result of inferred population structure from admixture and clustering analysis illustrated strong evidence of substructure in each geographical region. The results of phylogenetic tree, PCA analysis, and machine learning on population identifying SNPs also supported the inferred population structure.

Conclusion

The population structure inferred in this study contains five subpopulations that tend to group individuals based on location. So, each subpopulation has unique genetic patterns, agronomic traits, as well as different environmental conditions. This study can serve as a reference point of the nation-wide population structure for supporting breeders and researchers who are interested in Thai rice.
Insights into the molecular mechanisms of cell fate decision making processes from chromosome structural dynamics
Authors: Chu Xiakun , Wang Jin
Published: May 2021

Cell state transitions or cell fate decision making processes, such as cell development and cell pathological transformation, are believed to be determined by the regulatory network of genes, which intimately depend on the structures of chromosomes in the cell nucleus. The high temporal resolution picture of how chromosome reorganizes its 3D structure during the cell state transitions is the key to understanding the mechanisms of these fundamental cellular processes. However, this picture is still challenging to acquire at present. Here, we studied the chromosome structural dynamics during the cell state transitions among the pluripotent embryonic stem cell (ESC), the terminally differentiated normal cell and the cancer cell using landscape-switching model implemented in the molecular dynamics simulation. We considered up to 6 transitions, including differentiation, reprogramming, cancer formation and reversion. We found that the pathways can merge at certain stages during the transitions for the two processes having the same destination as the ESC or the normal cell. Before reaching the merging point, the two pathways are cell-type-specific. The chromosomes at the merging points show high structural similarity to the ones at the final cell states in terms of the contact maps, TADs and compartments. The post-merging processes correspond to the adaption of the chromosome global shape geometry through the chromosome compaction without significantly disrupting the contact formation. On the other hand, our detailed analysis showed no merging point for the two cancer formation processes initialized from the ESC and the normal cell, implying that cancer progression is a complex process and may be associated with multiple pathways. Our results draw a complete molecular picture of cell development and cancer at the dynamical chromosome structural level, and help our understanding of the molecular mechanisms of cell fate decision making processes.
Organ-specific metabolic pathways distinguish prediabetes, type 2 diabetes and normal tissues
Authors: Diamanti Klev , Cavalli Marco , Pereira Maria J. , Pan Gang , Castillejo-Lopez Casimiro , Kumar Chanchal , Mundt Filip , Komorowski Jan , Deshmukh Atul Shahaji , Mann Matthias , Korsgren Olle , Eriksson Jan W. , Wadelius Claes
Published: May 2021

Defects in pancreatic islets and the progression of multi-tissue insulin resistance in combination with environmental factors are the main causes of type 2 diabetes (T2D). Mass spectrometry-based proteomics of five key-metabolic tissues on a cohort of 42 multi-organ donors provided deep coverage of the proteomes of pancreatic islets, visceral adipose tissue (VAT), liver, skeletal muscle and serum. Enrichment analysis of gene ontology (GO) terms built a tissue-specific map of the chronological order of altered biological processes across healthy controls (CTRL), pre-diabetes (PD) and T2D subjects. This unique dataset allowed us to explore alterations of entire biological pathways and individual proteins in multiple tissues. We confirmed the significant decrease of the citric acid cycle and the respiratory electron transport in VAT and muscle of T2D and we provided a thorough visual representation of the complete set of downregulated proteins. Importantly, we found widespread novel alterations in relevant biological pathways including the increase in hemostasis in pancreatic islets of PD, the increase in the complement cascade in liver and pancreatic islets of PD and the elevation in cholesterol biosynthesis in liver of T2D. Overall, our findings suggest inflammatory, immune and vascular impairments in pancreatic islets as potentially causal factors of insufficient insulin production and increased glucagon levels in the early stages of T2D. In contrast alterations in lipid metabolism and mitochondrial function in the liver and VAT/muscle, respectively, became evident later in manifest T2D. This first multi-tissue proteomic map indicates the temporal order of tissue-specific metabolic dysregulation in T2D development.
Human iPSC-derived mesodermal progenitor cells preserve their vasculogenesis potential after extrusion and form hierarchically organized blood vessels
Authors: Dogan Leyla , Scheuring Ruben , Wagner Nicole , Ueda Yuichiro , Wörsdörfer Philipp , Groll Jürgen , Ergün Süleyman
Published: May 2021

