bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining the HIV Capsid Binding Site of Nucleoporin 153
Authors: Li Shunji , Patel Jagdish Suresh , Yang Jordan , Crabtree Angela Marie , Rubenstein Brenda M. , Lund-Andersen Peik Karl , Ytreberg Frederick Marty , Rowley Paul Andrew
Published: May 2022

The interaction between the HIV-1 capsid (CA) and human nucleoporin 153 (NUP153) is vital for delivering the HIV-1 preintegration complex into the nucleus via the nuclear pore complex. The interaction with CA requires a phenylalanine/glycine-containing motif in the C-terminus of NUP153. This study used molecular modeling and biochemical assays to determine the amino acids of NUP153 that are essential for its interactions with CA. Molecular dynamics, FoldX, and PyRosetta simulations delineated the minimal CA binding motif of NUP153 based on the known structure of NUP153 bound to the HIV-1 CA hexamer. Computational predictions were experimentally validated by testing the interaction of NUP153 with CA using an in vitro binding assay and a cell-based TRIM-NUP153C restriction assay. This multidisciplinary approach identified eight amino acids from P1411 to G1418 that stably engage with CA, with significant correlations between molecular models and empirical experiments. Specifically, P1411, V1414, F1415, T1416, F1417, and G1418 were confirmed as critical amino acids required to interact NUP153 with CA.

IMPORTANCE

Human immunodeficiency virus (HIV) can infect non-dividing cells by interacting with host nuclear pores. The host nuclear pore protein NUP153 directly interacts with the HIV capsid to promote viral nuclear entry. This study used a multidisciplinary approach combining computational and experimental techniques to map the essential amino acids of NUP153 required for HIV capsid interaction. This approach revealed that the HIV capsid interacts specifically with only six amino acids of NUP153, suggesting other FG-containing motifs could also interact with the capsid. Based on molecular modeling, naturally occurring polymorphisms in human and non-human primates would be predicted to prevent NUP153 interaction with capsid, potentially protecting from HIV infection.
The proteomic and transcriptomic landscapes altered by Rgg2/3 activity in Streptococcus pyogenes
Authors: Rued Britta E. , Anderson Caleb M. , Federle Michael J.
Published: May 2022

Streptococcus pyogenes, otherwise known as Group A Streptococcus (GAS), is an important and highly adaptable human pathogen with the ability to cause both superficial and severe diseases. Understanding how S. pyogenes senses and responds to its environment will likely aid in determining how it causes a breadth of diseases. One regulatory network involved in GAS’s ability to sense and respond to the changing environment is the Rgg2/3 quorum sensing (QS) system, which responds to metal and carbohydrate availability and regulates changes to the bacterial surface. To better understand the impact of Rgg2/3 QS on S. pyogenes physiology, we performed RNA-seq and TMT-LC-MS/MS analysis on cells in which this system was induced or disrupted. Primary findings confirmed that pheromone stimulation in wildtype cultures is limited to the induction of operons whose promoters contain previously determined Rgg2/3 binding sequences. However, supplementing exogenous pheromone to a deletion mutant of rgg3, a strain that endogenously produces elevated amounts of pheromone, led to extended alterations of the transcriptome and proteome, ostensibly by stress-induced pathways. Under such exaggerated pheromone conditions (Δrgg3+SHP), a connection was identified between Rgg2/3 and the stringent response. Mutation of relA, the bifunctional guanosine tetra- and penta-phosphate nucleoside synthetase/hydrolase, and alarmone synthase genes sasA and sasB, impacted culture doubling times and disabled induction of Rgg2/3 in response to mannose, while manipulation of Rgg2/3 signaling modestly altered nucleotide levels. Our findings indicate that excessive pheromone production or exposure places stress on GAS resulting in an indirect altered proteome and transcriptome beyond primary pheromone signaling.

IMPORTANCE

Streptococcus pyogenes causes several important human diseases. This study evaluates how the induction or disruption of a cell-cell communication system alters S. pyogenes’s gene expression and, in extreme conditions, its physiology. Using transcriptomic and proteomic approaches, the results define the pheromone-dependent regulon of the Rgg2/3 quorum sensing system. In addition, we find that excessive pheromone stimulation, generated by genetic disruption of the system, leads to stress responses that are associated with the stringent response. Disruption of this stress response affects the ability of the cell-cell communication system to respond under certain conditions. These findings assist in the determination of how S. pyogenes is impacted by and responds to non-traditional sources of stress.
PHi-C2: interpreting Hi-C data as the dynamic 3D genome state
Authors: Shinkai Soya , Itoga Hiroya , Kyoda Koji , Onami Shuichi
Published: May 2022

Hi-C is a widely used assay for studying three-dimensional (3D) genome organization across the whole genome. Here, we present PHi-C2, a Python package supported by mathematical and biophysical polymer modeling, that converts an input Hi-C matrix data into the polymer model’s dynamics, structural conformations, and rheological features. The updated optimization algorithm to regenerate a highly similar Hi-C matrix provides a fast and accurate optimal solution compared to the previous version by eliminating a computational bottleneck in the iterative optimization process. Besides, we newly set up the availability on Google Colab workflow to run, easily change parameters and check the results in the notebook. Overall, PHi-C2 can be a valuable tool to mine the dynamic 3D genome state embedded in Hi-C data.

