bluuebunny/crossref_metadata_2025 huggingface dataset:
Inner membrane complex proteomics reveals a palmitoylation cascade regulating intraerythrocytic development of malaria parasite
Authors: Qian Pengge , Wang Xu , Zhong Chuan-Qi , Wang JiaXu , Cai Mengya , Nguitragool Wang , Li Jian , Cui Huiting , Yuan Jing
Published: February 2022

Malaria is caused by infection of the erythrocytes by the parasitesPlasmodium. Inside the erythrocytes, the parasites multiply via schizogony, an unconventional cell division mode. The Inner Membrane Complex (IMC), an organelle located beneath the parasite plasma membrane, serving as the platform for protein anchorage, is essential for schizogony. So far, complete repertoire of IMC proteins and their localization determinants remain unclear. Here we used biotin ligase (TurboID)-based proximity labelling to compile the proteome of the schizont IMC of rodent malaria parasitePlasmodium yoelii.In total, 300 TurboID-interacting proteins were identified. 19 of the 22 selected candidates were confirmed to localize in the IMC, indicating good reliability. In light of the existing palmitome ofPlasmodium falciparum, 83 proteins of theP. yoeliiIMC proteome are potentially palmitoylated. We further identified DHHC2 as the major resident palmitoyl-acyl-transferase of the IMC. Depletion of DHHC2 led to defective schizont segmentation and growth arrest bothin vitroandin vivo. DHHC2 was found to palmitoylate two critical IMC proteins CDPK1 and GAP45 for their IMC localization. In summary, this study reports an inventory of new IMC proteins and demonstrates a central role of DHHC2 in governing IMC localization of proteins during the schizont development.
Learning the Vector Coding of Egocentric Boundary Cells from Visual Data
Authors: Lian Yanbo , Williams Simon , Alexander Andrew S. , Hasselmo Michael E. , Burkitt Anthony N.
Published: January 2022

The use of spatial maps to navigate through the world requires a complex ongoing transformation of egocentric views of the environment into position within the allocentric map. Recent research has discovered neurons in retrosplenial cortex and other structures that could mediate the transformation from egocentric views to allocentric views. These egocentric boundary cells respond to the egocentric direction and distance of barriers relative to an animals point of view. This egocentric coding based on the visual features of barriers would seem to require complex dynamics of cortical interactions. However, computational models presented here show that egocentric boundary cells can be generated with a remarkably simple synaptic learning rule that forms a sparse representation of visual input as an animal explores the environment. Simulation of this simple sparse synaptic modification generates a population of egocentric boundary cells with distributions of direction and distance coding that strikingly resemble those observed within the retrosplenial cortex. This provides a framework for understanding the properties of neuronal populations in the retrosplenial cortex that may be essential for interfacing egocentric sensory information with allocentric spatial maps of the world formed by neurons in downstream areas including the grid cells in entorhinal cortex and place cells in the hippocampus.
A novel genomic DNA library preparation method with low GC bias
Authors: Kelly S. Thomas , Hakoyama Tsuneo , Kumaishi Kie , Okuda-Yabukami Haruka , Kato Sachi , Hayashi Makoto , Minoda Aki , Ichihashi Yasunori
Published: February 2022

The amount of input DNA available to prepare next-generation sequencing (NGS) libraries is often limited, which can lead to GC content bias and enrichment of specific genomic regions with currently available protocols. In this study, we used breath capture technology to incorporate sequencing adapters into DNA to develop a novel cost-effective protocol for the preparation of genomic DNA libraries. We performed a benchmarking experiment comparing our protocol with common commercially available kits for genomic DNA library preparation with input DNA amount in the range of 1 to 50 ng. Our protocol can generate high-quality genomic sequence data with a marked improvement in coverage breadth and low GC bias, in contrast to standard protocols. Further, our protocol reduces sample handling time and reagent costs, and requires comparatively fewer enzymatic steps relative to other protocols, making it suitable for a range of genomics applications.
Synthetic glycans that control gut microbiome structure mitigate colitis in mice
Authors: Tolonen Andrew C , Beauchemin Nicholas , Bayne Charlie , Li Lingyao , Tan Jie , Lee Jackson , Meehan Brian , Meisner Jeffrey , Millet Yves , LeBlanc Gabrielle , Kottler Robert , Rapp Erdmann , Murphy Chris , Turnbaugh Peter J , von Maltzahn Geoffrey , Liu Christopher M , van Hylckama Vlieg Johan ET
Published: January 2022

Relative abundances of bacterial species in the gut microbiome have been linked to many diseases. Species of gut bacteria are ecologically differentiated by their abilities to metabolize different glycans, making glycan delivery a powerful way to alter the microbiome to promote health. We describe the properties and therapeutic potential of chemically diverse synthetic glycans (SGs). Fermentation of SGs by gut microbiome cultures resulted in compound-specific shifts in taxonomic and metabolite profiles not observed with reference glycans, including prebiotics. Model enteric pathogens grow poorly on most SGs, potentially increasing their safety for at-risk populations. SGs increased survival, reduced weight loss, and improved clinical scores in mouse models of colitis. Synthetic glycans are thus a promising modality to improve health through selective changes to the gut microbiome.
Complex and critical roles for the AtrR transcription factor in control of cyp51A expression in Aspergillus fumigatus
Authors: Paul Sanjoy , Verweij Paul E. , Melchers Willem J.G. , Moye-Rowley W. Scott
Published: January 2022

