bluuebunny/crossref_metadata_2025 huggingface dataset:
Chromatin Reprogramming of In Vitro Fertilized and Somatic Cell Nuclear Transfer Bovine Embryos During Embryonic Genome Activation
Authors: Grow Edward J. , Liu Ying , Fan Zhiqiang , Perisse Iuri Viotti , Patrick Tayler , Regouski Misha , Shadle Sean , Polejaeva Irina , White Kenneth L. , Cairns Bradley R.
Published: April 2023

Reprogramming of the gamete into a developmentally competent embryo identity is a fundamental aspect of preimplantation development. One of the most important processes of this reprogramming is the transcriptional awakening during embryonic genome activation (EGA), which robustly occurs in fertilized embryos but is defective in most somatic cell nuclear transfer (SCNT) embryos. However, little is known about the genome-wide underlying chromatin landscape during EGA in SCNT embryos and how it differs from a fertilized embryo. By profiling open chromatin genome-wide in both types of bovine embryos, we find that SCNT embryos fail to reprogram a subset of the EGA gene targets that are normally activated in fertilized embryos. Importantly, a small number of transcription factor (TF) motifs explain most chromatin regions that fail to open in SCNT embryos suggesting that over-expression of a limited number of TFs may provide more robust reprogramming. One such TF, the zygotically-expressed bovine gene DUXC which is a homologue of EGA factors DUX/DUX4 in mouse/human, is alone capable of activating ∼84% of all EGA transcripts that fail to activate normally in SCNT embryos. Additionally, single-cell chromatin profiling revealed low intra-embryo heterogeneity but high inter-embryo heterogeneity in SCNT embryos and an uncoupling of cell division and open chromatin reprogramming during EGA. Surprisingly, our data also indicate that transcriptional defects may arise downstream of promoter chromatin opening in SCNT embryos, suggesting additional mechanistic insights into how and why transcription at EGA is dysregulated. We anticipate that our work will lead to altered SCNT protocols to increase the developmental competency of bovine SCNT embryos.
Lower Limb Vertical Stiffness and Frontal Plane Angular Impulse during Perturbation-Induced Single Limb Stance and Their Associations with Gait in Individuals Post-Stroke
Authors: Shen Keng-Hung , Borrelli James , Gray Vicki L. , Rogers Mark W. , Hsiao Hao-Yuan
Published: April 2023

Background

After stroke, deficits in paretic single limb stance (SLS) are commonly observed and affect walking performance. During SLS, the hip abductor musculature is critical in providing vertical support and regulating balance. Although disrupted paretic hip abduction torque production has been identified in individuals post-stroke, interpretation of previous results is limited due to the discrepancies in weight-bearing conditions.

Objective

To investigate whether deficits in hip abduction torque production, vertical body support, and balance regulation remain during SLS when controlling for weight-bearing using a perturbation-based assessment, and whether these measures are associated with gait performance.

Methods

We compared hip abduction torque, vertical stiffness, and frontal plane angular impulse between individuals post-stroke and healthy controls when SLS was induced by removing the support surface underneath one limb. We also tested for correlations between vertical stiffness and angular impulse during perturbation-induced SLS and gait parameters during overground walking.

Results

During the perturbation-induced SLS, lower hip abduction torque, less vertical stiffness, and increased frontal plane angular impulse were observed at the paretic limb compared to the non-paretic limb, while no differences were found between the paretic limb and healthy controls. Vertical stiffness during perturbation-induced SLS was positively correlated with single support duration during gait at the paretic limb and predicted self-selected and fast walking speeds in individuals post-stroke.

Conclusions

Reduced paretic hip abduction torque during SLS likely affects vertical support and balance control. Enhancing SLS hip abduction torque production could be an important rehabilitation target to improve walking function for individuals post-stroke.
Liproxstatin-1 alleviates cartilage degradation by inhibiting chondrocyte ferroptosis in temporomandibular joint
Authors: Cheng Bei , Zhang Jun , Shen Qinhao , Sun Zheyi , Luo Yingwei , Hu Yu
Published: April 2023

Ferroptosis contribute to temporomandibular joint osteoarthritis (TMJOA) lesion development is still poorly understood. In this study, we used different TMJOA animal models to detect whether ferroptosis is related to onset of TMJOA which modelling by monosodium iodoacetate (MIA), IL-1β, occlusion disorder (OD) and unilateral anterior crossbite (UAC). Immunohistochemical staining and Western blot analysis were used to detect ferroptosis proteins and cartilage degradation related protein expression. Our results revealed that lower level of ferroptosis-related proteins GPX4 in cartilage layer, but the level of ACSL4 and P53 increase in that of condyle. Injection of ferroptosis inhibitor liproxstatin-1 (Lip-1) effectively decrease ACSL4, P53 and TRF expression. In vitro, IL-1β induced the reduction of cartilage extracellular matrix expression in mandibular condylar chondrocytes (MCCs). Lip-1 maintain the morphology and function of mitochondria, and inhibited the aggravation of lipid peroxidation and reactive oxygen species (ROS) production which induced by IL-1β. These results suggested that chondrocytes ferroptosis play an important role in the development and progression of TMJOA. Inhibition of condylar chondrocyte ferroptosis could be a promising therapeutic strategy for TMJOA.