Availability and Implementation

PHi-C2 as the phic Python package is freely available under the GPL license and can be installed from the Python package index. The source code is available from GitHub at https://github.com/soyashinkai/PHi-C2. Without preparing a Python environment, PHi-C2 can run on Google Colab (https://bit.ly/3rlptGI).

Contact

soya.shinkai@riken.jp or sonami@riken.jp
Highly specialized carbohydrate metabolism capability in Bifidobacterium strain associated with intestinal barrier maturation in early preterm infants
Authors: Ma Bing , Sundararajan Sripriya , Nadimpalli Gita , France Michael , McComb Elias , Rutt Lindsay , Lemme-Dumit Jose M , Janofsky Elise , Roskes Lisa S. , Gajer Pawel , Fu Li , Yang Hongqiu , Humphrys Mike , Tallon Luke J , Sadzewicz Lisa , Pasetti Marcela F , Ravel Jacques , Viscardi Rose M
Published: May 2022

“Leaky gut”, or high intestinal barrier permeability, is common in preterm newborns. The role of microbiota in this process remains largely uncharacterized. We employed both short- and long-read sequencing of the 16S rRNA gene and metagenomes to characterize the intestinal microbiome of a longitudinal cohort of 113 preterm infants born between 240/7-326/7 weeks of gestation. Enabled by enhanced taxonomic resolution, we found significantly increased abundance of Bifidobacterium breve and a diet rich in mother’s breastmilk to be associated with intestinal barrier maturation during the first week of life. We combined these factors using genome- resolved metagenomics and identified a highly specialized genetic capability of the Bifidobacterium strains to assimilate human milk oligosaccharides and host-derived glycoproteins. Our study proposed mechanistic roles of breastmilk feeding and intestinal microbial colonization in postnatal intestinal barrier maturation; these observations are critical towards advancing therapeutics to prevent and treat hyperpermeable gut- associated conditions, including necrotizing enterocolitis.

IMPORTANCE

Despite improvements in neonatal intensive care, necrotizing enterocolitis (NEC) remains a leading cause of morbidity and mortality. “Leaky gut”, or intestinal barrier immaturity with elevated intestinal permeability, is the proximate cause of susceptibility to NEC. Early detection and intervention to prevent leaky gut in “at-risk” preterm neonates is critical to lower the risk for potentially life-threatening complications like NEC. However, the complex interactions between the developing gut microbial community, nutrition, and intestinal barrier function, remain largely uncharacterized. In this study, we revealed the critical role of sufficient breastmilk feeding volume and specialized carbohydrate metabolism capability of Bifidobacterium in coordinated postnatal improvement of intestinal barrier. Determining the clinical and microbial biomarkers that drive the intestinal developmental disparity will inform early detection and novel therapeutic strategies to promote appropriate intestinal barrier maturation, prevent NEC and other adverse health conditions in preterm infants.
DNA metabarcoding of gut contents reveals key habitat and seasonal drivers of trophic networks involving generalist predators in agricultural landscapes
Authors: Saqib Hafiz Sohaib Ahmed , Sun Linyang , Pozsgai Gabor , Liang Pingping , You Minsheng , Gurr Geoff M. , You Shijun
Published: May 2022

BACKGROUND

Understanding the networks of trophic interactions into which generalist predators are embedded is key to assessing their ecological role of in trophic networks and the biological control services they provide. The advent of affordable DNA metabarcoding approaches greatly facilitates quantitative understanding of trophic networks and their response to environmental drivers. Here, we examine how key environmental gradients interact to shape predation by Lycosidae in highly dynamic vegetable growing systems in China.

RESULTS

For the sampled Lycosidae, crop identity, pesticide use, and seasons shape the abundance of preydetected in spider guts. For the taxonomic richness of prey, local- and landscape-scale factors gradients were more influential. Multivariate ordinations confirm that these crop-abundant spiders dynamically adjust their diet to reflect environmental constraints and seasonal availability to prey.

CONCLUSION

The plasticity in the diet composition is likely to account for the persistence of spiders in relatively ephemeral brassica crops. Our findings provide further insights into the optimization of habitat management for predator-based biological control practices.
Potential future climate change effects on global reptile distributions and diversity
Authors: Biber Matthias F. , Voskamp Alke , Hof Christian
Published: May 2022

Aim

Until recently, complete information on global reptile distributions has not been widely available. Here, we provide the first comprehensive climate impact assessment for reptiles on a global scale.

Location

Global, excluding Antarctica

Time period

1995, 2050, 2080

Major taxa studied

Reptiles

Methods

We modelled the distribution of 6,296 reptile species and assessed potential global as well as realm-specific changes in species richness, the change in global species richness across climate space, and species-specific changes in range extent, overlap and position under future climate change. To assess the future climatic impact on 3,768 range-restricted species, which could not be modelled, we compared the future change in climatic conditions between both modelled and non-modelled species.

Results

Reptile richness was projected to decline significantly over time, globally but also for most zoogeographic realms, with the greatest decrease in Brazil, Australia and South Africa. Species richness was highest in warm and moist regions, with these regions being projected to shift further towards climate extremes in the future. Range extents were projected to decline considerably in the future, with a low overlap between current and future ranges. Shifts in range centroids differed among realms and taxa, with a dominating global poleward shift. Non-modelled species were significantly stronger affected by projected climatic changes than modelled species.