Aspergillus fumigatus is the major filamentous fungal pathogen in humans. The gold standard treatment of A. fumigatus is based on azole drug use but the appearance of azole-resistant isolates is increasing at an alarming rate. The cyp51A gene encodes the enzymatic target of azole drugs and azole-resistant alleles of cyp51A often have an unusual genetic structure containing a duplication of a 34 or 46 bp region in the promoter causing enhanced gene transcription. These tandem repeats are called TR34/TR46 and produce duplicated binding sites for the SrbA and AtrR transcription factors. Using site-directed mutagenesis, we demonstrate that both the SrbA (sterol response element: SRE) and AtrR binding sites (AtrR response element: ATRE) are required for normal cyp51A gene expression. Loss of either the SRE or ATRE from the distal 34 bp repeat of the TR34 promoter (further 5’ from the transcription start site) caused loss of expression of cyp51A and decreased voriconazole resistance. Surprisingly, loss of these same binding sites from the proximal 34 or 46 bp repeat led to increased cyp51A expression and voriconazole resistance. These data indicate that these duplicated regions in the cyp51A promoter function differently. Our findings suggest that the proximal 34 or 46 bp repeat in cyp51A recruits a corepressor that requires multiple factors to act while the distal repeat is free of this repression and provides the elevated cyp51A expression caused by these promoter duplications.

Importance

Aspergillus fumigatus is the most common human filamentous fungal pathogen. Azole drugs are the current therapy of choice for A. fumigatus but the prevalence of azole resistance is increasing. The main genetic alteration causing azole resistance is a change in the cyp51A gene that encodes the target of these drugs. Azole-resistant cyp51A alleles routinely contain duplications in their promoter regions that cause increased gene transcription. Here, we demonstrate that clinical isolates containing a 34 or 46 bp duplication in the cyp51A promoter required the presence of the transcription factor-encoding atrR gene to exhibit elevated azole resistance. Elimination of transcription factor binding sites in the cyp51A gene have differential actions on expression of the resulting mutant allele. These data dissect the molecular inputs to cyp51A transcription and reveal a complicated function of the promoter of this gene that is critical in azole resistance.
Sensory plasticity in a socially plastic bee
Authors: Boulton Rebecca A , Field Jeremy
Published: January 2022

Abstract

The social Hymenoptera have contributed much to our understanding of the evolution of sensory systems. Attention has focussed chiefly on how sociality and sensory systems have evolved together. In the Hymenoptera, the antennal sensilla are important for optimising the perception of olfactory social information. Social species have denser antennal sensilla than solitary species, which is thought to enhance social cohesion through nest-mate recognition. In the current study, we test whether sensilla numbers vary between populations of the socially plastic sweat bee Halictus rubicundus from regions that vary in climate and the degree to which sociality is expressed. We found region level differences in both olfactory and hygro/thermoreceptive sensilla numbers. We also found evidence that olfactory sensilla density is developmentally plastic: when we transplanted bees from Scotland to the south-east of England, their offspring (which developed in the south) had more olfactory hairs than the transplanted individuals themselves (which developed in Scotland). The transplanted bees displayed a mix of social (a queen plus workers) and solitary nesting, but neither individual nor nest phenotype was related to sensilla density. We suggest that this general, rather than caste-specific sensory plasticity provides a flexible means to optimise sensory perception according to the most pressing demands of the environment. Sensory plasticity may support social plasticity in H. rubicundus but does not appear to be causally related to it.
Oncogene expression from extrachromosomal DNA is driven by copy number amplification and does not require spatial clustering
Authors: Purshouse Karin , Friman Elias T. , Boyle Shelagh , Dewari Pooran Singh , Grant Vivien , Hamdan Alhafidz , Morrison Gillian M. , Brennan Paul M , Beentjes Sjoerd V. , Pollard Steven M. , Bickmore Wendy A.
Published: January 2022

Extrachromosomal DNA (ecDNA) are frequently observed in human cancers and are responsible for high levels of oncogene expression. In glioblastoma (GBM), ecDNA copy number correlates with poor prognosis. It is hypothesized that their copy number, size and chromatin accessibility facilitate clustering of ecDNA and colocalization with transcriptional condensates, and that this underpins their elevated transcriptional activity. Here, we use super-resolution imaging and quantitative image analysis to evaluate GBM stem cells harboring distinct ecDNA species (EGFR, MYC, PDGFR). We found no evidence that ecDNA cluster with one another or closely interact with transcriptional condensates. Cells with EGFR-containing ecDNA have increased EGFR transcriptional output, but transcription per gene copy was similar in ecDNA compared to the endogenous chromosomal locus. These data suggest that is the increased copy number of oncogene-harbouring ecDNA that primarily drives high levels of oncogene transcription, rather than specific interactions of ecDNA with the cellular transcriptional machinery.
A guide to sampling design for GPS-based studies of animal societies
Authors: He Peng , Klarevas-Irby James A. , Papageorgiou Danai , Christensen Charlotte , Strauss Eli D. , Farine Damien R.
Published: January 2022