SUMMARY STATEMENT

Ferroptosis contributed the development and progression of Temporomandibular Joint Osteoarthritis cartilage degeneration. Lip-1 can effective improvement the cartilage degradation of condyle.
Simulation-based Reconstructed Diffusion unveils the effect of aging on protein diffusion in Escherichia coli
Authors: Mantovanelli Luca , Linnik Dmitrii S. , Punter Michiel , Kojakhmetov Hildeberto Jardón , Śmigiel Wojciech M. , Poolman Bert
Published: April 2023

We have developed Simulation-based Reconstructed Diffusion (SbRD) to determine diffusion coefficients corrected for confinement effects and for the bias introduced by two-dimensional models describing a three-dimensional motion. We validate the method on simulated diffusion data in three-dimensional cell-shaped compartments. We use SbRD, combined with a new cell detection method, to infer the diffusion coefficients of a set of native proteins inEscherichia coli.We observe slower diffusion at the cell poles than in the nucleoid region of exponentially growing cells. We find that this observation is independent of the presence of polysomes. Furthermore, we show that the newly formed pole of dividing cells exhibits a faster diffusion than the old one. We hypothesize that the observed slowdown at the cell poles is caused by the accumulation of aggregated or damaged proteins, and that the effect is asymmetric due to cell aging.
Wealth Effects of the Decrease in Under-five Mortality in India, 2005-2021
Authors: Chaurasia Aalok Ranjan
Published: April 2023

The present paper analyses the contribution of different population sub-groups classified by the wealth index quantiles groups to the change in the risk of death in the first five years of life in India during 2005-06 through 2019-21. The analysis reveals that the poorest and the poorer population sub-groups have primarily contributed to the decrease in the risk of death in the first five years of life in India whereas the contribution of the contribution of the richest population sub-group has been negative during the period under reference. The analysis also reveals that the wealth effects of the decrease in under-five mortality in different states of the country are different and, in many states, the contribution of the richest population sub-group to the decrease in the risk of death in the first five years of life in the state has been negative because of the change in the proportionate share of currently married women of reproductive age across different population sub-groups and their fertility. The paper emphasises the need of reinvigorating the health care services delivery system of the country so as to prevent under five deaths which cannot be prevented through the low-cost appropriate medical technology.
Effectiveness of mRNA COVID-19 monovalent and bivalent vaccine booster doses against Omicron severe outcomes among adults aged ≥50 years in Ontario, Canada
Authors: Grewal Ramandip , Buchan Sarah A , Nguyen Lena , Nasreen Sharifa , Austin Peter C. , Brown Kevin A. , Gubbay Jonathan , Lee Nelson , Schwartz Kevin L , Tadrous Mina , Wilson Kumanan , Wilson Sarah E , Kwong Jeffrey C
Published: April 2023

Objective

We estimated the effectiveness of booster doses of monovalent and bivalent mRNA COVID-19 vaccines against Omicron-associated severe outcomes among adults aged ≥50 years in Ontario, Canada.

Methods

We used a test-negative design to estimate vaccine effectiveness (VE), with unvaccinated adults as the comparator, against hospitalization or death among SARS-CoV-2-tested adults aged ≥50 years between June 19, 2022 and January 28, 2023 stratified by time since vaccination. We explored VE by vaccine product (Moderna Spikevax®monovalent; Pfizer-BioNTech Comirnaty®monovalent; Moderna Spikevax®BA.1 bivalent; Pfizer-BioNTech Comirnaty®BA.4/BA.5 bivalent).

Results

We included 3,755 Omicron cases and 14,338 test-negative controls. For the Moderna and Pfizer-BioNTech monovalent vaccines, VE 7-29 days after vaccination was 85% (95% confidence interval [CI], 72-92%) and 88% (95%CI, 82-92%), respectively, and was 82% (95%CI, 76-87%) and 82% (95%CI, 77-86%) 90-119 days after vaccination. For the Moderna BA.1 bivalent vaccine, VE was 86% (95%CI, 82-90%) 7-29 days after vaccination and was 76% (95%CI, 66-83%) 90-119 days after vaccination. For the Pfizer-BioNTech BA.4/BA.5 bivalent vaccine, VE 7-29 days after vaccination was 83% (95%CI, 77-88%) and was 81% (95%CI 72-87%) 60-89 days after vaccination.

Conclusions

Booster doses of monovalent and bivalent mRNA COVID-19 vaccines provided similar, strong initial protection against severe outcomes in community-dwelling adults aged ≥50 years in Ontario. Nonetheless, uncertainty remains around waning protection of these vaccines.
A methodological framework for assessing the benefit of SARS-CoV-2 vaccination following previous infection: case study of five to eleven year olds
Authors: Pagel Christina , Wilde Harrison , Tomlinson Christopher , Mateen Bilal , Brown Katherine
Published: April 2023

Vaccination rates against SARS-CoV-2 in children aged five to 11 years remain low in many countries. The current benefit of vaccination in this age group has been questioned given that the large majority of children have now experienced at least one SARS-CoV-2 infection. However, protection from infection, vaccination or both wanes over time. National decisions on offering vaccines to this age group have tended to be made without considering time since infection.

There is an urgent need to evaluate the additional benefits of vaccination in previously infected children and under what circumstances those benefits accrue. We present a novel methodological framework for estimating the potential benefits of COVID-19 vaccination in previously infected children aged five to 11, accounting for waning. We apply this framework to the UK context and for two adverse outcomes: hospitalisation related to SARS-CoV-2 infection and Long Covid.