Main conclusions

With ongoing future climate change, reptile richness is likely to decrease significantly across most parts of the world. This effect as well as considerable impacts on species’ range extent, overlap, and position were visible across lizards, snakes and turtles alike. Together with other anthropogenic impacts, such as habitat loss and harvesting of species, this is a cause for concern. Given the historical lack of global reptile distributions, this calls for a reassessment of global reptile conservation efforts, with a specific focus on anticipated future climate change.
Significant phylogenetic signal is not enough to trust phylogenetic predictions
Authors: Molina-Venegas Rafael , Morales-Castilla Ignacio , Á. Rodríguez Miguel
Published: May 2022

In a recent study, Cantwell-Jones et al. (2022) proposed a list of 1044 species as promising key sources of B vitamins based primarily on phylogenetic predictions. To identify candidate plants, they fitted lambda models of evolution to edible species with known values in each of six B vitamins (232 to 280 species) and used the estimated parameters to predict B-vitamin profiles of edible plants lacking nutritional data (6460 to 6508 species). The latter species were defined as potential sources of a B vitamin if the predicted vitamin content was ≥15% towards recommended dietary allowances for active females between 31-50 years per 100 g of fresh edible plant material consumed. Unfortunately, the reliability of the predictions that informed the list of candidate species is questionable due to insufficient phylogenetic signal in the data (Pagel’s λ between 0.171 and 0.665) and a high incidence of species with missing values (over 95% of all the species analyzed in the study). We found that of the 1044 species proposed as promising B-vitamin sources, 626 to 993 species showed accuracies that were indistinguishable from those obtained under a white noise model of evolution (i.e. random predictions conducted in absence of any phylogenetic structure) in at least one of the vitamins, which proves the weakness of the inference drawn from imputed information in the original study. We hope this commentary serves as a cautionary note for future phylogenetic imputation exercises to carefully assess whether the data meet the requirements for the predictions to be valuable, or at least more accurate than expected by chance.
Allogeneic testes transplanted into partially castrated adult medaka (Oryzias latipes) can produce donor-derived offspring by natural mating over a prolonged period
Authors: Kayo Daichi , Kanda Shinji , Okubo Kataaki
Published: May 2022

Generally, successful testis transplantation has been considered to require immune suppression in the recipient to avoid rejection of the transplanted tissue. In the present study, we demonstrate in medaka that allogeneic adult testicular tissue will engraft in adult recipients immediately after partial castration without the use of immunosuppressive drugs. The allografted testes are retained in the recipient’s body for at least three months and are able to produce viable sperm that yield offspring after natural mating. Some recipients showed a high frequency (over 60%) of offspring derived from spermatozoa produced by the transplanted testicular tissue. Histological analyses showed that allografted testicular tissues included both germ cells and somatic cells that had established within an immunocompetent recipient testis. The relative simplicity of this testis transplantation approach will benefit investigations of the basic processes of reproductive immunology and will improve the technique of gonadal tissue transplantation.
Population genomics provide insights into the global genetic structure of Colletotrichum graminicola, the causal agent of maize anthracnose
Authors: Rogério Flávia , Baroncelli Riccardo , Cuevas-Fernández Francisco Borja , Becerra Sioly , Crouch JoAnne , Bettiol Wagner , Azcárate-Peril M. Andrea , Malapi-Wight Martha , Ortega Veronique , Betran Javier , Tenuta Albert , Dambolena José S. , Esker Paul D. , Revilla Pedro , Jackson-Ziems Tamra A. , Hiltbrunner Jürg , Munkvold Gary , Buhiniček Ivica , Vicente-Villardón José L. , Sukno Serenella A. , Thon Michael R.
Published: May 2022

Background

Colletotrichum graminicola, the causal agent of maize anthracnose, is an important crop disease worldwide. Understanding the genetic diversity and mechanisms underlying genetic variation in pathogen populations is crucial to the development of effective control strategies. The genus Colletotrichum is largely recognized as asexual, but several species have been reported to have a sexual cycle. Here, we employed a population genomics approach to investigate the genetic diversity and reproductive biology of C. graminicola isolates infecting maize. We sequenced 108 isolates of C. graminicola collected in 14 countries using restriction site-associated DNA sequencing (RAD-Seq) and whole-genome sequencing (WGS).

Results

Clustering analyses based on single-nucleotide polymorphisms showed populational differentiation at a global scale, with three genetic groups delimited by continental origin, compatible with short-dispersal of the pathogen, and geographic subdivision. Distinct levels of genetic diversity were observed between these clades, suggesting different evolutionary histories. Intra and inter-continental migration was predicted between Europe and South America, likely associated with the movement of contaminated germplasm. Low clonality and evidence of genetic recombination were detected from the analysis of linkage disequilibrium and the pairwise homoplasy index (PHI) test for clonality. We show evidence that even if rare (possibly due to losses of sex and meiosis-associated genes) C. graminicola can undergo sexual recombination based on lab assays and genomic analyses.