GPS-based tracking is widely used for studying wild social animals. Much like traditional observational methods, using GPS devices requires making a number of decisions about sampling that can affect the robustness of a study’s conclusions. For example, sampling fewer individuals per group across more distinct social groups may not be sufficient to infer group- or subgroup-level behaviours, while sampling more individuals per group across fewer groups limits the ability to draw conclusions about populations. Here, we provide quantitative recommendations when designing GPS-based tracking studies of animal societies. We focus on the trade-offs between three fundamental axes of sampling effort: 1) sampling coverage—the number and allocation of GPS devices among individuals in one or more social groups; 2) sampling duration—the total amount of time over which devices collect data; 3) sampling frequency—the temporal resolution at which GPS devices record data. We first test GPS tags under field conditions to quantify how these aspects of sampling design can affect both GPS accuracy (error in absolute positional estimates) and GPS precision (error in the estimate relative position of two individuals), demonstrating that GPS error can have profound effects when inferring distances between individuals. We then use data from whole-group tracked vulturine guineafowl (Acryllium vulturinum) to demonstrate how the trade-off between sampling frequency and sampling duration can impact inferences of social interactions and to quantify how sampling coverage can affect common measures of social behaviour in animal groups, identifying which types of measures are more or less robust to lower coverage of individuals. Finally, we use data-informed simulations to extend insights across groups of different sizes and cohesiveness. Based on our results, we are able to offer a range of recommendations on GPS sampling strategies to address research questions across social organizational scales and social systems—from group movement to social network structure and collective decision-making. Our study provides practical advice for empiricists to navigate their decision-making processes when designing GPS-based field studies of animal social behaviours, and highlights the importance of identifying the optimal deployment decisions for drawing informative and robust conclusions.
Quantitative evaluation of warming and hemodilution as two techniques to increase the flow rate of blood during simulated massive transfusion of packed red blood cells
Authors: Shah Netra
Published: January 2022

Massive bleeding is a leading cause of deaths in trauma, surgeries, wartime injuries, and childbirth. In these situations of ongoing blood loss, it is critical for patients to be rapidly resuscitated. Currently, patients who require major transfusions are given cold and concentrated blood from the blood bank. This blood does not flow fast due to its viscosity. Equipment for rapid resuscitation such as rapid transfusers are very costly and are not accessible everywhere. Additionally, specialized training is required to operate these machines. Therefore, it is necessary to determine simple, quick, and effective ways to increase the flow rate of blood. The flow rate can be increased by warming and hemodilution. The purpose of this study was to quantify the effects of these simple and quick methods since they can be implemented anywhere with easily accessible equipment. In this experiment, expired packed red blood cells were warmed and diluted. The time the blood took to flow through the tubing was measured and a flow rate was calculated for each trial. The research hypothesis stated that diluted blood at 39°C would have the fastest flow rate. The research hypothesis was supported and there was a 366% in flow rate by warming and diluting blood. There was a 232% increase by simply diluting the blood and a 170% increase by warming. Six t-tests were conducted for this data and they were all significant at a level of 0.001. These results indicate the significant effects of warming and diluting blood and this research could improve patient care during emergencies and massive blood loss.
Naïve Bayes Assessment of Mediterranean Basin Ecosystem Wildfires Associated With Vegetation Vigor in August 2021
Authors: Wibowo Andri
Published: January 2022

The Mediterranean basin, located in the Southern Mediterranean Sea in the North of Africa, is one of the ecosystems that are vulnerable to wildfire hazards. A massive wildfire occurred in this ecosystem in August 2021. Here, this study aims to detect the burnt areas and assess the ecosystem covariates related to the wildfire occurrences. Wildfire assessments were conducted using remote sensing (RS) analysis. Measured ecosystem covariates include vegetation cover, moisture, and the Normalized Difference Vegetation Index (NDVI). The RS analysis confirms at least 17090 ha of vegetation cover were damaged. The burnt vegetation cover was associated with the vegetation moisture and NDVI. The result shows 61.93% of burnt areas were observed within areas that had low vegetation moisture. While 51.75% of burnt areas occurred within areas that had low NDVI values. Naïve Bayes classifier confirms that vegetation moisture and NDVI covariates can be used to estimate the presences of wildfires with values of Kappa, accuracy, precision, recall, and F1 score are 0.7, 0.85, 0.89, 0.8, and 0.84. The area under (AUC) the receiver operating characteristic (ROC) curve values for vegetation moisture and NDVI covariates were 0.945 and 0.399. This value indicates that low vegetation moisture contributes more to the wildfire presences than low NDVI.
3D Printable High Performance Conducting Polymer Hydrogel for All-Hydrogel Bioelectronics
Authors: Zhou Tao , Yuk Hyunwoo , Hu Faqi , Wu Jingjing , Tian Fajuan , Roh Heejung , Shen Zequn , Gu Guoying , Xu Jingkun , Lu Baoyang , Zhao Xuanhe
Published: January 2022

Owing to the unique combination of electrical conductivity and tissue-like mechanical properties, conducting polymer hydrogels have emerged as a promising candidate for bioelectronic interfacing with biological systems. However, despite the recent advances, the development of hydrogels with both excellent electrical and mechanical properties in physiological environments remains a lingering challenge. Here, we report a bi-continuous conducting polymer hydrogel (BC-CPH) that simultaneously achieves high electrical conductivity (over 11 S cm-1), stretchability (over 400%) and fracture toughness (over 3,300 J m-2) in physiological environments, and is readily applicable to advanced fabrication methods including 3D printing. Enabled by the BC-CPH, we further demonstrate multi-material 3D printing of monolithic all-hydrogel bioelectronic interfaces for long-term electrophysiological recording and stimulation of various organs. This study may offer promising materials and a platform for future bioelectronic interfacing.
Web and social media searches highlight menstrual irregularities as a global concern in COVID-19 vaccinations
Authors: Katz Ariel , Tepper Yoav , Birk Ohad , Eran Alal
Published: February 2022

Background

Delineation of public concerns that prevent vaccine compliance is a major step in generating assurances and enhancing the success of COVID-19 prevention programs. We therefore sought to identify public concerns associated with COVID-19 vaccines, as reflected by web and social media searches, with a focus on menstrual irregularities.