We show that the most important drivers of benefit are: the degree of protection provided by previous infection; the protection provided by vaccination; the time since previous infection; and future attack rates. Vaccination can be very beneficial for previously infected children if future attack rates are high and several months have elapsed since the previous major wave in this group. Benefits are generally larger for Long Covid than hospitalisation, because Long Covid is both more common than hospitalisation and previous infection offers less protection against it.

Our framework provides a structure for policy makers to explore the additional benefit of vaccination across a range of adverse outcomes and different parameter assumptions. It can be easily updated as new evidence emerges.
Alignment of spatial transcriptomics data using diffeomorphic metric mapping
Authors: Clifton Kalen , Anant Manjari , Aihara Gohta , Atta Lyla , Aimiuwu Osagie K. , Kebschull Justus M. , Miller Michael I. , Tward Daniel , Fan Jean
Published: April 2023

Spatial transcriptomics (ST) technologies enable high throughput gene expression characterization within thin tissue sections. However, comparing spatial observations across sections, samples, and technologies remains challenging. To address this challenge, we developed STalign to align ST datasets in a manner that accounts for partially matched tissue sections and other local non-linear distortions using diffeomorphic metric mapping. We apply STalign to align ST datasets within and across technologies as well as to align ST datasets to a 3D common coordinate framework. We show that STalign achieves high gene expression and cell-type correspondence across matched spatial locations that is significantly improved over landmark-based affine alignments. Applying STalign to align ST datasets of the mouse brain to the 3D common coordinate framework from the Allen Brain Atlas, we highlight how STalign can be used to lift over brain region annotations and enable the interrogation of compositional heterogeneity across anatomical structures. STalign is available as an open-source Python toolkit athttps://github.com/JEFworks-Lab/STalignand as supplementary software with additional documentation and tutorials available athttps://jef.works/STalign.
RTEL1 is required for silencing and epigenome stability
Authors: Olivier Margaux , Hesketh Amy , Pouch-Pélissier Marie-Noëlle , Pélissier Thierry , Huang Ying , Latrasse David , Benhamed Moussa , Mathieu Olivier
Published: April 2023

Transcriptional silencing is an essential mechanism for controlling the expression of genes, transgenes and heterochromatic repeats through specific epigenetic marks on chromatin that are maintained during DNA replication. In Arabidopsis, silenced transgenes and heterochromatic sequences are typically associated with high levels of DNA methylation, while silenced genes are enriched in H3K27me3. Reactivation of these loci is often correlated with decreased levels of these repressive epigenetic marks. Here, we report that the DNA helicase REGULATOR OF TELOMERE ELONGATION 1 (RTEL1) is required for transcriptional silencing. RTEL1 deficiency causes upregulation of many genes enriched in H3K27me3 accompanied by a moderate decrease in this mark, but no loss of DNA methylation at reactivated heterochromatic loci. Instead, heterochromatin exhibits DNA hypermethylation and increased H3K27me3 inrtel1. We further find that loss of RTEL1 suppresses the release of heterochromatin silencing caused by the absence of the MOM1 silencing factor. RTEL1 is conserved among eukaryotes and plays a key role in resolving DNA secondary structures during DNA replication. Inducing such aberrant DNA structures using DNA cross-linking agents also results in a loss of transcriptional silencing. These findings uncover unappreciated roles for RTEL1 in transcriptional silencing and in stabilizing DNA methylation and H3K27me3 patterns.
Terminal type-specific cannabinoid CB1 receptor alterations in patients with schizophrenia: a pilot study
Authors: Chou Shinnyi , Fish Kenneth N , Lewis David A , Sweet Robert A
Published: April 2023

Background

Individuals with schizophrenia are at elevated genetic risks for comorbid cannabis use, and often experience exacerbations of cognitive and psychotic symptoms when exposed to cannabis. These findings have led a number of investigators to examine cannabinoid CB1 receptor (CB1R) alterations in schizophrenia, though with conflicting results. We recently demonstrated the presence of CB1R in both excitatory and inhibitory boutons in the human prefrontal cortex, with differential levels of the receptor between bouton types. We hypothesized that the differential enrichment of CB1R between bouton types – a factor previously unaccounted for when examining CB1R changes in schizophrenia – may resolve prior discrepant reports and increase our insight into the effects of CB1R alterations on the pathophysiology of schizophrenia.

Methods

Using co-labeling immunohistochemistry and fluorescent microscopy, we examined total CB1R levels and CB1R levels within excitatory (vGlut1-positive) and inhibitory (vGAT-positive) boutons of prefrontal cortex samples from ten pairs of individuals diagnosed with schizophrenia and non-psychiatric comparisons.

Results

Significantly higher total CB1R levels were found within samples from individuals with schizophrenia. Terminal type-specific analyses identified significantly higher CB1R levels within excitatory boutons in samples from individuals with schizophrenia relative to comparisons. In contrast, CB1R levels within the subset of inhibitory boutons that normally express high CB1R levels (presumptive cholecystokinin neuron boutons) were lower in samples from individuals with schizophrenia relative to comparison samples.