Conclusions

Our results support hypotheses of intra and intercontinental pathogen migration and genetic recombination with great impact on C. graminicola population structure.
Climate and ant richness explain the global distribution of ant-plant mutualisms
Authors: Luo Yangqing , Taylor Amanda , Weigelt Patrick , Guénard Benoit , Economo Evan P. , Nowak Arkadiusz , Inderjit  , Kreft Holger
Published: May 2022

Biotic interactions are known to play an important role in shaping species geographic distributions and diversity patterns. However, the role of mutualistic interactions in shaping global diversity patterns remains poorly quantified, particularly with respect to interactions with invertebrates. Moreover, it is unclear how the nature of different mutualisms interacts with abiotic drivers and affects diversity patterns of mutualistic organisms. Here, we present a global-scale biogeographic analysis of three different ant-plant mutualisms, differentiating between plants bearing domatia, extrafloral nectaries (EFNs), and elaiosomes, based on comprehensive geographic distributions of ∼15,000 flowering plants and ∼13,000 ant species. Domatia and extrafloral nectaries involve indirect plant defenses provided by ants, while elaiosomes attract ants to disperse seeds. Our results show distinct biogeographic patterns of different ant-plant mutualisms, with domatium- and EFN-bearing plant richness decreasing sharply from the equator towards the poles, while elaiosome-bearing plants prevail at mid-latitudes. Contemporary climate, especially mean annual temperature and precipitation, emerge as the most important predictor of ant-associated plant diversity. In hot and moist regions, typically the tropics, domatium- and EFN-bearing plant richness increases with related ant guild richness, while in warm regions plants with elaiosomes are strongly linked to interacting ants. Our results suggest that ant richness in combination with climate drives the spatial variation of plants bearing domatia, extrafloral nectaries, and elaiosomes, highlighting the importance of mutualistic interactions for understanding plant biogeography and its response to global change.
Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages
Authors: Hsu Chia George , Li Wenjia , Sowden Mark , Chávez Camila Lage , Berk Bradford C.
Published: May 2022

Polyribonucleotide nucleotidyltransferase 1 (Pnpt1) plays critical roles in mitochondrial homeostasis by controlling mitochondrial RNA (mt-RNA) processing, trafficking and degradation. Pnpt1 deficiency results in mitochondrial dysfunction that triggers a Type I interferon response, suggesting a role in inflammation. However, the role of Pnpt1 in inflammasome activation remains largely unknown. In this study, we generated myeloid-specific Pnpt1-knockout mice, and demonstrated that Pnpt1 depletion enhanced interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion in mouse sepsis models. Using cultured peritoneal and bone marrow-derived macrophages we demonstrated that Pnpt1 regulated NLRP3 inflammasome dependent IL-1β release in response to lipopolysaccharides (LPS), followed by nigericin, ATP or poly (I:C) treatment. Pnpt1 deficiency in macrophages increased glycolysis after LPS, and mt-reactive oxygen species (mt-ROS) after NLRP3 inflammasome activation. Pnpt1 activation of the inflammasome was dependent on both increased glycolysis and expression of the mitochondrial antiviral-signaling protein (MAVS), but not NF-κB signaling. Collectively, these data strengthen the concept that Pnpt1 is an important mediator of inflammation as shown by activation of the NLRP3 inflammasome in mouse sepsis and cultured macrophages.
Cyst size variability in invasive American Artemia franciscana Kellogg, 1906 (Branchiopoda: Anostraca) in Asia: a commercial approach
Authors: Wu Xiao-Fang , Shen Chun-Yang , Fu Chun-Zheng , Yang Ning , Pei-Zheng Wang , Eimanifar Amin , Asem Alireza
Published: May 2022

Artemia is the most common live food which is used in aquaculture worldwide. This study reports on biometrical variation of introduced American Artemia franciscana cyst from 24 non-native localities and two native habitats in Asia and USA, respectively. Results showed the largest diameter of untreated cyst, diameter of decapsulated cyst and thicker chorion ordinarily belong to invasive populations. Because of the small cysts, which have an effect on increasing quantity per unit weight and could be the cause of increased hatching efficiency, commercial productions of A. franciscana cyst from native sources should potentially be considered higher quality than productions from non-indigenous environments. Principal Component Analysis revealed that all cyst batches from San Francisco Bay were classified in one group and the most invasive populations could arrange in other separated group. Although, diameter of decapsulated cyst and chorion thickness showed a negative and significant correlation among invasive populations, there was no significant relationship within native populations. These observations contrast with biometrical patterns of parthenogenetic populations.
A synthetic tear protein resolves dry eye through promoting corneal nerve regeneration.
Authors: Efraim Yael , Chen Feeling Yu Ting , Cheong Ka Neng , Gaylord Eliza A , McNamara Nancy A , Knox Sarah M
Published: May 2022

Corneal architecture is essential for vision and is greatly perturbed by the absence of tears due to the highly prevalent disorder dry eye. With no regenerative therapies available, pathological alterations of the ocular surface in response to dryness, including persistent epithelial defects and poor wound healing, result in lifelong morbidity. Here, using a mouse model of aqueous-deficient dry eye, we reveal that topical application of the synthetic tear protein lacripep reverses the pathological outcomes of dry eye through restoring the extensive network of corneal nerves that are essential for tear secretion, barrier function, epithelial homeostasis and wound healing. Intriguingly, the restorative effects of lacripep occur despite extensive immune cell infiltration, suggesting tissue reinnervation and regeneration can be achieved under chronic inflammatory conditions. In summary, our data highlight lacripep as a first-in-class regenerative therapy for returning the cornea to a near homeostatic state in individuals who suffer from dry eye.
ATXN2 is a target of N-terminal proteolysis
Authors: Chitre Monika , Emery Patrick
Published: May 2022