Methods

We used trajectory analyses of web and social media search data in combination with global COVID-19 data to reveal time-dependent correlations between vaccination rates and the relative volume of vaccine and period related searches.

Results

A surge of period and vaccine related Google searches followed the introduction of Covid vaccines around the world, and the commencement of vaccination programs in English speaking countries and across the United States. The relative volume of searches such as “Covid vaccine menstrual irregularities”, “Covid vaccine menstrual period”, “Pfizer vaccine menstruation”, and “Moderna vaccine menstruation” was each significantly correlated with vaccination rates (Spearman r = 0.42-0.88, P = 4.33 × 10−34-1.55 × 10−5), and significantly different before and after the introduction of COVID vaccines (Mann-Whitney P = 2.00 × 10−21-7.10 × 10−20). TikTok users were more engaged in period problems in 2021 than ever before.

Conclusions

International, national, and state-level correlations between COVID-19 vaccinations and online activity demonstrate a global major concern of vaccine-related menstrual irregularities. Whether it is a potential side effect or an unfounded worry, monitoring of web and social media activity could reveal the public perception of COVID-19 prevention efforts, which could then be directly addressed and translated into insightful public health strategies.
The effects of sequencing depth on the assembly of coding and noncoding transcripts in the human genome
Authors: Babarinde Isaac Adeyemi , Hutchins Andrew Paul
Published: January 2022

Background

Investigating the functions and activities of genes requires proper annotation of the transcribed units. However, transcript assembly efforts have produced a surprisingly large variation in the number of transcripts, and especially so for noncoding transcripts. The heterogeneity of the assembled transcript sets might be partially explained by sequencing depth.

Results

Here, we used real and simulated short-read sequencing data as well as long-read data to systematically investigate the impact of sequencing depths on the accuracy of assembled transcripts. We assembled and analyzed transcripts from 671 human short-read data sets and four long-read data sets. At the first level, there is a positive correlation between the number of reads and the number of recovered transcripts. However, the effect of the sequencing depth varied based on cell or tissue type, the type of read considered and the nature and expression levels of the transcripts. The detection of coding transcripts saturated rapidly for both short-read and long-reads, however, there was no sign of saturation for noncoding transcripts at any sequencing depth. Increasing long-read sequencing depth specifically benefited transcripts containing transposable elements. Finally, we show how single-cell RNA-seq can be guided by transcripts assembled from bulk long-read samples, and demonstrate that noncoding transcripts are expressed at similar levels to coding transcripts but are expressed in fewer cells.

Conclusions

This study shows the impact of sequencing depth on transcript assembly. Sequencing read depth has a relatively minor impact on coding transcript assembly, but a major effect on the assembly of noncoding transcripts. This study highlights important factors to consider when deciding the sequencing read depths to be used for transcript assembly.
HiC-LDNet: A general and robust deep learning framework for accurate chromatin loop detection in genome-wide contact maps
Authors: Chen Siyuan , Wang Jiuming , Gao Xin , Li Yu
Published: February 2022

Motivation

Identifying chromatin loops from genome-wide interaction matrices like Hi-C data is notoriously difficult. Such kinds of patterns can span through the genome from a hundred kilobases to thousands of kilobases. Most loop patterns are frequently related to biological functions, such as providing contacts between regulatory regions and promoters. They can also affect the cell-specific biological functions of different regulatory regions of DNA, thus leading to disease and tumorigenesis. While most statistical methods failed in the generalization to multiple cell types, recently proposed machine learning-based methods struggled when tested on sparse single-cell Hi-C (scHi-C) contact maps. We notice that there is an urgent need for an algorithm that can handle sparse scHi-C maps, and at the same time, can generate confident loop calls on regular cell lines.

Results

Therefore, we propose a novel deep learning-based framework for Hi-C chromatin loop detection (HiC-LDNet) and provide corresponding downstream analysis. HiC-LDNet can give relatively more accurate predictions in multiple tissue types and contact technologies. Compared to other loop calling algorithms, such as HiCCUPS, Peakachu, and Chromosight, HiC-LDNet recovers a higher number of loop calls in multiple experimental platforms (Hi-C, ChIA-PET, DNA-SPRITE, and HiChIP), and achieves higher confidence scores in multiple cell types (Human GM12878, K562, HAP1, and H1-hESC). For example, in genome-wide loop detection on the human GM12878 cell line, HiC-LDNet successfully recovered 82.5% of loops within only 5 pixels of 10k bp resolution. Furthermore, in the sparse scHi-C ODC tissue, HiC-LDNet achieves superior performance by recovering 93.5% of ground truth loops with high confidence scores, compared with that of Peakachu (31.5%), Chromosight(69.6%), and HiCCUPS(9.5%). Therefore, our method is a robust and general pipeline for genome-wide chromatin loop detection for both bulk Hi-C and scHi-C data.