Post-fabrication formation of a proper vasculature remains an unresolved challenge in bioprinting. Established strategies focus on the supply of the fabricated structure with nutrients and oxygen and either rely on the mere formation of a channel system using fugitive inks, or additionally use mature endothelial cells and/or peri-endothelial cells such as smooth muscle cells for the formation of blood vessels in vitro. Functional vessels, however, exhibit a hierarchical organization and multilayered wall structure that is important for their function. Human induced pluripotent stem cell-derived mesodermal progenitor cells (hiMPCs) have been shown to possess the capacity to form blood vessels in vitro, but have so far not been assessed for their applicability in bioprinting processes. Here, we demonstrate that hiMPCs, after formulation into an alginate / collagen type 1 bioink and subsequent extrusion, retain their ability to give rise to the formation of complex vessels that display a hierarchical network in a process that mimicks the embryonic steps of vessel formation by vasculogenesis. Histological evaluations at different time points of extrusion revealed initial formation of spheres, followed by lumen formation and further structural maturation as evidenced by building a multilayered vessel wall and a vascular network. These findings are supported by immunostainings for endothelial and peri-endothelial cell markers as well as electron microscopic analyses at the ultrastructural level. Moreover, capillary-like vessel structures deposited a basement membrane-like matrix structure at the basal side between the vessel wall and the alginate-collagen matrix. These results evidence the applicability and great potential of hiMPCs for the bioprinting of vascular structures mimicking the basic morphogenetic steps of de novo vessel formation during embryogenesis.
Cytokinin oxidase/dehydrogenase family genes exhibit functional divergence and overlap in ricegrowth and development, especially in control of tillering
Authors: Rong Chenyu , Liu Yuexin , Chang Zhongyuan , Liu Ziyu , Ding Yanfeng , Ding Chengqiang
Published: May 2021

Cytokinins play key roles in plant growth and development; hence, cytokinin biosynthesis and degradation have been extensively studied. Cytokinin oxidase/dehydrogenases (CKXs) are a group of enzymes that regulate oxidative cleavage to maintain cytokinin homeostasis. In rice, 11 OsCKX genes have been identified to date; however, most of their functions remain unknown. Here, we comprehensively analyzed the expression patterns and functions of OsCKX genes. Using CRISPR/Cas9 technology, we constructed mutants of all OsCKX genes to determine the functions of OsCKXs in rice development. The results revealed that the single osckx and higher-order osckx4 osckx9 mutant lines showed functional overlap and subfunctionalization. Notably, the osckx1 osckx2 and osckx4 osckx9 double mutants displayed contrasting phenotypic changes in tiller number and panicle size compared to the wild type. Moreover, we identified several genes with significantly altered expression in osckx4 and osckx9 single and double mutant plants. Many differentially expressed genes were found to be associated with auxin and cytokinin pathways. Additionally, the cytokinins in osckx4 osckx9 mutants were increased compared to the wild type. Overall, our findings provide new insights into the functions of OsCKX genes in rice growth and may be used as a foundation for future studies aimed at improving rice yield. Key words: Cytokinin, expression pattern, OsCKX, panicle, phenotype, rice, tiller

Highlight

The osckx4 osckx9 double mutant had a significantly greater number of tillers, whereas the osckx1 osckx2 double mutant showed the opposite phenotypic change, compared to the wild type
Neutrophils impose strong selective pressure against PfEMP1 variants implicated in cerebral malaria
Authors: Zelter Tamir , Strahilevitz Jacob , Simantov Karina , Yajuk Olga , Jensen Anja Ramstedt , Dzikowski Ron , Granot Zvi
Published: May 2021

Plasmodium falciparum, the deadliest form of human malaria, remains one of the major threats to human health in endemic regions. Its virulence is attributed to its ability to modify infected red blood cells (iRBC) to adhere to endothelial receptors by placing variable antigens known as PfEMP1 on the surface of the red cell. PfEMP1 expression on the red cell surface determines the cytoadhesive properties of the iRBCs and is implicated in severe manifestations of malaria. To evade antibody mediated responses the parasite undergoes continuous switches of expression between different PfEMP1 variants. Recently it became clear that in addition to antibody mediated responses, PfEMP1 triggers an innate immune response, however, the role of neutrophils, the most abundant white blood cells in the human circulation, in malaria remains elusive. Here we show that neutrophils recognize and kill blood stages of several P. falciparum isolates, and we identify neutrophil ICAM-1 and specific PfEMP1s implicated in cerebral malaria as the key molecules involved in this killing. Our data provide mechanistic insight into the interactions between neutrophils and iRBCs and demonstrate the important influence of PfEMP1 on the selective innate response to cerebral malaria.
Morph-specific investment in testes mass in a trimorphic beetle, Proagoderus watanabei
Authors: Parrett Jonathan M. , Slade Eleanor M. , Knell Robert J.
Published: May 2021