Conclusion

Given CB1R’s role in suppressing neurotransmission upon activation, these results suggest an overall shift in excitatory and inhibitory balance regulation toward a net reduction of excitatory activity in schizophrenia.
SpatialCTD: a large-scale TME spatial transcriptomic dataset to evaluate cell type deconvolution for immuno-oncology
Authors: Ding Jiayuan , Venegas Julian , Lu Qiaolin , Wang Yixin , Wu Lidan , Jin Wei , Wen Hongzhi , Liu Renming , Tang Wenzhuo , Li Zhaoheng , Zuo Wangyang , Chang Yi , Lei Yu Leo , Danaher Patrick , Xie Yuying , Tang Jiliang
Published: April 2023

Recent technological advancements have enabled spatially resolved transcriptomic profiling but at multi-cellular resolution. The task of cell type deconvolution has been introduced to disentangle discrete cell types from such multi-cellular spots. However, existing datasets for cell type deconvolution are limited in scale, predominantly encompassing data on mice, and are not designed for human immuno-oncology. In order to overcome these limitations and promote comprehensive investigation of cell type deconvolution for human immuno-oncology, we introduce a large-scale spatial transcriptomic dataset named SpatialCTD, encompassing 1.8 million cells from the human tumor microenvironment across the lung, kidney, and liver. Distinct from existing approaches that primarily depend on single-cell RNA sequencing data as a reference without incorporating spatial information, we introduce Graph Neural Network-based method (i.e., GNNDeconvolver) that effectively utilize the spatial information from reference samples, and extensive experiments show that GNNDeconvolveroften outperforms existing state-of-the-art methods by a substantial margin, without requiring single-cell RNA-seq data. To enable comprehensive evaluations on spatial transcriptomics data from flexible protocols, we provide an online tool capable of converting spatial transcriptomic data from other platforms (e.g., 10x Visium, MERFISH and sci-Space) into pseudo spots, featuring adjustable spot size. The SpatialCTD dataset and GNNDeconvolverimplementation are available athttps://github.com/OmicsML/SpatialCTD, and the online converter tool can be accessed athttps://omicsml.github.io/SpatialCTD/.
ARDitox: platform for the prediction of TCRs potential off-target binding
Authors: Pienkowski Victor Murcia , Boschert Tamara , Skoczylas Piotr , Sanecka-Duin Anna , Jasiński Maciej , Król-Józaga Bartłomiej , Mazzocco Giovanni , Stachura Sławomir , Bunse Lukas , Kaczmarczyk Jan , Green Edward W , Blum Agnieszka
Published: April 2023

Cellular immunotherapies, such as those utilizing T lymphocytes expressing native or engineered T cell receptors (TCRs), have already demonstrated therapeutic efficacy. However, some high-affinity TCRs have also proved to be fatal due to off-target immunotoxicity. This process occurs when the immune system acts against epitopes found on both tumor cells and healthy tissues. Moreover, some TCRs can be cross-reactive to epitopes with highly dissimilar sequences. To address this issue, we developed ARDitox, a novelin silicomethod based on computational immunology and artificial intelligence (AI) for predicting and analyzing potential off-target binding. We tested the performance of ARDitoxin silicoon different cases found in the literature where TCRs were used to target cancer-related antigens, as well as on a set of TCRs targeting a viral epitope. ARDitox was able to identify previously reported cross-reactive epitopes in line with the data available in the literature. In addition, we investigated a TCR targeting an HLA-A*02:01-restricted immunodominant epitope from the glioblastoma-associated antigen NLGN4X, identifying a cross-reactive ADH1A epitope that would not be detected in murine models. In conclusion, ourin silicoapproach is a powerful tool that identifies potential off-target epitopes, complementing preclinical studies in developing safer cell therapies targeting tumor(- associated) antigens.
Retrovirus-Like Gag Protein Arc/Arg3.1 is Involved in Extracellular-Vesicle-Mediated mRNA Transfer between Glioma Cells
Authors: Othman Aya Al , Bagrov Dmitry , Rozenberg Julian M , Glazova Olga , Skryabin Gleb , Tchevkina Elena , Mezentsev Alexandre , Durymanov Mikhail
Published: April 2023

Activity-regulated cytoskeleton-associated (Arc) protein is expressed in neural tissue of vertebrates, where it plays a pivotal role in modulation of synaptic communication. In addition, Arc protein forms capsid-like particles, which can encapsulate and transfer mRNA in extracellular vesicles (EVs) between neurons, that could modulate synaptic function and plasticity. Glioma cell networks actively interact with neuronsviaparacrine signaling and formation of neurogliomal glutamatergic synapses that contribute to cancer cell survival, proliferation, and invasion. Here, we revealed that Arc is expressed in human glioma cell lines, which can produce EVs containing Arc protein andArcmRNA (or “Arc EVs”). Recombinant Arc protein binds toArcmRNA with 1.5-fold higher affinity as compared with controlmCherrymRNA. Arc EVs from U87 glioma cells internalize and deliverArcmRNA to recipient U87 cells, where it is translated into a protein. Arc overexpression significantly increases EV production, alters EV morphology, and enhances intercellular transfer of highly expressed mRNA in glioma cell culture. These findings indicate involvement of Arc EVs into mRNA transfer between glioma cells that could contribute to tumor progression and affect synaptic plasticity in cancer patients.
Erythroid differentiation intensifies RNA mis-splicing inSF3B1-mutant myelodysplastic syndromes with ring sideroblasts
Authors: Moura Pedro L. , Mortera-Blanco Teresa , Hofman Isabel J.F. , Todisco Gabriele , Kretzschmar Warren W. , Björklund Ann-Charlotte , Creignou Maria , Hagemann-Jensen Michael , Ziegenhain Christoph , Granados David C. , Barbosa Indira , Walldin Gunilla , Jansson Monika , Ashley Neil , Mead Adam J. , Lundin Vanessa , Dimitriou Marios , Yoshizato Tetsuichi , Woll Petter S. , Ogawa Seishi , Sandberg Rickard , Jacobsen Sten Eirik W. , Hellström-Lindberg Eva
Published: April 2023