Availability

https://github.com/frankchen121212/HiC-LDNet

Contact

liyu@cse.cuhk.edu.hk and xin.gao@kaust.edu.sa
Do place cells dream of deceptive moves in a signaling game?
Authors: Fenton André A. , Hurtado José R. , Broek Jantine A.C. , Park EunHye , Mishra Bud
Published: February 2022

We consider the possibility of applying game theory to analysis and modeling of neurobiological systems. Specifically, the basic properties and features of information asymmetric signaling games are considered and discussed as having potential to explain diverse neurobiological phenomena at levels of biological function that include gene regulation, molecular and biochemical signaling, cellular and metabolic function, as well as the neuronal action potential discharge that can represent cognitive variables such as memory and purposeful behavior. We begin by arguing that there is a pressing need for conceptual frameworks that can permit analysis and integration of information and explanations across the many scales of diverse levels of biological function. Developing such integrative frameworks is crucial if we are to understand cognitive functions like learning, memory, and perception. The present work focuses on systems level neuroscience organized around the connected brain regions of the entorhinal cortex and hippocampus. These areas are intensely studied in rodent subjects as model neuronal systems that undergo activity-dependent synaptic plasticity to form and represent memories and spatial knowledge used for purposeful navigation. Examples of cognition-related spatial information in the observed neuronal discharge of hippocampal place cell populations and medial entorhinal head-direction cell populations are used to illustrate possible challenges to information maximization concepts. It may be natural to explain these observations using the ideas and features of information asymmetric signaling games.
The occurrence and characteristics of severe pain in patients with axial spondyloarthritis
Authors: Jones Gareth T , Rotariu Ovidiu , Dean Linda E , MacDonald Alan G , Macfarlane Gary J
Published: February 2022

Objectives

Pharmacological management of axial spondylarthritis (axSpA) seek to control inflammation. Even if successful, available evidence suggests that many patients continue to experience pain. The aim of the current study was to determine the prevalence and characteristics of severe pain, among persons with axSpA.

Methods

The Scotland Registry for Ankylosing Spondylitis (SIRAS) collected clinical and patient-reported data from adults seen in secondary care in Scotland with a clinical diagnosis of ankylosing spondylitis. Questionnaires asked about severe pain (high pain intensity; high pain interference; and extreme/unbearable pain), lifestyle, and various aspects of health. The relationship between severe pain and clinical/patient-reported factors was assessed using logistic regression.

Results

929 participants had pain data available (73% male; median symptom duration 20yrs). High pain intensity and pain interference were more common (57% and 42%) than extreme/unbearable pain (11%). Prevalence did not differ with age, although women were less likely to report severe pain than men (Odds Ratios (ORs) 0.56-0.61) as were those with longer duration of education, and those from more affluent areas. The odds of severe pain increased with every 1 unit increase in BASFI (ORs 1.44-1.56). Strong associations were also seen with disease activity, spinal mobility, fatigue, poor sleep, and worse quality of life.

Conclusion

In axSpA, severe pain is common, with a clear socio-economic gradient and major impact on quality of life. Rheumatologists need to be aware of the large unmet need in terms of pain management in this patient group with around 1 in 9 patients reporting extreme/unbearable pain.

KEY MESSAGES

What is already known about this subject?

Axial spondyloarthritis is a painful inflammatory arthritis, although the epidemiology of specific pain phenotypes – and ‘severe’ pain in particular – is unknown.

What does this study add?

Severe pain (extreme/unbearable pain, pain of high intensity, or with a high level of interference) is commonly reported among people with axial spondyloarthritis.

Three-quarters of individuals reporting severe pain still report severe pain two years later.

Patients with severe pain are characterised by certain demographic characteristics, higher disease activity, poorer function, and a number of other clinical and lifestyle factors.

How might this impact on clinical practice or future developments?

Rheumatologists should be aware of the large unmet need in terms of pain management in this patient group. Specific pain management strategies should be considered to complement therapies aimed at reducing inflammation.
Omicron-specific mRNA vaccine induced potent neutralizing antibody against Omicron but not other SARS-CoV-2 variants
Authors: Lee I-Jung , Sun Cheng-Pu , Wu Ping-Yi , Lan Yu-Hua , Wang I-Hsuan , Liu Wen-Chun , Tseng Sheng-Che , Tsung Szu-I , Chou Yu-Chi , Kumari Monika , Chang Yu-Wei , Chen Hui-Feng , Lin Yin-Shiou , Chen Tsung-Yen , Chiu Chi-Wen , Hsieh Chung-Hsuan , Chuang Cheng-Ying , Lin Chih-Chao , Cheng Chao-Min , Lin Hsiu-Ting , Chen Wan-Yu , Chiang Po-Cheng , Lee Chong-Chou , Liao James C. , Wu Han-Chung , Tao Mi-Hua
Published: February 2022