When competition between males for mates is intense it is common to find that some males will adopt alternative tactics for acquiring fertilisations, often involving the use of ‘sneak’ tactics whereby males avoid contests. These alternative tactics are sometimes associated with discrete differences in male morphology, with sneak males investing less in weaponry but more in traits such as testes which will give an advantage in sperm competition. In some cases it appears that males develop into more than two morphs, with a number of examples of tri- and even tetramorphic arthropod species being described. Here we analyse the scaling relations of the dung beetle species Proagoderus watanabei, which expresses two distinct weapon traits: paired head horns and a pronotal horn. We find that males of this species are trimorphic, with alpha males expressing long head horns and a pronotal horn, beta males with long head horns but no pronotal horn, and gamma males with short head horns only. We also find that alpha males invest less in testes than do beta or gamma males, indicating that beta and gamma males in this species probably experience higher risks of sperm competition than do alphas.
Using Repetitive Control to Enhance Force Control During Human-Robot Interaction in Quasi-Periodic Tasks
Authors: McGrath Robert L. , Sergi Fabrizio
Published: May 2021

We investigated the use of repetitive control (RC) to enhance force control during human-robot interaction in quasi-periodic tasks. We first developed a two-mass spring damper model and formulated three different RCs under force control: a 1st order RC (RC-1), a 3rd order RC designed for random period error, and a 3rd order RC designed for constant period error. Then, we quantified the performance of these three RCs through simulations and experiments conducted on a bench top linear platform, subject to nominal cyclical inputs (input signal and fundamental frequency: 0.5 Hz), and subject to inputs with random and constant period errors. Moreover, we compared the performance achieved with the RCs with those achievable with a passive proportional controller (PPC), subject to known theoretical limits for passivity and coupled stability.

In both simulated and real-world experiments, the root mean square force error under nominal conditions was reduced most effectively by the RC-1 to 0.7% and 12.9%, respectively, of the error achieved with the PPC. Subject to inputs with constant period errors, RCs performed better than PPC for period error values below 0.05 Hz, with the RC-1 performing significantly better than both 3rd order RCs. Subject to inputs with random period errors, all RCs performed better than PPC up to 0.11 Hz of frequency error. Our results indicate that RC can successfully integrated in force control schemes to improve performance beyond the one achievable with a PPC, in the range of period variability expected in applications such as walking assistance and rehabilitation.
The SWI/SNF and RSC Cooperatively Remodel the Promoters of Unfolded Protein Response Targets and Heat Shock Genes
Authors: Sahu Rakesh Kumar , Singh Sakshi , Tomar Raghuvir Singh
Published: May 2021

The ATP-dependent chromatin remodelling complexes maintain the chromatin dynamics, enabling the gene expression or its silencing. The SWI/SNF subfamily remodelers (SWI/SNF and RSC) generally promote gene expression by displacing or evicting nucleosomes at the promoter regions. Their action creates a nucleosome-depleted region where transcription machinery accesses the DNA. Their involvement has been shown critical for the induction of stress-responsive transcription programs. Although the role of SWI/SNF and RSC complexes in transcription regulation of heat shock responsive genes is well studied, their involvement at other pathway genes such as UPR, HSP and PQC is less known. In this study, we showed that the SWI/SNF occupies promoters of UPR, HSP and PQC genes in response to the unfolded protein stress, and its recruitment at UPR promoters is dependent on the Hac1 transcription factor and other epigenetic factors like Ada2 and Ume6. Disruption of SWI/SNF’s activity does not affect the remodelling of these promoters or gene expression. However, inactivation of both RSC and SWI/SNF complexes diminishes expression of most of the UPR, HSP and PQC genes tested. Altogether these results suggest that these two remodelers work together or one compensates the loss of the other to ensure optimal induction of the stress-responsive genes.
FTY720 (Fingolimod), a modulator of sphingosine-1-phosphate receptors, increases baseline hypothalamic-pituitary adrenal axis activity and alters behaviors relevant to affect and anxiety
Authors: Corbett Brian , Luz Sandra , Sotuyo Nathaniel , Pearson-Leary Jiah , Moorthy Ganesh S. , Zuppa Athena F. , Bhatnagar Seema
Published: May 2021