Spinocerebellar ataxia 2 (SCA2) is a neurodegenerative disorder caused by the expansion of the poly-glutamine (polyQ) tract of Ataxin-2 (ATXN2). Other polyQ-containing proteins such as ATXN7 and huntingtin are associated with the development of neurodegenerative diseases when their N-terminal polyQ domains are expanded. Furthermore, they undergo proteolytic processing events that produce N-terminal fragments that include the polyQ stretch, which are implicated in pathogenesis. Interestingly, N-terminal ATXN2 fragments were reported in a brain extract from a SCA2 patient, but it is currently unknown whether an expanded polyQ domain contributes to ATXN2 proteolytic susceptibility. Here, we used transient expression in HEK293 cells to determine whether ATXN2 is a target for specific N-terminal proteolysis. We found that ATXN2 proteins with either normal or expanded polyQ stretches undergo proteolytic cleavage releasing an N-terminal polyQ-containing fragment. We identified a short amino acid sequence downstream of the polyQ domain that is necessary for N-terminal cleavage of full-length ATXN2 and sufficient to induce proteolysis of a heterologous protein. However, this sequence is not required for cleavage of a short ATXN2 isoform produced from an alternative start codon located just upstream of the CAG repeats encoding the polyQ domain. Our study extends our understanding of ATXN2 posttranslational regulation by revealing that this protein can be the target of specific proteolytic cleavage events releasing polyQ-containing products that are modulated by the N-terminal domain of ATXN2. N-terminal ATXN2 proteolysis of expanded polyQ domains might contribute to SCA2 pathology, as observed in other neurodegenerative disorders caused by polyQ domain expansion.
The metastatic capacity of high-grade serous ovarian cancer cells changes along disease progression: inhibition by mifepristone
Authors: Ritch Sabrina J. , Noman Abu S. M. , Goyeneche Alicia A. , Telleria Carlos M.
Published: May 2022

Background

Reductionist two-dimensional (2D) in vitro assays have long been the standard for studying the metastatic abilities of cancer cells. However, tri-dimensional (3D) organotypic models provide a more complex environment, closer to that seen in patients, and thereby provide a more accurate representation of their true capabilities. Our laboratory has previously shown that the antiprogestin and antiglucocorticoid mifepristone can reduce the growth, adhesion, migration, and invasion of various aggressive cancer cells assessed using 2D assays. In this study, we characterize the metastatic capabilities of high-grade serous ovarian cancer cells generated along disease progression, in both 2D and 3D assays, and the ability of cytostatic doses of mifepristone to inhibit them.

Methods

High-grade serous ovarian cancer cells collected from two separate patients at different stages of their disease were used throughout the study. The 2D wound healing and Boyden chamber assays were used to study migration, while a layer of extracellular matrix was added to the Boyden chamber to study invasion. A 3D organotypic model, composed of fibroblasts embedded in collagen I and topped with a monolayer of mesothelial cells was used to further study cancer cell adhesion and mesothelial displacement. All assays were studied in cells representing different stages of disease progression in the absence or presence of cytostatic doses of mifepristone.

Results

2D in vitro assays demonstrated that the migration and invasive rates of the cells isolated from both patients decreased along disease progression. Conversely, in both patients, cells representing late-stage disease demonstrated a higher adhesion capacity to the 3D organotypic model than those representing an early-stage disease. This adhesive behavior is associated with the in vivo tumor capacity of the cells. Regardless of these differences in adhesive, migratory, and invasive behavior among the experimental protocols used, cytostatic doses of mifepristone were able to inhibit the adhesion, migration, and invasion rates of all cells studied, regardless of their basal capabilities over reductionist or organotypic metastatic in vitro model systems. Finally, we demonstrate that when cells acquire the capacity to grow spontaneously as spheroids, they do attach to a 3D organotypic model system when pre-incubated with conditioned media. Of relevance, mifepristone was able to cause dissociation or “cleavage” of these multicellular structures.

Conclusion

Differences in cellular behaviours were observed between reductionist 2D and 3D assays when studying the metastatic capabilities of high-grade serous ovarian cancer cells representing disease progression. Mifepristone inhibited these metastatic capabilities in all assays studied.
Comparative genomic and crystal structure analyses identify a collagen glucosyltransferase from Acanthamoeba Polyphaga Mimivirus
Authors: Wu Wenhui , Kim Jeong Seon , Richards Stephen J. , Buhlheller Christoph , Bailey Aaron O. , Russell William , Chen Tiantian , Chen Tingfei , Chen Zhenhang , Liang Bo , Yamauchi Mitsuo , Guo Houfu
Published: May 2022

