Miracle-dz/UniFAR-FTUs huggingface dataset:
SIPA1L1/SPAR1 is a non-PSD protein involved in GPCR signaling

SIPA1L1 (also known as SPAR1) has been proposed to regulate synaptic functions that are important in maintaining normal neuronal activities, such as regulating spine growth and synaptic scaling, as a component of the postsynaptic density (PSD)-95/N-methyl-D-aspartate receptor (NMDA-R)-complex. However, contrary to this view, our super-resolution and immunoelectron microscopic analyses demonstrate that SIPA1L1 is mainly localized to general submembranous and cytoplasmic regions in neurons, but scarcely to PSD. Our screening for native interactors of SIPA1L1 identified spinophilin and neurabin-1, regulators of G protein-coupled receptor (GPCR) signaling, but rejected PSD-95/NMDA-R-complex components. Furthermore, Sipa1l1-/- mice showed normal spine size distribution and NMDA-R-dependent synaptic plasticity. Nevertheless, Sipa1l1-/- mice showed aberrant responses to α2-adrenergic receptor (a spinophilin target) or adenosine A1 receptor (a neurabin-1 target) agonist stimulation and striking behavioral anomalies, such as hyperactivity, enhanced anxiety, learning impairments, social interaction deficits, and enhanced epileptic seizure susceptibility. Our findings revealed unexpected properties of SIPA1L1, suggesting a possible association of SIPA1L1 deficiency with neuropsychiatric disorders related to dysregulated GPCR signaling, such as epilepsy, attention deficit hyperactivity disorder (ADHD), autism, or fragile X syndrome.
Comparative Analysis of Mammal Genomes Unveils Key Genomic Variability for Human Life Span

Mammals vary 100-fold in their maximum lifespan. This enormous variation is the result of the adaptations of each species to their own biological trade-offs and ecological conditions. Comparative genomics studies have demonstrated that the genomic factors underlying the lifespans of species and the longevity of individuals are shared across the tree of life. Here, we set out to compare protein-coding regions across the mammalian phylogeny, aiming to detect individual amino acid changes shared by the most long-lived mammal species and genes whose rates of protein evolution correlate with longevity. We discovered a total of 2,737 amino acid changes in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance (p=0.003). The detected genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 amino acids, located in 996 different genes, showed a significant association with maximum lifespan in a phylogenetically controlled test. Interestingly, most of the detected amino acids positions do not vary in extant human populations (>81.2%) or have allele frequencies below 1% (99.78%), Consequently, almost none could have been detected by Genome-Wide Association Studies (GWAS). Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected by chance, successfully demonstrating for the first time that comparative genomics can be used to enhance the interpretation of human GWAS. Finally, we show that the human longevity-associated proteins coded by the detected genes are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.
Tumor expressed CD95 causes suppression of anti-tumor activity of NK cells in a model of triple negative breast cancer

The apoptosis inducing receptor CD95/Fas has multiple tumorigenic activities. Stimulation by its cognate ligand CD95L on many cancer cells increases their growth, motility, ability to invade and/or their cancer stemness. Using genetically engineered mouse models of ovarian and liver cancer, we previously reported that deletion of CD95 in the tumor cells strongly reduced their ability to grow in vivo [1, 2]. Using a combination of immune-deficient and immune-competent mouse models, we now establish that loss of CD95 in metastatic triple negative breast cancer cells prevents tumor growth by modulating the immune landscape. CD95 deficient but not wild-type tumors barely grow in an immune-competent environment and show an increase in immune infiltrates into the tumor. This growth reduction is caused by NK cells and does not involve CD8+ T cells. On the other hand, in immune compromised mice CD95 k.o. cells are not growth inhibited, but they fail to form metastases. In summary, we demonstrate that in addition to its tumor and metastasis promoting activities, CD95 expression by tumor cells can exert immune suppressive activities providing a new target for immune therapy.
Murine ex vivo cultured alveolar macrophages provide a novel tool to study tissue-resident macrophage behavior and function

Tissue-resident macrophages are of vital importance as they preserve tissue homeostasis in all mammalian organs. Nevertheless, appropriate cell culture models are still limited. Here, we propose a novel culture model to study and expand murine primary alveolar macrophages (AMs), the tissue-resident macrophages of the lung, in vitro over several months. By providing a combination of GM-CSF, TGFβ and the PPARγ activator rosiglitazone, we maintain and expand mouse ex vivo cultured AMs, short mexAMs, over several months. MexAMs maintain typical morphologic features and stably express primary AM surface markers throughout in vitro culture. They respond to microbial ligands and exhibit an AM-like transcriptional profile, including the expression of AM specific transcription factors. Furthermore, when transferred into AM deficient mice, mexAMs efficiently engraft in the lung and fulfill key macrophage functions leading to a significantly reduced surfactant load in those mice. Altogether, mexAMs provide a novel, simple and versatile tool to study AM behavior in homeostasis and disease settings. KEYPOINTS A novel method to culture and expand primary alveolar macrophages over several months ex vivo Murine ex vivo cultured alveolar macrophages (mexAMs) restore lung function in a murine pulmonary alveolar proteinosis model
VIA: Generalized and scalable trajectory inference in single-cell omics data

