Miracle-dz/UniFAR-FTUs huggingface dataset:
Proteomic data from leaves of twenty-four sunflower genotypes underwater deficit

This article describes how the proteomic data were produced on sunflower plants subjected to water deficit. Twenty-four sunflower genotypes were selected to represent genetic diversity within cultivated sunflower. They included both inbred lines and their hybrids Water deficit was applied to plants in pots at the vegetative stage using the high-throughput phenotyping platform Heliaphen. Here, we provide proteomic data from sunflower leaves corresponding to the identification of 3062 proteins and the quantification of 1211 of them in these 24 genotypes grown in two watering conditions. These data differentiate both treatment and the different genotypes and constitute a valuable resource to the community to study adaptation of crops to drought and the molecular basis of heterosis.
GDSL-domain containing proteins mediate suberin biosynthesis and degradation, enabling developmental plasticity of the endodermis during lateral root emergence

Roots anchor plants and deliver water and nutrients from the soil. The root endodermis provides the crucial extracellular diffusion barrier by setting up a supracellular network of lignified cell walls, called Casparian strips, supported by a subsequent formation of suberin lamellae. Whereas lignification is thought to be irreversible, formation of suberin lamellae was demonstrated to be dynamic, facilitating adaptation to different soil conditions. Plants shape their root system through the regulated formation of lateral roots emerging from within the endodermis, requiring local breaking and re-sealing of the endodermal diffusion barriers. Here, we show that differentiated endodermal cells have a distinct auxin-mediated transcriptional response that regulates cell wall remodelling. Based on this data set we identify a set of GDSL-lipases that are essential for suberin formation. Moreover, we find that another set of GDSL-lipases mediates suberin degradation, which enables the developmental plasticity of the endodermis required for normal lateral root emergence.
Heterogeneous adaptation of cysteine reactivity to a covalent oncometabolite

An important context in which metabolism influences tumorigenesis is the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), a disease in which mutation of the tricarboxylic acid cycle enzyme fumarate hydratase (FH) causes hyperaccumulation of fumarate. This electrophilic oncometabolite can alter gene activity at the level of transcription, via reversible inhibition of epigenetic dioxygenases, as well as posttranslationally, via covalent modification of cysteine residues. To better understand the potential for metabolites to influence posttranslational modifications important to tumorigenesis and cancer cell growth, here we report a chemoproteomic analysis of a kidney-derived HLRCC cell line. Using a general reactivity probe, we generated a data set of proteomic cysteine residues sensitive to the reduction in fumarate levels caused by genetic reintroduction of active FH into HLRCC cell lines. This revealed a broad up-regulation of cysteine reactivity upon FH rescue, which evidence suggests is caused by an approximately equal proportion of transcriptional and posttranslational modification–mediated regulation. Gene ontology analysis highlighted several new targets and pathways potentially modulated by FH mutation. Comparison of the new data set with prior studies highlights considerable heterogeneity in the adaptive response of cysteine-containing proteins in different models of HLRCC. This is consistent with emerging studies indicating the existence of cell- and tissue-specific cysteine-omes, further emphasizing the need for characterization of diverse models. Our analysis provides a resource for understanding the proteomic adaptation to fumarate accumulation and a foundation for future efforts to exploit this knowledge for cancer therapy.
Phosphorylation of the GARP Subunit Vps53 by Snf1 Leads to the Formation of a Golgi – Mitochondria Contact Site (GoMiCS) in Yeast

The canonical function of the Golgi-associated retrograde protein (GARP) complex is the tethering of transport carriers. GARP belongs to the complexes associated with tethering containing helical rods (CATCHR) family and is a hetero-tetrameric complex consisting of the subunits Vps51, Vps52, Vps53 and Vps54. How the activity of GARP is regulated and if it possesses other functions besides tethering remains largely unknown. Here we identify the GARP subunit Vps53 as a novel regulatory target of the S. cerevisiae AMP kinase (AMPK) homolog Snf1. We find that Vps53 is both an in vivo and in vitro target of Snf1 and show that phosphorylation depends on the nature and quantity of the available carbon source. Phosphorylation of Vps53 does not affect the canonical trafficking pathway, but results in altered mitochondrial dynamics and the formation of a previously unknown contact site between the Golgi apparatus and mitochondria, termed GoMiCS. Our results provide an example of a subunit of a CATCHR complex with a constitutive function in membrane trafficking and an inducible role in organelle contact site formation. We anticipate our results to be the starting point for the characterization of this novel contact site.
RICH: implementing reductions in the cache hierarchy