Humans and Acanthamoeba Polyphaga Mimivirus share numerous homologous genes, including collagens and collagen-modifying enzymes. To explore the homology, we performed a genome-wide comparison between human and mimivirus using DELTA-BLAST (Domain Enhanced Lookup Time Accelerated BLAST) and identified 52 new mimiviral proteins that are homologous with human proteins. To gain functional insights into mimiviral proteins, their human protein homologs were organized into Gene Ontology (GO) and REACTOME pathways to build a functional network. Collagen and collagen-modifying enzymes form the largest subnetwork with most nodes. Further analysis of this subnetwork identified a putative collagen glycosyltransferase R699. Protein expression test suggested that R699 is highly expressed in E coli, unlike the human collagen-modifying enzymes. Enzymatic activity assays showed that R699 catalyzes the conversion of unique galactosylhydroxylysine within the GXXXUG motif (U=galactosylhydroxylysine) to glucosylgalactosylhydroxylysine on collagen using uridine diphosphate glucose (UDP-Glc) as a sugar donor, suggesting R699 is a mimiviral collagen galactosylhydroxylysyl glucosyltransferase (GGT) with defined substrate specificity. Structural study of R699 produced the first crystal structure of a collagen GGT with a visible UDP-Glc. Sugar moiety of the UDP-Glc resides in a previously unrecognized pocket. Mn2+ coordination and nucleoside-diphosphate binding site are conserved among GGT family members and critical for R699’s collagen GGT activity. To facilitate further analysis of human and mimiviral homologous proteins, we presented an interactive and searchable genome-wide comparison website for quickly browsing human and Acanthamoeba Polyphaga Mimivirus homologs, which is available at RRID Resource ID: SCR_022140 or https://guolab.shinyapps.io/app-mimivirus-publication/.
Nitric oxide-induced tyrosine nitration of TrkB impairs BDNF signaling and restrains neuronal plasticity
Authors: Biojone Caroline , Casarotto Plinio C , Cannarozzo Cecilia , Fred Senem Merve , Herrera-Rodríguez Rosa , Lesnikova Angelina , Voipio Mikko , Castrén Eero
Published: May 2022

Nitric oxide has been long recognized as an important modulator of neural plasticity, but characterization of the molecular mechanisms involved - specially the guanylyl cyclase-independent ones - has been challenging. There is evidence that NO could modify BDNF-TRKB signaling, a key mediator of neuronal plasticity. However, the mechanism underlying the interplay of NO and TRKB remains unclear. Here we show that nitric oxide induces nitration of the tyrosine 816 in the TRKB receptorin vivoandin vitro,and that post-translational modification inhibits TRKB phosphorylation and binding of phospholipase Cγ1 (PLCγ1) to this same tyrosine residue. Additionally, nitration triggers clathrin-dependent endocytosis of TRKB through the adaptor protein AP2M and ubiquitination, thereby increasing translocation of TRKB away from the neuronal surface and directing it towards lysosomal degradation. Accordingly, inhibition of nitric oxide increases TRKB phosphorylation and TRKB-dependent neurite branching in neuronal cultures.In vivo,chronic inhibition of neuronal nitric oxide synthase (nNOS) dramatically reduced TRKB nitration and facilitated TRKB signaling in the primary visual cortex, and promoted a shift in ocular dominance upon monocular deprivation in the visual cortex - an indicator of increased plasticity. Altogether, our data describe and characterize a new molecular brake on plasticity, namely nitration of TRKB receptors.

Significance statement

We described the nitration of TRKB receptors at the tyrosine residue 816 as a new post-translational modification (PTM) that restrains the signaling of the neurotrophic factor BDNF in neurons. This new PTM leads to endocytosis and degradation of the TRKB receptors. Intriguingly, this mechanism is tonically active under physiological conditionsin vivo,and it is important for restricting ocular dominance plasticity in the visual cortex. This mechanism directly links two major systems involved in brain plasticity, BDNF/TRKB and nitric oxide. Our data provides a model forhowNO production from nNOS can compromise TRKB function, and for the effects of nNOS inhibitors promoting plasticity.
Simultaneous and sequential multi-species coronavirus vaccination
Authors: Peng Lei , Fang Zhenhao , Renauer Paul A. , McNamara Andrew , Park Jonathan J. , Lin Qianqian , Zhou Xiaoyu , Dong Matthew B. , Zhu Biqing , Zhao Hongyu , Wilen Craig B. , Chen Sidi
Published: May 2022

Although successful COVID-19 vaccines have been developed, multiple pathogenic coronavirus species exist, urging for development of multi-species coronavirus vaccines. Here we developed prototype LNP-mRNA vaccine candidates against SARS-CoV-2 (Delta variant), SARS-CoV and MERS-CoV, and test how multiplexing of these LNP-mRNAs can induce effective immune responses in animal models. A triplex scheme of LNP-mRNA vaccination induced antigen-specific antibody responses against SARS-CoV-2, SARS-CoV and MERS-CoV, with a relatively weaker MERS-CoV response in this setting. Single cell RNA-seq profiled the global systemic immune repertoires and the respective transcriptome signatures of multiplexed vaccinated animals, which revealed a systemic increase in activated B cells, as well as differential gene expression signatures across major adaptive immune cells. Sequential vaccination showed potent antibody responses against all three species, significantly stronger than simultaneous vaccination in mixture. These data demonstrated the feasibility, antibody responses and single cell immune profiles of multi-species coronavirus vaccination. The direct comparison between simultaneous and sequential vaccination offers insights on optimization of vaccination schedules to provide broad and potent antibody immunity against three major pathogenic coronavirus species.