Inferring cellular trajectories using a variety of omic data is a critical task in single-cell data science. However, accurate prediction of cell fates, and thereby biologically meaningful discovery, is challenged by the sheer size of single-cell data, the diversity of omic data types, and the complexity of their topologies. We present VIA, a scalable trajectory inference algorithm that overcomes these limitations by using lazy-teleporting random walks to accurately reconstruct complex cellular trajectories beyond tree-like pathways (e.g. cyclic or disconnected structures). We show that VIA robustly and efficiently unravels the fine-grained sub-trajectories in a 1.3-million-cell transcriptomic mouse atlas without losing the global connectivity at such a high cell count. We further apply VIA to discovering elusive lineages and less populous cell fates missed by other methods across a variety of data types, including single-cell proteomic, epigenomic, multi-omics datasets, and a new in-house single-cell morphological dataset.
Polygenic prediction of type 2 diabetes in continental Africa

Objective Polygenic prediction of type 2 diabetes in continental Africans is adversely affected by the limited number of genome-wide association studies (GWAS) of type 2 diabetes from Africa, and the poor transferability of European derived polygenic risk scores (PRS) in diverse ethnicities. We set out to evaluate if African American or multi-ethnic derived PRSs would improve polygenic prediction in continental Africans. Research Design and Methods Using the PRSice software, ethnic-specific PRSs were computed with weights from the type 2 diabetes GWAS of the Million Veteran Program (MVP) study. The South African Zulu study (1602 cases and 976 controls) was used as the target data set. Replication and assessment of the best predictive PRS association with age at diagnosis was done in the Africa America Diabetes Mellitus (AADM) study (1031 cases and 738 controls). Results The African American derived PRS was more predictive of type 2 diabetes compared to the European and multi-ethnic derived scores. Notably, participants in the 10th decile of this PRS had a 3.19-fold greater risk (OR 3.19; 95%CI (1.94-5.29), p = 5.33 x10-6) of developing diabetes and were diagnosed 2.6 years earlier compared to those in the first decile. Conclusions African American derived PRS enhances polygenic prediction of type 2 diabetes in continental Africans. Improved representation of non-Europeans populations (including Africans) in GWAS, promises to provide better tools for precision medicine interventions in type 2 diabetes.
Importance of viscosity contrast for the motion of erythrocytes in microcapillaries

The dynamics and deformation of red blood cells (RBCs) in microcirculation affect the flow resistance and transport properties of whole blood. One of the key properties that can alter RBC dynamics in flow is the contrast λ (or ratio) of viscosities between RBC cytosol and blood plasma. Here, we study the dependence of RBC shape and dynamics on the viscosity contrast in tube flow, using mesoscopic hydrodynamics simulations. State diagrams of different RBC dynamical states, including tumbling cells, parachutes, and tank-treading slippers, are constructed for various viscosity contrasts and wide ranges of flow rates and tube diameters (or RBC confinements). Despite similarities in the classification of RBC behavior for different viscosity contrasts, there are notable differences in the corresponding state diagrams. In particular, the region of parachutes is significantly larger for λ = 1 in comparison to λ = 5. Furthermore, the viscosity contrast strongly affects the tumbling-to-slipper transition, thus modifying the regions of occurrence of these states as a function of flow rate and RBC confinement. Also, an increase in cytosol viscosity leads to a reduction in membrane tension induced by flow stresses. Physical mechanisms that determine these differences in RBC dynamical states as a function of λ are discussed.
Abscisic-acid-dependent regulation of Arabidopsis thaliana ammonium transport relies on ABI1 control of CIPK23 and AMT1