Myelodysplastic syndromes with ring sideroblasts (MDS-RS) commonly originate from mutations in the splicing factorSF3B1(SF3B1mt).SF3B1mtcause RNA mis-splicing, mechanistically established as the major driver of RS development. However, little is known about RS fate and biology after their initial formation in the human bone marrow. We here achieve isolation of viable RS from patient samples, enabling the first complete investigation ofSF3B1mtdevelopment from stem cell to RS. We show that RS skew MACS-isolated CD34+data towards erythroid features not recapitulated in single-cell RNAseq. We demonstrate that RS divide, differentiate, enucleate and actively respond to mis-splicing/oxidative stress, decreasing wildtype stem cell fitness via GDF15 overproduction. We identify circulating RS as a uniform clinical feature associated with disease burden. Finally, we establish thatSF3B1mtmis-splicing intensifies during erythroid differentiation and demonstrate through combined transcriptomics/proteomics an uncoupling of RNA/protein biology in RS encompassing severe and dysfunctional mis-splicing of proapoptotic genes.

Statement of significance

We here combine a novel method for RS isolation with state-of-the-art multiomics to perform the first complete investigation ofSF3B1mtMDS-RS hematopoiesis from stem cell to RS. We identify the survival mechanisms underlyingSF3B1mterythropoiesis and establish an active role for erythroid differentiation and RS themselves inSF3B1mtMDS-RS pathogenesis.
PITAR, a DNA damage-inducible Cancer/Testis long noncoding RNA, inactivates p53 by binding and stabilizing TRIM28 mRNA
Authors: Jana Samarjit , Mondal Mainak , Mahale Sagar , Gupta Bhavana , Prasasvi Kaval Reddy , Kandasami Lekha , Jha Neha , Chowdhury Abhishek , Santosh Vani , Kanduri Chandrasekhar , Somasundaram Kumaravel
Published: April 2023

In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR (p53InactivatingTRIM28associatedRNA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR, in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28-dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR, which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target.
Tr1 cell-mediated protection against autoimmune disease by intranasal administration of a fusion protein targeting cDC1 cells
Authors: Hansson Charlotta , Lebrero-Fernández Cristina , Schön Karin , Angeletti Davide , Lycke Nils
Published: April 2023

Curative therapies against autoimmune diseases are lacking. Indeed, most of currently available treatments are only targeting symptoms. We have developed a novel strategy for a therapeutic vaccine against autoimmune diseases based on intranasal administration of a fusion protein tolerogen, which consists of a mutant, enzymatically inactive, cholera toxin A1-subunit genetically fused to disease relevant high affinity peptides and a dimer of D-fragments from protein A. The CTA1R7K-MOG/PLP-DD fusion proteins effectively reduced clinical symptoms in the experimental autoimmune encephalitis (EAE)-model of multiple sclerosis (MS). The treatment induced Tr1 cells, in the draining lymph node, which produced IL-10 and suppressed effector CD4+T cell responses. This effect was dependent on IL-27 signalling, since treatment was ineffective in bone marrow chimeras lacking IL-27Rα within their hematopoietic compartment. scRNA-seq of dendritic cells (DC) in draining lymph nodes demonstrated distinct gene transcriptional changes of cDC1, including enhanced lipid metabolic pathways, induced by the tolerogenic fusion protein. Thus, our results with the tolerogenic fusion protein demonstrates the possibility to vaccinate and protect against disease progression by reinstating tolerance in MS and other autoimmune diseases.
In depth amino acid mutational analysis of the key interspecific incompatibility transmembrane factor Stigmatic Privacy 1
Authors: Kato Yoshinobu , Tadokoro Shun , Ishida Shota , Niidome Maki , Kimura Yuka , Takayama Seiji , Fujii Sota
Published: April 2023

In plants, there is an active prezygotic interspecific-incompatibility mechanism to prevent unfavorable hybrids between two species. We previously reported that an uncharacterized protein with four-transmembrane domains, named as Stigmatic Privacy 1 (SPRI1), is responsible for rejecting hetero-specific pollen grains inArabidopsis thaliana.

We have conducted a functional study of the SPRI1 protein, via point-mutational experiments and biochemical analysis. We studied the molecular regulatory mechanisms of SPRI1 and the relationships with its function.

The alanine- and glycine-scanning experiments together with the evolutional analysis showed that the structural integrity of the C-terminal regions of the extracellular domain of this protein is important for its function. In addition, we found two cysteines (C67 and C80) within the extracellular domain that may be involved in the formation of intermolecular disulfide bonds. SPRI1 may form homo-multimers and is present as part of a ca. 300 kDa complex.