Reductions constitute a frequent algorithmic pattern in high-performance and scientific computing. Sophisticated techniques are needed to ensure their correct and scalable concurrent execution on modern processors. Reductions on large arrays represent the most demanding case where traditional approaches are not always applicable due to low performance scalability. To address these challenges, we propose RICH, a runtime-assisted solution that relies on architectural and parallel programming model extensions. RICH updates the reduction variable directly in the cache hierarchy with the help of added in-cache functional units. Our programming model extensions fit with the most relevant parallel programming solutions for shared memory environments like OpenMP. RICH does not modify the ISA, which allows the use of algorithms with reductions from pre-compiled external libraries. Experiments show that our solution achieves the performance improvements of 11.2% on average, compared to the state-of-the-art hardware-based approaches, while it introduces 2.4% area and 3.8% power overhead.
A survivin-driven tumour-activatable minicircle system for prostate cancer theranostics

Gene vectors driven by tumour-specific promoters to express reporter genes and therapeutic genes are an emerging approach for improved cancer diagnosis and treatment. Minicircles (MCs) are shortened plasmids stripped of prokaryotic sequences and have potency and safety characteristics that are beneficial for clinical translation. We previously developed survivin-driven, tumour-activatable MCs for cancer detection via a secreted blood reporter assay. Here we present a novel theranostic system for prostate cancer featuring a pair of survivin-driven MCs, combining selective detection of aggressive tumours via a urinary reporter test and subsequent tumour treatment with gene-directed enzyme prodrug therapy. Methods We engineered both diagnostic and therapeutic survivin-driven MCs expressing Gaussia luciferase, a secreted reporter that is detectable in the urine, and cytosine deaminase:uracil phosphoribosyltransferase fusion, respectively. Diagnostic MCs were evaluated in mice carrying orthotopic prostate tumours with varying survivin levels, measuring reporter activity in serial urine samples. Therapeutic MCs were evaluated in mice receiving prodrug using bioluminescence imaging to assess cancer cell viability over time. Results Diagnostic MCs revealed mice with aggressive prostate tumours exhibited significantly higher urine reporter activity than mice with non-aggressive tumours and tumour-free mice. Combined with 5-fluorocytosine prodrug treatment, therapeutic MCs resulted in reduced bioluminescence signal in mice with aggressive prostate tumours compared to control mice. Conclusion Sequential use of these MCs may be used to first identify patients carrying aggressive prostate cancer by a urinary reporter test, followed by stringent treatment in stratified individuals identified to have high-risk lesions. This work serves to highlight tumour-activatable MCs as a viable platform for development of gene-based tumour-activatable theranostics.
Designing parallelism in surrogate-assisted multiobjective optimization based on decomposition

On the one hand, surrogate-assisted evolutionary algorithms are established as a method of choice for expensive black-box optimization problems. On the other hand, the growth in computing facilities has seen a massive increase in potential computational power, granted the users accommodate their approaches with the offered parallelism. While a number of studies acknowledge the impact of parallelism for single-objective expensive optimization assisted by surrogates, extending such techniques to the multi-objective setting has not yet been properly investigated, especially within the state-of-the-art decomposition framework. We first highlight the different degrees of parallelism in existing surrogate-assisted multi-objective evolutionary algorithms based on decomposition (S-MOEA/D). We then provide a comprehensive analysis of the key steps towards a successful parallel S-MOEA/D approach. Through an extensive benchmarking effort relying on the well-established bbob-biobj test functions, we analyze the performance of the different algorithm designs with respect to the problem dimensionality and difficulty, the amount of parallel cores available, and the supervised learning models considered. In particular, we show the difference in algorithm scalability based on the selected surrogate-assisted approaches, the performance impact of distributing the model training task and the efficacy of the designed parallel-surrogate methods.
Diverse scientific benchmarks for implicit membrane energy functions

Energy functions are fundamental to biomolecular modeling. Their success depends on robust physical formalisms, efficient optimization, and high-resolution data for training and validation. Over the past 20 years, progress in each area has advanced soluble protein energy functions. Yet, energy functions for membrane proteins lag behind due to sparse and low-quality data, leading to overfit tools. To overcome this challenge, we assembled a suite of 12 tests on independent datasets varying in size, diversity, and resolution. The tests probe an energy function’s ability to capture membrane protein orientation, stability, sequence, and structure. Here, we present the tests and use the franklin2019 energy function to demonstrate them. We then present a vision for transforming these “small” datasets into “big data” that can be used for more sophisticated energy function optimization. The tests are available through the Rosetta Benchmark Server (https://benchmark.graylab.jhu.edu/) and GitHub (https://github.com/rfalford12/Implicit-Membrane-Energy-Function-Benchmark).
Predicting evolutionary change at the DNA level in a natural Mimulus population