Ammonium uptake at plant roots is regulated at the transcriptional, post-transcriptional and post-translational levels. Phosphorylation by the protein kinase CIPK23 transiently inactivates the ammonium transporters (AMT1s) but the phosphatases activating AMT1s remain unknown. Here, we have identified the PP2C phosphatase ABI1 as an activator of AMTs in Arabidopsis thaliana. We show that high external ammonium concentrations elevate the stress phytohormone abscisic acid (ABA) by de-glycosylation. Active ABA is sensed by ABI1-PYL complexes followed by the inactivation of ABI1 activating CIPK23. Under favourable growth conditions, ABI1 reduces AMT1 phosphorylation, both by binding and inactivating CIPK23, and by the direct dephosphorylation of AMT1s. Thus, ABI1 is a positive regulator of ammonium uptake, coupling nutrient acquisition to abiotic stress signalling. Elevated ABA reduces ammonium uptake during stress situations, such as ammonium toxicity, whereas ABI1 reactivates AMT1s under favourable growth conditions.
Fighting over defence chemicals disrupts mating behaviour

Studies on intraspecific contest behaviour predominantly focus on contests between individuals of the same sex, however contest behaviour is also expected to occur between individuals of the opposite sex including possible mates. Here we investigate potential trade-offs between mating and fighting behaviour in the turnip sawfly (Athalia rosae). Adults of this species collect chemical defence compounds (clerodanoids) directly from plants but also indirectly by nibbling on conspecifics that have already obtained clerodanoids themselves, a highly aggressive behavioural interaction. An A. rosae individual without clerodanoids may therefore be the potential mate or attacker of an individual of the opposite sex that has gained clerodanoids. We paired males and females with or without clerodanoid access and manipulated body mass differences between the sexes via the early life starvation of females. We show that asymmetrical clerodanoid acquisition between male-female pairs causes an increase in agonistic nibbling behaviour, irrespective of sex. Moreover, fighting over clerodanoids disrupted mating behaviour, and the frequency of aggressive nibbling behaviour in these pairs was determined by the comparative body mass of the attacking individual. Our study highlights the vital importance of investigating agonistic intersex interactions not only over mating but also over resources.
CCG•CGG interruptions in high penetrance SCA8 families increase RAN translation and protein toxicity

Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8 we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (N=77). We show that repeat expansion mutations from individuals with two or more affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability and steady state levels of SCA8 RAN polyAla and polySer proteins. Additionally, the CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame increase the toxicity of the resulting proteins. In summary, CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.
Calcium Sensitive Allostery Regulates the PI(4,5)P2 Binding Site of the Dysferlin C2A Domain

C2 domains are the second-most abundant calcium binding module in the proteome. Activity of the muscular dystrophy associated protein dysferlin is dependent on the C2A domain at the N-terminus of the protein, which couples calcium and PI(4,5)P2 binding through an unknown mechanism. Using solution state nuclear magnetic resonance spectroscopy we confirm the phosphoinositide binding site for the domain and find that calcium binding attenuates millisecond to microsecond motions at both in the calcium binding loops and the concave face of the C2A, including a portion of the phosphoinositide binding site. Our results support a model whereby increasing calcium concentrations shift the phosphoinositide binding pocket of C2A into a binding-competent state, allowing for calcium dependent membrane targeting. This model contrasts with the canonical mechanism for C2 domain-phosphoinositide interaction and provides a basis for how pathogenic mutations in the C2A domain result in loss of function and disease.
Soil, senescence and exudate utilisation: characterisation of the Paragon var. spring bread wheat root microbiome

Background Conventional methods of agricultural pest control and crop fertilisation are unsustainable. To meet growing demand, we must find ecologically responsible means to control disease and promote crop yields. The root-associated microbiome can aid plants with disease suppression, abiotic stress relief, and nutrient bioavailability. The aim of the present work was to profile the community of bacteria, fungi, and archaea associated with the wheat rhizosphere and root endosphere in different conditions. We also aimed to use 13 CO 2 stable isotope probing (SIP) to identify microbes within the root compartments that were capable of utilising host-derived carbon. Results Metabarcoding revealed that community composition shifted significantly for bacteria, fungi, and archaea across compartments. This shift was most pronounced for bacteria and fungi, while we observed weaker selection on the ammonia oxidising archaea-dominated archaeal community. Across multiple soil types we found that soil inoculum was a significant driver of endosphere community composition, however, several bacterial families were identified as core enriched taxa in all soil conditions. The most abundant of these were Streptomycetaceae and Burkholderiaceae . Moreover, as the plants senesce, both families were reduced in abundance, indicating that input from the living plant was required to maintain their abundance in the endosphere. Stable isotope probing showed that bacterial taxa within the Burkholderiaceae family, among other core enriched taxa such as Pseudomonadaceae, were able to use root exudates, but Streptomycetaceae were not. Conclusions The consistent enrichment of Streptomycetaceae and Burkholderiaceae within the endosphere, and their reduced abundance after developmental senescence, indicated a significant role for these families within the wheat root microbiome. While Streptomycetaceae did not utilise root exudates in the rhizosphere, we provide evidence that Pseudomonadaceae and Burkholderiaceae family taxa are recruited to the wheat root community via root exudates. This deeper understanding crop microbiome formation will enable researchers to characterise these interactions further, and possibly contribute to ecologically responsible methods for yield improvement and biocontrol in the future.
Tiara: deep learning-based classification system for eukaryotic sequences