Our present study indicates that molecular complex formation ability of SPRI1 may be important to maintain its stability and interspecific incompatibility functions in cells.
Environmental legacy effects impact maize growth and microbiome assembly under drought stress
Authors: Swift Joel F. , Kolp Matthew R. , Carmichael Amanda , Ford Natalie E. , Hansen Paige M. , Sikes Benjamin A. , Kleiner Manuel , Wagner Maggie R.
Published: April 2023

Background and Aims

As the climate changes, plants and their associated microbiomes face greater water limitation and increased frequency of drought. Historical environmental patterns can leave a legacy effect on soil and root-associated microbiomes, but the impact of this conditioning on future drought performance is poorly understood. Precipitation gradients provide a means to assess these legacy effects.

Methods

We collected soil microbiomes from four native prairies across a steep precipitation gradient in Kansas, USA. Seedlings of twoZea maysgenotypes were inoculated with each soil microbiome in a factorial drought experiment. We investigated plant phenotypic and root microbiome responses to drought and modeled relationships between plant growth metrics and climatic conditions from the soil microbiome origin sites.

Results

Drought caused plants to accumulate shoot mass more slowly and achieve greater root/shoot mass ratios. Drought restructured the bacterial root-associated microbiome via depletion of Pseudomonadota and enrichment of Actinomycetota, whereas the fungal microbiome was largely unaffected. An environmental legacy effect on prairie soil microbiomes influenced plants’ drought responses: counterintuitively, prairie soil inocula from historically wetter locations increased shoot biomass under drought more than inocula from historically drier prairie soils.

Conclusion

We demonstrated links between soil microbiome legacy effects and plant performance under drought, suggesting that future drying climates may condition soils to negatively impact plant performance.
Touching the (almost) untouchable: a minimally-invasive workflow for microbiological and biomolecular analyses of cultural heritage objects
Authors: Flocco Cecilia G. , Methner Anika , Burkart Franziska , Geppert Alicia , Overmann Jörg
Published: April 2023

Microbiological and biomolecular approaches to cultural heritage research have expanded the established research horizon -from the prevalent focus on the cultural object’s conservation and human health protection to the relatively recent applications to provenance inquiry and assessment of environmental impacts on heritage objects in a global context of a changing climate. Standard microbiology and molecular biology methods were developed for other materials, specimens, disciplines and contexts. Although they could in principle be applied to cultural heritage research, certain characteristics common to several heritage objects – such as uniqueness, fragility, high value and restricted access, demand tailored approaches. In addition, samples from heritage objects often yield low microbial biomass, rendering them highly susceptible to cross-contamination. Therefore, dedicated methodology that addresses these material limitations and operational hurdles along all procedural steps are needed. Here were propose a step-by-step standardized laboratory and bioinformatic workflow to analyse the microbiome of cultural heritage objects. The methodology was developed targeting the challenging side of the spectrum of cultural heritage objects, such as the delicate written record, while retaining modularity and flexibility to adapt and/or upscale the proposed workflow to heritage artefacts of a more robust nature or larger dimensions. We hope this review and workflow will facilitate the interdisciplinary inquiry and interactions among the cultural heritage research community.
Neural signatures of automatic repetition detection in temporally regular and jittered acoustic sequences
Authors: Ringer Hanna , Schröger Erich , Grimm Sabine
Published: April 2023

Detection of repeating patterns within continuous sound streams is crucial for efficient auditory perception. Previous studies demonstrated a remarkable sensitivity of the human auditory system to periodic repetitions in randomly generated sounds. Automatic repetition detection was reflected in different EEG markers, including sustained activity, neural synchronisation, and event-related responses to pattern occurrences. The current study investigated how listeners’ attention and the temporal regularity of a sound modulate repetition perception, and how this influence is reflected in different EEG markers that were previously suggested to subserve dissociable functions. We reanalysed data of a previous study in which listeners were presented with random acoustic sequences with and without repetitions of a certain sound segment. Repeating patterns occurred either regularly or with a temporal jitter within the sequences, and participants’ attention was directed either towards or away from the auditory stimulation. Across both regular and jittered sequences during both attention and in-attention, pattern repetitions led to increased sustained activity throughout the sequence, evoked a characteristic positivity-negativity complex in the event-related potential, and enhanced inter-trial phase coherence of low-frequency oscillatory activity time-locked to repeating pattern onsets. While regularity only had a minor (if any) influence, attention significantly strengthened pattern repetition perception, which was consistently reflected in all three EEG markers. These findings suggest that the detection of pattern repetitions within continuous sounds relies on a flexible mechanism that is robust against in-attention and temporal irregularity, both of which typically occur in naturalistic listening situations. Yet, attention to the auditory input can enhance processing of repeating patterns and improve repetition detection.
The potential effects of tree planting on allergenic pollen production in New York City
Authors: Katz Daniel S.W.
Published: April 2023