One sentence summary

Multiplexed mRNA vaccination in simultaneous and sequential modes provide broad and potent immunity against pathogenic coronavirus species.
Multi-level force-dependent allosteric enhancement of αE-catenin binding to F-actin by vinculin
Authors: Bax Nicolas A. , Wang Amy , Huang Derek L. , Pokutta Sabine , Weis William I. , Dunn Alexander R.
Published: May 2022

Classical cadherins are transmembrane proteins whose extracellular domains link neighboring cells, and whose intracellular domains connect to the actin cytoskeleton via β-catenin, α- catenin. The cadherin-catenin complex transmits forces that drive tissue morphogenesis and wound healing. In addition, tension-dependent changes in αE-catenin conformation enables it to recruit the actin-binding protein vinculin to cell-cell junctions, where it contributes to junctional strengthening. How and whether multiple cadherin-complexes cooperate to reinforce cell-cell junctions in response to load remains poorly understood. Here, we used single-molecule optical trap measurements to examine how multiple cadherin-catenin complexes interact with F-actin under load, and how this interaction is influenced by the presence of vinculin. We show that force oriented toward the (-) end of the actin filament results in mean lifetimes 3-fold longer than when force was applied towards the barbed (+) end. Further, load is distributed asymmetrically among complexes, such that only one bears the majority of applied load. We also measured force-dependent actin binding by a quaternary complex comprising the cadherin-catenin complex and the vinculin head region, which cannot itself bind actin. Binding lifetimes of this quaternary complex increased as additional complexes bound F-actin, but only when load was oriented toward the (-) end. In contrast, the cadherin-catenin complex alone did not show this form of cooperativity. These findings reveal multi-level, force-dependent regulation that enhances the strength of the association of multiple cadherin/catenin complexes with F-actin, conferring positive feedback that may strengthen the junction and polarize F-actin to facilitate the emergence of higher-order cytoskeletal organization.
Responses of Agricultural plants to Lithium pollution: Trends, Meta-Analysis, and Perspectives
Authors: Shakoor Noman , Adeel Muhammad , Azeem Imran , Ahmad Muhammad Arslan , Zain Muhammad , Abbas Aown , Zhou Pingfan , Li Yuanbo , Ming Xu , Rui Yukui
Published: May 2022

Lithium (Li) is gaining attention due to rapid rise of modern industries but their ultimate fingerprints on plants are not well established. Herein, we executed a meta-analysis of the existing recent literature investigating the impact of Li sources and levels on plant species under different growth conditions to understand the existing state of knowledge. Toxic effects of Li exposure in plants varies as a function of medium and interestingly, more negative responses are reported in hydroponic media as compared to soil and foliar application. Additionally, toxic effects of Li vary with Li source materials and LiCl more negatively affected plant development parameters such as plant germination (n=48) and root biomass (n=57) and recorded highly uptake in plants (n=78), while LiNO3 has more negative effects on shoot biomass. The Li at <50 mg L-1 concentrations significantly influenced the plant physiological indicators including plant germination and root biomass, while 50-500 mg L-1 Li concentration influence the biochemical parameters. The uptake potential of Li is dose dependent and their translocation/bioaccumulation remains unknown. Future work should include complete lifespan studies of the crop to elucidate the bioaccumulation of Li in edible tissues and to investigate possible trophic transfer of Li.

Environmental significance

Accumulation of Li sources is increasing in ecosystem compartments, and this might be vulnerable to plants.
Spatial cumulant models enable spatially informed treatment strategies and analysis of local interactions in cancer systems
Authors: Hamis Sara , Somervuo Panu , Ågren J. Arvid , Tadele Dagim Shiferaw , Kesseli Juha , Scott Jacob G. , Nykter Matti , Gerlee Philip , Finkelshtein Dmitri , Ovaskainen Otso
Published: May 2022

Theoretical and applied cancer studies that use individual-based models (IBMs) have been limited by the lack of a mathematical formulation that enables rigorous analysis of these models. However, spatial cumulant models (SCMs), which have arisen from theoretical ecology, describe population dynamics generated by a specific family of IBMs, namely spatio-temporal point processes (STPPs). SCMs are spatially resolved population models formulated by a system of differential equations that approximate the dynamics of two STPP-generated summary statistics: first-order spatial cumulants (densities), and second-order spatial cumulants (spatial covariances).

We exemplify how SCMs can be used in mathematical oncology by modelling theoretical cancer cell populations comprising interacting growth factor-producing and non-producing cells. To formulate model equations, we use computational tools that enable the generation of STPPs, SCMs and mean-field population models (MFPMs) from user-defined model descriptions (Cornell et al., 2019). To calculate and compare STPP, SCM and MFPM-generated summary statistics, we develop an application-agnostic computational pipeline. Our results demonstrate that SCMs can capture STPP-generated population density dynamics, even when MFPMs fail to do so. From both MFPM and SCM equations, we derive treatment-induced death rates required to achieve non-growing cell populations. When testing these treatment strategies in STPP-generated cell populations, our results demonstrate that SCM-informed strategies outperform MFPM-informed strategies in terms of inhibiting population growths. We thus demonstrate that SCMs provide a new framework in which to study cell-cell interactions, and can be used to describe and perturb STPP-generated cell population dynamics. We, therefore, argue that SCMs can be used to increase IBMs’ applicability in cancer research.