Evolution by natural selection occurs when the frequencies of genetic variants change because individuals differ in Darwinian fitness components such as survival or reproductive success. Differential fitness has been demonstrated in field studies of many organisms, but our ability to quantitatively predict allele frequency changes from fitness measurements remains unclear. Here, we characterize natural selection on millions of Single Nucleotide Polymorphisms (SNPs) across the genome of the annual plant Mimulus guttatus. We use fitness estimates to calibrate population genetic models that effectively predict observed allele frequency changes into the next generation. Hundreds of SNPs experienced “male selection” in 2013 with one allele at each SNP elevated in frequency among successful male gametes relative to the entire population of adults. In the following generation, allele frequencies at these SNPs consistently shifted in the predicted direction. A second year of study revealed that SNPs had effects on both viability and reproductive success with pervasive trade-offs between fitness components. SNPs favored by male selection were, on average, detrimental to survival. These trade-offs (antagonistic pleiotropy and temporal fluctuations in fitness) may be essential to the long-term maintenance of alleles undergoing substantial changes from generation to generation. Despite the challenges of measuring selection in the wild, the strong correlation between predicted and observed allele frequency changes suggests that population genetic models have a much greater role to play in forward-time prediction of evolutionary change. Author summary For the last 100 years, population geneticists have been deriving equations for Δp, the change in allele frequency owing to mutation, selection, migration, and genetic drift. Seldom are these equations used directly, to match a prediction for Δp to an observation of Δp. Here, we apply genomic sequencing technologies to samples from natural populations, obtaining millions of observations of Δp. We estimate natural selection on SNPs in a natural population of yellow monkeyflowers and find extensive evidence for selection through differential male success. We use the SNP-specific fitness estimates to calibrate a population genetic model that predicts observed Δp into the next generation. We find that when male selection favored one nucleotide at a SNP, that nucleotide increased in frequency in the next generation. Since neither observed nor predicted Δp are generally large in magnitude, we developed a novel method called “haplotype matching” to improve prediction accuracy. The method leverages intensive whole genome sequencing of a reference panel (187 individuals) to infer sequence-specific selection in thousands of field individuals sequenced at much lower coverage. This method proved essential to accurately predicting Δp in this experiment and further development may facilitate population genetic prediction more generally.
Substrate Transport and Specificity in a Phospholipid Flippase

Type 4 P-type ATPases are lipid flippases which help maintain asymmetric phospholipid distribution in eukaryotic membranes by driving unidirectional translocation of phospholipid substrates. Recent cryo-EM and crystal structures have provided a detailed view of flippases, and we here use molecular dynamics simulations to study the first steps of phospholipid transport and lipid substrate specificity. Our simulations and new cryo-EM structure shows phospholipid binding to a groove and subsequent movement towards the centre of the membrane, and reveal a preference for phosphatidylserine lipids. We find that only the lipid head group stays in the groove while the lipid tails remain in the membrane, thus visualizing how flippases have evolved to transport large substrates. The flippase also induces deformation and thinning of the outer leaflet facilitating lipid recruitment. Our simulations provide insight into substrate binding to flippases and suggest that multiple sites and steps in the functional cycle contribute to substrate selectivity.
Projecting single-cell transcriptomics data onto a reference T cell atlas to interpret immune responses

Single-cell RNA-sequencing (scRNA-seq) has emerged as a revolutionary technology for characterizing the heterogeneity of cell populations. However, robust reference atlases that can be used to systematically interpret cellular states across studies and diseases are currently lacking. Here, we generated the first cross-study T cell atlases for cancer and viral infection and developed a novel algorithm, ProjecTILs, that enables the projection of new scRNA-seq data onto these reference atlases. ProjecTILs accurately predicted the effects of multiple perturbations, including the ablation of immunoregulatory targets controlling T cell differentiation, such as Tox, Ptpn2, miR-155 and Regnase-1, and suggested novel gene programs that were altered in these cells. Moving beyond mouse models, we used ProjecTILs to conduct a meta-analysis of human tumor-infiltrating T lymphocytes (TILs), revealing a remarkable conservation of TIL subtypes between human and mouse and across cancer types. Clonotype analysis supported a model in which rare human tumor-specific effector-memory (EM)-like CD8 TILs that resemble blood-circulating EM cells, differentiate into proliferative terminal exhausted/dysfunctional effector TILs through a progenitor subtype that upregulates the exhaustion master regulator TOX. Our novel computational method allows exploring the effect of human and murine T cell perturbations (e.g. as the result of therapy or genetic engineering) in terms of reference cellular states, altered genetic programs and clonotype structure, revealing mechanisms of action behind immunotherapies and opening opportunities for their improvement.
Incorporation of n-3 fatty acids by the liver of mice fed linseed oil as a function of feeding duration