FTY720 (fingolimod) is an analog of sphingosine, a ubiquitous sphingolipid. Phosphorylated FTY720 (FTY720-P) non-selectively binds to sphingosine-1-phosphate receptors (S1PRs) and regulates multiple cellular processes including cell proliferation, inflammation, and angiogenesis. We recently demonstrated that S1PR3 expression in the medial prefrontal cortex (mPFC) of rats promotes stress resilience and that S1PR3 expression in blood may serve as a biomarker for PTSD. Here we investigate the effects of FTY720 in regulating the stress response. We found that single and repeated intraperitoneal injections of FTY720 increased baseline plasma adrenocorticotropic hormone (ACTH) and corticosterone concentrations. FTY720 also mitigated restraint-induced increases in ACTH and corticosterone. FTY720 reduced social anxiety- and despair-like behavior as assessed by increased social interaction time and reduced time spent immobile in the Porsolt forced swim test. In blood, FTY720 administration reduced lymphocyte and reticulocyte counts, but raised erythrocyte counts. FTY720 also reduced mRNA of angiopoietin 1, endothelin 1, plasminogen 1, Vegf-B, and Mmp2 in the medial prefrontal cortex, suggesting that FTY720 reduced angiogenesis. The antidepressant-like and anxiolytic-like effects of FTY720 may be attributed to reduced angiogenesis as increased stress-induced blood vessel density in the brain contributes to depression- and anxiety-like behavior in rats. Together, these results suggest that S1PRs regulate baseline HPA axis activity but reduces social anxiety and despair providing further evidence that S1PRs are important and novel regulators of stress-related functions.
Cold survival and its molecular mechanisms in a locally adapted nematode population
Authors: Wang Wenke , Flury Anna G. , Garrison Jennifer L. , Brem Rachel B.
Published: May 2021

Since Darwin, evolutionary biologists have sought to understand the drivers and mechanisms of natural trait diversity. The field advances toward this goal with the discovery of phenotypes that vary in the wild, their relationship to ecology, and their underlying genes. Here, we established resistance to extreme low temperature in the free-living nematode Caenorhabditis briggsae as an ecological and evolutionary model system. We found that C. briggsae strains of temperate origin were strikingly more cold-resistant than those isolated from tropical localities. Transcriptional profiling revealed expression patterns unique to the resistant temperate ecotype, including dozens of genes expressed at high levels even after multiple days of cold-induced physiological slowdown. Mutational analysis validated a role in cold resistance for seven such genes. As the temperate C. briggsae population likely diverged only ~700 years ago from tropical ancestors, our findings highlight a candidate case of very rapid, robust, and genetically complex adaptation, and shed light on the mechanisms at play.
Live 3D imaging and mapping of shear stresses within tissues using incompressible elastic beads
Authors: Souchaud Alexandre , Boutillon Arthur , Charron Gaëlle , Asnacios Atef , Noûs Camille , David Nicolas B. , Graner François , Gallet François
Published: May 2021

To investigate the role of mechanical constraints in morphogenesis and development, we develop a pipeline of techniques based on incompressible elastic sensors. These techniques combine the advantages of incompressible liquid droplets, which have been used as precise in situ shear stress sensors, and of elastic compressible beads, which are easier to tune and to use. Droplets of a polydimethylsiloxane (PDMS) mix, made fluorescent through specific covalent binding to a rhodamin dye, are produced by a microfluidics device. The elastomer rigidity after polymerization is adjusted to the tissue rigidity. Its mechanical properties are carefully calibrated in situ, for a sensor embedded in a cell aggregate submitted to uniaxial compression. The local shear stress tensor is retrieved from the sensor shape, accurately reconstructed through an active contour method. In vitro, within cell aggregates, and in vivo, in the prechordal plate of the Zebrafish embryo during gastrulation, our pipeline of techniques demonstrates its efficiency to directly measure the three dimensional shear stress repartition within a tissue, and its time evolution.