Motivation With a large number of metagenomic datasets becoming available, the eukaryotic metagenomics emerged as a new challenge. The proper classification of eukaryotic nuclear and organellar genomes is an essential step towards the better understanding of eukaryotic diversity. Results We developed Tiara, a deep-learning-based approach for identification of eukaryotic sequences in the metagenomic data sets. Its two-step classification process enables the classification of nuclear and organellar eukaryotic fractions and subsequently divides organellar sequences to plastidial and mitochondrial. Using test dataset, we have shown that Tiara performs similarly to EukRep for prokaryotes classification and outperformed it for eukaryotes classification with lower calculation time. Tiara is also the only available tool correctly classifying organellar sequences. Availability and implementation Tiara is implemented in python 3.8, available at https://github.com/ibe-uw/tiara and tested on Unix-based systems. It is released under an open-source MIT license and documentation is available at https://ibe-uw.github. io/tiara. Version 1.0. 1 of Tiara has been used for all benchmarks.
DROP: Molecular voucher database for identification of Drosophila parasitoids

Molecular identification is increasingly used to speed up biodiversity surveys and laboratory experiments. However, many groups of organisms cannot be reliably identified using standard databases such as GenBank or BOLD due to lack of sequenced voucher specimens identified by experts. Sometimes a large number of sequences are available, but with too many errors to allow identification. Here we address this problem for parasitoids of Drosophila by introducing a curated open-access molecular reference database, DROP (Drosophila parasitoids). Identifying Drosophila parasitoids is challenging and poses a major impediment to realize the full potential of this model system in studies ranging from molecular mechanisms to food webs, and in biological control of Drosophila suzukii. In DROP (http://doi.org/10.5281/zenodo.4519656), genetic data are linked to voucher specimens and, where possible, the voucher specimens are identified by taxonomists and vetted through direct comparison with primary type material. To initiate DROP, we curated 154 laboratory strains, 856 vouchers, 554 DNA sequences, 16 genomes, 14 transcriptomes, and 6 proteomes drawn from a total of 183 operational taxonomic units (OTUs): 114 described Drosophila parasitoid species and 69 provisional species. We found species richness of Drosophila parasitoids to be heavily underestimated and provide an updated taxonomic catalogue for the community. DROP offers accurate molecular identification and improves cross-referencing between individual studies that we hope will catalyze research on this diverse and fascinating model system. Our effort should also serve as an example for researchers facing similar molecular identification problems in other groups of organisms.
Cutevariant: a GUI-based desktop application to explore genetics variations

Cutevariant is a user-friendly GUI based desktop application for genomic research designed to search for variations in DNA samples collected in annotated files and encoded in the Variant Calling Format. The application imports data into a local relational database wherefrom complex filter-queries can be built either from the intuitive GUI or using a Domain Specific Language (DSL). Cutevariant provides more features than any existing applications without compromising on performance. The plugin based architecture provides highly customizable features. Cutevariant is distributed as a multiplatform client-side software under an open source licence and is available at https://github.com/labsquare/Cutevariant. It has been designed from the beginning to be easily adopted by IT-agnostic end-users.
Environmental responsiveness of flowering time in cassava genotypes and associated transcriptome changes

Cassava is an important food security crop in tropical regions of the world. Cassava improvement by breeding is limited by its delayed and poor production of flowers, such that cassava flowering under field conditions indirectly lengthens the breeding cycle. By studying genotype and environment interaction under two Nigerian field conditions (Ubiaja and Ibadan) and three controlled temperature conditions (22°C/18°C, 28/24°C and 34/30°C (day/night)), we found that while early flowering genotypes flowered at similar times and rates under all growing conditions (unfavorable and favorable field and controlled-temperature environments), late flowering genotypes were environmentally sensitive such that they were substantially delayed in unfavorable environments. Flowering times of late genotypes approached the flowering time of early flowering genotypes under relatively cool Ubiaja field conditions and in growth chambers at 22°C, whereas warmer temperatures elicited a delaying effect. Analysis of field and controlled temperature transcriptomes in leaves revealed that conditions that promote early flowering in cassava have low expression of the flowering repressor gene TEMPRANILLO 1 (TEM1), before and after flowering, among others. Field transcriptomes showed that the balance between flower promoting and inhibitory signaling, appeared to correlate with flowering time across the environments and genotypes.