Abstract

Tree selection decisions affect urban pollen production but the overall importance of tree planting to airborne pollen concentrations remains poorly understood. A synthesis of existing data and available literature could inform tree -planting decisions and potentially help reduce future airborne pollen concentrations. This is especially relevant for the many cities that are considering tree planting campaigns, such as New York City. Here, I examine which allergenically -important tree taxa could be most influenced by municipal tree selectio n decisions in New York City by comparing tree species abundance from a representative plot-based city-wide tree survey with a street tree inventory. I then estimate pollen production from several allergenic tree taxa by combining these tree datasets with allometric equations of pollen production as a function of tree size. Pollen production is also compared to several years of airborne pollen measurements. The potential effect of a proposed planting campaign is estimated over time by combining growth rate equations with pollen production equations. Several tree genera are especially important producers of allergenic pollen in New York City, includingQuercus, Platanus, Morus, andBetula; these taxa also comprise 71% of airborne pollen measured and 93% of estimated pollen production (107 quadrillion pollen grains ; however pollen production could not be estimated for all taxa).Platanus×acerifoliais predominantly a street tree, indicating that previous municipal planting decisions have resulted in its current abundance (it accounts for 34% of total street tree basal area and has an estimated annual pollen production of almost 30 quadrillion grains) and will determine its future abundance. In contrast,MorusandBetulaare uncommon as street trees, indicating that municipal tree planting campaigns are unlikely to substantially affect their pollen production rates in NYC.Quercuswas the largest estimated producer of pollen in NYC (62 quadrillion pollen grains) and accounted for almost 25% of airborne pollen co llected, but its very high abundance outside of street trees suggest that the relative effect of planting trees in this genus will be relatively small. Overall, this study demonstrates how tree planting decisions can have important and long-lasting consequences for allergenic pollen production in certain circumstances, suggesting that pollen allergenicity should be considered in future tree selection decisions.
An improved genome assembly of the saguaro cactus (Carnegiea gigantea(Engelm.) Britton & Rose)
Authors: Copetti Dario , Búrquez Alberto , Shimizu Kentaro K. , Wing Rod A. , Sanderson Michael J. , Wojciechowski Martin F.
Published: April 2023

We present an improved genome assembly of the saguaro cactus (Carnegiea gigantea(Engelm.) Britton & Rose), obtained by incorporating long-read PacBio data to the existing short reads. The assembly improves in terms of total size, contiguity, and accuracy, allowing to extend the range of sequence analyses beyond the single-gene scale. Consequently, the assembly is 16% larger and has 20% more genes, expanding the resources for a neglected yet very remarkable plant family such as Cactaceae.

Species taxonomy

Eukaryota; Viridiplantae; Streptophyta; Streptophytina; Embryophyta; Tracheophyta; Euphyllophyta; Spermatophyta; Magnoliopsida; Mesangiospermae; eudicotyledons; Gunneridae; Pentapetalae; Caryophyllales; Cactineae; Cactaceae; Cactoideae; Echinocereeae; Carnegiea gigantea (Engelm.) Britton & Rose) (also known as saguaro cactus) (NCBI txid: 171969).
Egocentric cues influence the spatial memory of landmark configurations for memory-guided actions
Authors: Forster Pierre-Pascal , Fiehler Katja , Karimpur Harun
Published: April 2023

Allocentric and egocentric reference frames are used to determine the spatial position of action targets in reference to objects in the environment, i.e., landmarks (allocentric), or the observer (egocentric). Previous research investigated reference frames in isolation, for example, by shifting landmarks relative to the target and asking participants to reach to the remembered target location. Systematic reaching errors were found in the direction of the landmark shift and used as a proxy for allocentric spatial coding. Here we examined the interaction of both allocentric and egocentric reference frames by shifting the landmarksas well asthe observer. We asked participants to encode a 3D configuration of balls, and to reproduce this configuration from memory after a short delay followed by a landmark or observer shift. We also manipulated the number of landmarks to test its effect on the use of allocentric and egocentric reference frames. Shifting the observer resulted in larger configurational errors. In addition, an increase in the number of landmarks led to a stronger reliance on allocentric cues and a weaker contribution of egocentric cues. In sum, our results highlight the important role of egocentric cues for allocentric spatial coding in the context of memory-guided actions.

New & Noteworthy

Objects in our environment are coded relative to each other (allocentrically) and are thought to serve as independent and reliable cues (landmarks) in the context of unreliable egocentric signals. Contrary to this assumption, we demonstrate that egocentric cues alter the spatial memory of landmark configurations, which could reflect recently discovered interactions between allocentric and egocentric neural processing pathways. Further, additional landmarks lead to a higher contribution of allocentric and a lower contribution of egocentric cues.
G2GSnake: A Snakemake workflow for host-pathogen genomic association studies
Authors: Xu Zhi Ming , Naret Olivier , Fellay Jacques
Published: April 2023

Joint analyses of paired host and pathogen genome sequences have the potential to enhance our understanding of host-pathogen interactions. A systematic approach to conduct such a joint analysis is through a “genome-to-genome” (G2G) association study, which involves testing for associations between all host and pathogen genetic variants. Significant associations reveal host genetic factors that might drive pathogen variation, highlighting biological mechanisms likely to be involved in host control and pathogen escape. Here, we present a Snakemake workflow that allows researchers to conduct G2G studies in a reproducible and scalable manner. In addition, we have developed an intuitive R Shiny application that generates custom summaries of the results, enabling users to derive relevant insights.