The emerging SARS-CoV-2 variants of concern (VOC) harbor mutations associated with increasing transmission and immune escape, hence undermine the effectiveness of current COVID-19 vaccines. In late November of 2021, the Omicron (B.1.1.529) variant was identified in South Africa and rapidly spread across the globe. It was shown to exhibit significant resistance to neutralization by serum not only from convalescent patients, but also from individuals receiving currently used COVID-19 vaccines with multiple booster shots. Therefore, there is an urgent need to develop next generation vaccines against VOCs like Omicron. In this study, we develop a panel of mRNA-LNP-based vaccines using the receptor binding domain (RBD) of Omicron and Delta variants, which are dominant in the current wave of COVID-19. In addition to the Omicron- and Delta-specific vaccines, the panel also includes a “Hybrid” vaccine that uses the RBD containing all 16 point-mutations shown in Omicron and Delta RBD, as well as a bivalent vaccine composed of both Omicron and Delta RBD-LNP in half dose. Interestingly, both Omicron-specific and Hybrid RBD-LNP elicited extremely high titer of neutralizing antibody against Omicron itself, but few to none neutralizing antibody against other SARS-CoV-2 variants. The bivalent RBD-LNP, on the other hand, generated antibody with broadly neutralizing activity against the wild-type virus and all variants. Surprisingly, similar cross-protection was also shown by the Delta-specific RBD-LNP. Taken together, our data demonstrated that Omicron-specific mRNA vaccine can induce potent neutralizing antibody response against Omicron, but the inclusion of epitopes from other variants may be required for eliciting cross-protection. This study would lay a foundation for rational development of the next generation vaccines against SARS-CoV-2 VOCs.
Intervertebral disc cell chondroptosis elicits neutrophil response inStaphylococcus aureusspondylodiscitis
Authors: Schweizer Tiziano A. , Andreoni Federica , Acevedo Claudio , Scheier Thomas C. , Heggli Irina , Maggio Ewerton Marques , Eberhard Nadia , Brugger Silvio D. , Dudli Stefan , Zinkernagel Annelies S.
Published: February 2022

Objective

To understand the pathophysiology of spondylodiscitis due toStaphylococcus aureus, an emerging infectious disease of the intervertebral disc (IVD) and vertebral body with a high complication rate, by combining clinical insights and experimental approaches.

Design

Clinical data and histological material of nine patients suffering fromS. aureusspondylodiscitis were retrospectively collected at a single center. To mirror the clinical findings experimentally, we developed a novel porcineex vivomodel mimicking acuteS. aureusspondylodiscitis and assessed the interaction betweenS. aureusand IVD cells within their native environment. In addition, the inflammatory features underlying this interaction were assessed in primary human IVD cells. Finally, mirroring the clinical findings, we assessed primary human neutrophils for their ability to respond to secreted inflammatory modulators of IVD cells uponS. aureuschallenge.

Results

AcuteS. aureusspondylodiscitis in patients was characterized by tissue necrosis and neutrophil infiltration. Additionally, the presence of empty IVD cells’ lacunae was observed. This was mirrored in the ex vivo porcine model, whereS. aureusinduced extensive IVD cell death, leading to empty lacunae. Concomitant engagement of the apoptotic and pyroptotic cell death pathways was observed in primary human IVD cells, resulting in cytokine release. Among the released cytokines, functionally intact neutrophil-priming as well as broad pro- and anti-inflammatory cytokines known for their involvement in IVD degeneration were found.

Conclusions

In patients as well asex vivoin a novel porcine model,S. aureusspondylodiscitis infection caused IVD cell death, resulting in empty lacunae, which was accompanied by release of inflammation markers and recruitment of neutrophils. These findings offer valuable insights into the important role of inflammatory IVD cell death during the onset of spondylodiscitis and potential future therapeutic approaches.
HOW CONCERNING IS A SARS-COV-2 VARIANT OF CONCERN? COMPUTATIONAL PREDICTIONS AND THE VARIANTS LABELING SYSTEM
Authors: Ashoor Dana , Marzouq Maryam , Trabelsi Khaled , Chlif Sadok , Abotalib Nasser , Ben Khalaf Noureddine , Ramadan Ahmed R. , Fathallah M-Dahmani
Published: February 2022

We herein report a study to evaluate the use of computational prediction of SARS-CoV-2 genetic variations in improving the current variants labeling system. First, we reviewed the basis of the system developed by the World Health Organization (WHO) for the labeling of SARS-CoV-2 genetic variants and the adaptations made to it by the United States Center of Diseases Control (CDC). We observed that the labeling system is based upon the virus’ major attributes. However, we found that the labeling criteria of the SARS-CoV-2 variants derived from these attributes are not accurately defined and are used differently by the two health management agencies. Consequently, discrepancies exist between the labels given by WHO and CDC to same variants. Our observations suggest that giving the VOC label to a new variant is premature and might not be appropriate. Therefore, we carried out a comparative computational study to predict the effects of the mutations on the virus structure and functions of five VOCs. By linking these data to the criteria used by WHO and the CDC for variant labeling, we ascertained that comparative computational predictions of the impact of genetic variations are a better ground for rapid and more accurate labelling of SARS-CoV-2 variants. We propose to label all emergent variants VUM or VBM and to carry out computational predictive studies and thorough variants comparison, upon which more appropriate and informative labels can be attributed. Furthermore, harmonization of the variants labeling system would be globally beneficial to communicate about and fight COVID-19 pandemic.
A novel role of 3’,5’-cAMP in the regulation of actin cytoskeleton in Arabidopsis
Authors: Chodasiewicz Monika , Figueroa Nicolás E. , Franz Peter , Luzarowski Marcin , Moreno Juan C. , Childs Dorothee , Masiuk Aleksandra , Saluja Manny , Sampathkumar Arun , Tsiavaliaris Georgios , Skirycz Aleksandra
Published: February 2022