Statements and Declarations

The authors have no competing interests to declare that are relevant to the content of this article.
Cardiac patch treatment alleviates ischemic cardiomyopathy correlated with reverting Piezo1/2 expression by unloading left ventricular myocardium
Authors: Zhu Yang , Lu Yuwen , Jiang Sibo , Shen Ting , He Chengbin , Gao Yun , Shen Liyin , Jin Qiao , Zhao Yuting , Hu Hongjie , Ling Jun , He Jin , Zhuang Lenan
Published: May 2022

Pathologically elevated mechanical load promotes the adverse remodeling of left ventricle (LV) post myocardial infarction, which results in the progression from ischemic cardiomyopathy to heart failure. Cardiac patches could attenuate adverse LV remodeling by providing mechanical support to infarcted myocardium and border zone tissue. However, the mechanism of the translation from mechanical effects to favorable therapeutic outcome is still not clear. By transcriptome analysis, we found that the myocardial transcription levels of mechanosensitive ion channel proteins Piezo1 and Piezo2 significantly increased in patients with ischemic cardiomyopathy. In vitro tensile tests with local tissue information revealed a significant decrease in local strain and mechanical load in rat infarct. Cardiac function and geometry were preserved compared to non-treated control. Further, in LV myocardium of the patch-treated group, MI induced expression levels of Piezo1/2 were significantly reverted to the similar levels of the Sham group, indicating that cardiac patch beneficial effects were correlated with suppressing mechanosensitive genes, particularly Piezo1/2. These findings demonstrated the potential of cardiac patches in treating ICM patients with remodeling risks, and could provide guidance for improvement in next generation of patch devices.
Molecular determinants of TRAF6 binding specificity suggest that native interaction partners are not optimized for affinity
Authors: Halpin Jackson C. , Whitney Dustin , Rigoldi Federica , Sivaraman Venkat , Singer Avinoam , Keating Amy E.
Published: May 2022

TRAF6 is an adapter protein and E3 ubiquitin ligase involved in signaling downstream of cell receptors essential for development and the immune system. TRAF6 participates in many protein-protein interactions, some of which are mediated by a C-terminal MATH domain that recruits TRAF6 to cell-surface receptors and associated proteins. The TRAF6 MATH domain binds to short peptide segments containing the motif PxExx[FYWHDE], where x is any amino acid. Blocking TRAF6 interactions is associated with favorable effects in various disease models. To better define the TRAF6 MATH domain binding preferences, we generated a bacterial cell-surface peptide display library to sample the TRAF6 motif sequence space. We performed sorting experiments and identified 236 of the best TRAF6-interacting peptides and a set of 1,200 peptides that match the sequence PxE but do not bind TRAF6. Selected binders, tested by single-clone bacterial display titrations and bio-layer interferometry, bound TRAF6 tighter than previously measured native peptides. To elucidate the structural basis for TRAF6 interaction preferences, we built all-atom structural models of the TRAF6 MATH domain in complex with high-affinity binders and motif-matching nonbinders that were identified in the screen. We identified motif features that favor binding to TRAF6 as well as negative design elements distributed across the motif that can disfavor or preclude binding. Searching the human proteome for matches to the library screening-defined binding motif revealed that most known, biologically relevant TRAF6 motif matches occupy a different sequence space from the most enriched hits discovered in combinatorial library screening. Our experimentally determined binding preferences and structural models can support the design of peptide-based interaction inhibitors with higher affinities than endogenous TRAF6 ligands.
A Drosophila larvae-inspired vacuum-actuated soft robot
Authors: Sun Xiyang , Nose Akinao , Kohsaka Hiroshi
Published: May 2022

Peristalsis is one of the most common locomotion patterns in limbless animals. This motion is generated by propagating muscular contraction and relaxation along the body axis. While the kinematics of peristalsis has been examined intensively, the kinetics and mechanical control of peristalsis remain unclear, partially due to the lack of suitable physical models to analyse the force and temporal control in soft-bodied animals’ locomotion. Here, based on a soft-bodied animal, Drosophila larvae, we proposed a vacuum-actuated soft robot replicating their crawling behaviour. The soft structure, made with hyperelastic silicon rubber, was designed to mimic the larval hydrostatic structure. To estimate the adequate range of pressures and time scales for control of the soft robots, a numerical simulation by the finite element method was conducted. Pulse-Width-Modulation (PWM) was used to generate time-series signals to control the vacuum pressure in each segment. Based on this control system, the soft robots could exhibit the peristaltic pattern resembling fly larval crawling. The soft robots reproduced two previous experimental results on fly larvae: slower crawling speed in backward crawling than in forward crawling, and the involvement of segmental contraction duration and intersegmental delay in crawling speed. Furthermore, the soft robot provided a novel prediction that the larger the contraction force, the faster the crawling speed. These observations indicate that the use of soft robots could serve to examine the kinetics and mechanical regulation of crawling behaviour in soft-bodied animals.