Availability and implementation

G2GSnake is freely available at:https://github.com/zmx21/G2GSnakeunder the MIT license.
Defective pgsA contributes to increased membrane fluidity and cell wall thickening in S. aureus with high-level daptomycin resistance
Authors: Freeman Christian D. , Hansen Tayte , Urbauer Ramona , Wilkinson Brian J. , Singh Vineet K. , Hines Kelly M.
Published: April 2023

Daptomycin is a membrane-targeting last-resort antimicrobial therapeutic for the treatment of infections caused by methicillin- and/or vancomycin-resistantStaphylococcus aureus. In the rare event of failed daptomycin therapy, the source of resistance is often attributable to mutations directly within the membrane phospholipid biosynthetic pathway ofS. aureusor in the regulatory systems that control cell envelope response and membrane homeostasis. Here we describe the structural changes to the cell envelope in a daptomycin-resistant isolate ofS. aureusstrain N315 that has acquired mutations in the genes most commonly reported associated with daptomycin-resistance:mprF,yycG, andpgsA. In addition to the decreased phosphatidylglycerol (PG) levels that are the hallmark of daptomycin-resistance, the mutant with high-level daptomycin resistance had increased branched-chain fatty acids (BCFAs) in its membrane lipids, increased membrane fluidity, and increased cell wall thickness. However, the successful utilization of isotope-labeled straight-chain fatty acids (SCFAs) in lipid synthesis suggested that the aberrant BCFA:SCFA ratio arose from upstream alteration in fatty acid synthesis rather than a structural preference in PgsA. RT-qPCR studies revealed that expression of pyruvate dehydrogenase (pdhB) was suppressed in the daptomycin-resistant isolate, which is known to increase BCFA levels. While complementation with an additional copy ofpdhBhad no effect, complementation of thepgsAmutation resulted in increased PG formation, reduction in cell wall thickness, restoration of normal BCFA levels, and increased daptomycin susceptibility. Collectively, these results demonstrate thatpgsAcontributes to daptomycin resistance through its influence on membrane fluidity and cell wall thickness, in addition to phosphatidylglycerol levels.

IMPORTANCE

The cationic lipopeptide antimicrobial daptomycin has become an essential tool for combating infections withStaphylococcus aureusthat display reduced susceptibility to β-lactams or vancomycin. Since daptomycin’s activity is based on interaction with the negatively charged membrane ofS. aureus, routes to daptomycin-resistance occur through mutations in the lipid biosynthetic pathway surrounding phosphatidylglycerols and the regulatory systems that control cell envelope homeostasis. Therefore, there are many avenues to achieve daptomycin resistance and several different, and sometimes contradictory, phenotypes of daptomycin-resistantS. aureus,including both increased and decreased cell wall thickness and membrane fluidity. This study is significant because it demonstrates the unexpected influence of a lipid biosynthesis gene,pgsA, on membrane fluidity and cell wall thickness inS. aureuswith high-level daptomycin resistance.
COP9 Signalosome Promotes Neointimal Hyperplasia via Deneddylation and CSN5-Mediated Nuclear Export
Authors: Giri Samiksha , Suo Chao , Pardi Ruggero , Fishbein Gregory A. , Rezvani Khosrow , Chen Yabing , Wang Xuejun
Published: April 2023

BACKGROUND

Neointimal hyperplasia (NH) is a common pathological response to vascular injury and mediated primarily by vascular smooth muscle cell (VSMC) migration and proliferation. The COP9 signalosome (CSN) is formed by 8 canonical subunits (CSN1 through CSN8) with its deneddylation activity residing in CSN5. Each or some of CSN subunits may have deneddylation-independent function. Despite strong evidence linking the CSN to cell cycle regulation in cancer cells, the role of the CSN in vascular biology remains obscure.

METHODS

Neointimal CSN5 expression in the lung tissue of pulmonary hypertension (PAH) patients was assessed with immunohistochemistry. Adult mice with smooth muscle cell-restricted CSN5 knockout (CSN5-SMKO) or CSN8 hypomorphism (CSN8-hypo) and cultured mouse VSMCs were studied to determine the role and governing mechanisms of the CSN in NH. NH was induced by ligation of the left common carotid artery (LCCA) and PDGF-BB stimulation was used to mimic the vascular injury in cell cultures.

RESULTS

Remarkably higher CSN5 levels were detected in the neointimal VSMCs of the pulmonary arteries of human PAH. LCCA ligation induced NH and significantly increased the mRNA and protein levels of CSN subunits in the LCCA wall of adult wild type mice. CSN5-SMKO impaired Cullin deneddylation and the nuclear export of p27 in vessel walls and markedly inhibited VSMC proliferation in mice. On the contrary, CSN8-hypo significantly exacerbated NH and VSMC proliferationin vivoandin cellulo.

Cytoplasmic CSN5 mini-complexes and the nuclear export of p27 were significantly increased in CSN8-hypo mouse vessels and cultured CSN8-hypo VSMCs. Nuclear export inhibition with leptomycin attenuated the PDGF-BB-induced increases in VSMC proliferation in both CSN8-hypo and control VSMCs. Further, genetically disabling CSN5 nuclear export but not disabling CSN5 deneddylase activity suppressed the hyperproliferation and restored p27 nuclear localization in CSN8 hypomorphic VSMCs. Interestingly, CSN deneddylase inhibition by CSN5i-3 did not alter the hyperproliferation of cultured CSN8-hypo VSMCs but suppressed wild type VSMC proliferationin celluloandin vivoand blocked neointimal formation in wild type mice.

CONCLUSION

The CSN promotes VSMC proliferation and NH in injured vessels through deneddylation activity and CSN5-mediated nuclear export.