The role of cyclic adenosine monophosphate (3’,5’-cAMP) in plants is not well understood, and here, we report a novel role of 3’,5’-cAMP in regulating the actin cytoskeleton. The 3’,5’-cAMP treatment affects the thermal stability of 51 proteins, including a vegetative actin isoform, ACTIN2. Consistent with the above results, the increase in 3’,5’-cAMP levels, obtained either by feeding or by chemical modulation of 3’,5’-cAMP metabolism, is sufficient to partially rescue the short hypocotyl phenotype of the actin2 actin7 mutant, severely compromised in actin level. No such complementation was measured for a positional isomer of 3’,5’-cAMP, 2’,3’-cAMP, attesting to the specificity of 3’,5’-cAMP treatment. Moreover, supplementation of 3’,5’-cAMP partly counters the activity of an actin-depolymerizing drug latrunculin B. In vitro characterization of the 3’,5’-cAMP – actin interaction argues against the direct binding. Instead, based on the proteomics characterization of the act2act7 mutant supplemented with 3’,5’-cAMP, we hypothesize that 3’,5’-cAMP affects cytoskeleton dynamic by modulation of calcium signaling, and actin binding proteins.
Peptide location fingerprinting identifies species- and tissue-conserved structural remodelling of proteins as a consequence of ageing and disease
Authors: Eckersley Alexander , Ozols Matiss , Chen Peikai , Tam Vivian , Ward Liam J. , Hoyland Judith A. , Trafford Andrew , Yuan Xi-Ming , Schiller Herbert B. , Chan Danny , Sherratt Michael J.
Published: February 2022

Extracellular matrix (ECM) in the intervertebral disc (IVD), lung and artery are thought to undergo the age-dependant accumulation of damage by chronic exposure to mechanisms such as reactive oxygen species, proteases and glycation. It is unknown whether this damage accumulation is species-dependant (via differing lifespans and hence cumulative exposures) or whether it can influence the progression of age-related diseases such as atherosclerosis. Peptide location fingerprinting (PLF) is a new proteomic analysis method, capable of the non-targeted identification of structure-associated changes within proteins. Here we applied PLF to publicly available ageing human IVD (outer annulus fibrosus), ageing mouse lung and human arterial atherosclerosis datasets and identified novel target proteins alongside common age-associated differences within protein structures which were conserved between tissue regions, organs, sexes and species and in age-related disease. We identify peptide yield differences across protein structures which coincide with biological regions, potentially reflecting the functional consequences of ageing or atherosclerosis for macromolecular assemblies (collagen VI and fibrin), enzyme/inhibitor activity (cathepsin B and alpha-2 macroglobulin), activation states (complement C3 and thrombin) and interaction states (laminins, perlecan, fibronectin, filamin-A, collagen XIV and apolipoprotein-B). Furthermore, we show that alpha-2 macroglobulin, prothrombin, collagen XIV and apolipoprotein-B all exhibit possible shared structural consequences in IVD ageing and arterial atherosclerosis, providing novel links between an age-related disease and intrinsic ageing. Crucially, we also demonstrate that fibronectin, laminin beta chains and filamin-A all exhibit conserved age-associated structural differences between mouse lung and human IVD, providing evidence that ECM, and their associating proteins, may be subjected to potentially similar mechanisms or consequences of ageing across species, irrespective of differences in lifespan and tissue function.
Spatial Venomics - Cobra Venom System Reveals Spatial Differentiation of Snake Toxins by Mass Spectrometry Imaging
Authors: Hempel Benjamin-Florian , Damm Maik , Petras Daniel , Kazandjian Taline D. , Szentiks Claudia A. , Fritsch Guido , Nebrich Grit , Casewell Nicholas R. , Klein Oliver , Süssmuth Roderich D.
Published: February 2022

Among venomous animals, toxic secretions have evolved as biochemical weapons associated with various highly specialized delivery systems on many occasions. Despite extensive research, there is still limited knowledge of the functional biology of most animal toxins, including their venom production and storage, as well as the morphological structures within sophisticated venom producing tissues that might underpin venom modulation. Here we report on the spatial exploration of a snake venom gland system by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI), in combination with standard proteotranscriptomic approaches, to enable in situ toxin mapping in spatial intensity maps across a venom gland sourced from the Egyptian cobra (Naja haje). MALDI-MSI toxin visualization on the elapid venom gland reveals high spatial heterogeneity of different toxin classes at the proteoform level, which may be the result of physiological constraints on venom production and/or storage that reflects the potential for venom modulation under diverse stimuli.
Chromatin-associated microprocessor assembly is regulated by PRP40, the U1 snRNP auxiliary protein
Authors: Stepien Agata , Dolata Jakub , Gulanicz Tomasz , Bielewicz Dawid , Bajczyk Mateusz , Smolinski Dariusz J. , Szweykowska-Kulinska Zofia , Jarmolowski Artur
Published: February 2022

Cotranscriptional processing of RNA polymerase II-generated primary transcripts is a well-documented phenomenon. We recently showed that in plants, miRNA biogenesis is also a cotranscriptional event. Here, we report that Arabidopsis PRP40, the U1 snRNP auxiliary protein, positively regulates the recruitment of SE, the core component of the plant microprocessor, to miRNA genes. The association of DCL1, the microprocessor endoribonuclease, with chromatin was altered in prp40ab mutant plants. Impaired cotranscriptional microprocessor assembly was accompanied by RNA polymerase II accumulation at miRNA genes and retention of miRNA precursors at their transcription sites in the prp40ab mutant plants. We show that cotranscriptional microprocessor assembly, regulated by AtPRP40, positively affects RNAPII transcription of miRNA genes and is important to reach the correct levels of produced miRNAs.
SARS-CoV-2 invades cognitive centers of the brain and induces Alzheimer’s-like neuropathology
Authors: Shen Wei-Bin , Elahi Montasir , Logue James , Yang Penghua , Baracco Lauren , Reece E. Albert , Wang Bingbing , Li Ling , Blanchard Thomas G , Han Zhe , Rissman Robert A , Frieman Matthew B , Yang Peixin
Published: February 2022

The neurotropism of SARS-CoV-2 and the phenotypes of infected neurons are still in debate. Long COVID manifests with “brain diseases” and the cause of these brain dysfunction is mysterious. Here, we analyze 34 age- and underlying disease-matched COVID-19 or non-COVID-19 human brains. SARS-CoV-2 RNA, nucleocapsid, and spike proteins are present in neurons of the cognitive centers of all COVID-19 patients, with its non-structural protein NSF2 detected in adult cases but not in the infant case, indicating viral replications in mature neurons. In adult COVID-19 patients without underlying neurodegeneration, SARS-CoV-2 infection triggers Aβ and p-tau deposition, degenerating neurons, microglia activation, and increased cytokine, in some cases with Aβ plaques and p-tau pretangles. The number of SARS-CoV-2+ cells is higher in patients with neurodegenerative diseases than in those without such conditions. SARS-CoV-2 further activates microglia and induces Aβ and p-tau deposits in non-Alzheimer’s neurodegenerative disease patients. SARS-CoV-2 infects mature neurons derived from inducible pluripotent stem cells from healthy and Alzheimer’s disease (AD) individuals through its receptor ACE2 and facilitator neuropilin-1. SARS-CoV-2 triggers AD-like gene programs in healthy neurons and exacerbates AD neuropathology. An AD infectious etiology gene signature is identified through SARS-CoV-2 infection and silencing the top three downregulated genes in human primary neurons recapitulates the neurodegenerative phenotypes of SARS-CoV-2. Thus, our data suggest that SARS-CoV-2 invades the brain and activates an AD-like program.
Human Cardiac Organoids to Model COVID-19 Cytokine Storm Induced Cardiac Injuries
Authors: Arhontoulis Dimitrios C , Kerr Charles , Richards Dylan , Tjen Kelsey , Hyams Nathaniel , Jones Jefferey A. , Deleon-Pennell Kristine , Menick Donald , Lindner Diana , Westermann Dirk , Mei Ying
Published: February 2022

Acute cardiac injuries occur in 20-25% of hospitalized COVID-19 patients. Despite urgent needs, there is a lack of 3D organotypic models of COVID-19 hearts for mechanistic studies and drug testing. Herein, we demonstrate that human cardiac organoids (hCOs) are a viable platform to model the cardiac injuries caused by COVID-19 hyperinflammation. As IL-1βis an upstream cytokine and a core COVID-19 signature cytokine, it was used to stimulate hCOs to induce the release of a milieu of proinflammatory cytokines that mirror the profile of COVID-19 cytokine storm. The IL-1 β treated hCOs recapitulated transcriptomic, structural, and functional signatures of COVID-19 hearts. The comparison of IL-1β treated hCOs with cardiac tissue from COVID-19 autopsies illustrated the critical roles of hyper-inflammation in COVID-19 cardiac insults and indicated the cardioprotective effects of endothelium. The IL-1β treated hCOs also provide a viable model to assess the efficacy and potential side effects of immunomodulatory drugs, as well as the reversibility of COVID-19 cardiac injuries at baseline and simulated exercise conditions.
Growth cone macropinocytosis of neurotrophin receptor and neuritogenesis are regulated by Neuron Navigator 1
Authors: Powers Regina M. , Daza Ray , Koehler Alanna E. , Julien  , Calabrese Barbara , Hevner Robert F. , Halpain Shelley
Published: February 2022

Neuron Navigator 1 (Nav1) is a cytoskeleton-associated protein expressed during brain development that is necessary for proper neuritogenesis, but the underlying mechanisms are poorly understood. Here we show that Nav1 is present in elongating axon tracts during mouse brain embryogenesis. We found that depletion of Nav1 in cultured neurons disrupts growth cone morphology and neurotrophin-stimulated neuritogenesis. In addition to regulating both F-actin and microtubule properties, Nav1 promotes actin-rich membrane ruffles in the growth cone, and promotes macropinocytosis at those membrane ruffles, including internalization of the TrkB receptor for the neurotrophin BDNF (brain-derived neurotropic factor). Growth cone macropinocytosis is important for downstream signaling, neurite targeting, and membrane recycling, implicating Nav1 in one or more of these processes. Depletion of Nav1 also induces transient membrane blebbing via disruption of signaling in the Rho GTPase signaling pathway, supporting the novel role of Nav1 in dynamic actin-based membrane regulation at the cell periphery. These data demonstrate that Nav1 works at the interface of microtubules, actin, and plasma membrane to organize the cell periphery and promote uptake of growth and guidance cues to facilitate neural morphogenesis during development.