The objective of this study was to evaluate the incorporation of omega-3 fatty acids (n-3 FA) on male Swiss mice livers receiving diets based on linseed oil (LO) for up to 56 days. The mice were sacrificed at 7, 14, 28, 42, 56 days and FA concentration was analyzed by gas chromatography. A total of 13 FA were identified on LO feeds presenting alpha-linolenic acid (LNA) contents of 26.97 %. A total 22 FA were identified in the livers of the mice. Part of the LNA was converted into n-3 FA (20:3n-3, eicosapentaenoic acid-EPA, 22:5n-3, and docosahexaenoic acid-DHA), and some of the LNA was stored in the liver. LNA, EPA and DHA concentrations (mg/g total lipids ) from 0 days for up 56 days increased from 1.29 to 18.90 (LNA), 0.20 to 18.90 (EPA) and 41.26 to 99.17 (DHA). The concentration of n-3 FA in the livers varied with the duration of the LO diet. During LO feed, n-6 FA concentration fell and n-3 FA concentration rose through the experimental period.
Genetic structure and diversity of Triticum monococcum ssp. aegilopoides and T. urartu in Iran

To preliminarily evaluate the genetic diversity of the Iranian diploid Triticum L. gene pool, in this study, a total of 176 individuals belonging to T. monococcum L. ssp. aegilopoides (Link) Thell. and T. urartu Thum. ex Gandil. were pre-screened using single-strand conformation polymorphism (SSCP) analysis of the Acc-1 and Pgk-1 loci. A selected set of 76 DNA samples corresponding to the observed SSCP variants were sequenced for both loci and evaluated for nucleotide diversity associated with the taxonomic groups and geographical regions. We found three haplotypes, including one that was new for Iran, at each locus. Population structure and analysis of molecular variation results proved that the collection evaluated could be genetically divided into two distinct groups, which to a great extent was in accordance with the taxonomic classification. A genetic leakage from T. monococcum ssp. aegilopoides into T. urartu was observed during structure analysis, which was inferred on the basis of occasional outcrossing, despite their inbreeding nature. The results revealed that there was no variation within the populations belonging to T. urartu, while a meaningful variation was found between the geographical regions for T. monococcum ssp. aegilopoides. The median-joining networks revealed a conflict between morphology and haplotype variation, which was interpreted on the basis of introgressive hybridization, recombination signature and rapid speciation. In conclusion, we suggest that SSCP analysis is a useful tool in regions where thorough sequencing of an enormous number of DNA samples is time consuming and not affordable.
Reproductive Ecology of Trillium recurvatum (Trilliaceae) in Wisconsin

Abstract Trillium recurvatum Beck is a long lived perennial with its northernmost distributional range in southern Wisconsin and is listed as Special Concern. The breeding system and reproductive ecology of this purple sessile flowered Trillium have not been previously studied. To test the hypothesis that pollen limitation is a primary contributing factor to the rarity of T. recurvatum, its breeding system and reproductive ecology were studied. Pollinator activities, pollen to ovule ratios, fruit and seed set and breeding system dynamics via field crossing studies were assessed. Observations of insect visitations revealed a single effective pollinator Coleomegilla maculata De Greer. The estimated pollen to ovule ratio was 3255 to 1 suggesting strongly obligate outcrossing. Seeds were small weighing less than any species in the genus. Fruit set in hand pollinated, outcrossed flowers was significantly greater than in open pollinated controls, demonstrating pollen limitation. Autogamous crosses yielded less than 2% fruit set, indicating self incompatibility. Seed set was greater in open pollinated controls than in manipulated flowers, indicating high pollen load depositions. This study demonstrates that pollen limitation is present in T. recurvatum but loss of habitat, habitat fragmentation and effects of distributional range limitation may not be discounted as forces influencing its rarity.
JAGGED1 Stimulates Cranial Neural Crest Cell Osteoblast Commitment Pathways and Bone Regeneration Independent of Canonical NOTCH Signaling

Craniofacial bone loss is a complex clinical problem with limited regenerative solutions. Currently, BMP2 is used as a bone-regenerative therapy in adults, but in pediatric cases of bone loss, it is not FDA-approved due to concerns of life-threatening inflammation and cancer. Development of a bone-regenerative therapy for children will transform our ability to reduce the morbidity associated with current autologous bone grafting techniques. We discovered that JAGGED1 (JAG1) induces cranial neural crest (CNC) cell osteoblast commitment during craniofacial intramembranous ossification, suggesting that exogenous JAG1 delivery is a potential craniofacial bone-regenerative approach. In this study, we found that JAG1 delivery using synthetic hydrogels containing O9-1 cells, a CNC cell line, into critical-sized calvarial defects in C57BL/6 mice provided robust bone-regeneration. Since JAG1 signals through canonical (Hes1/Hey1) and non-canonical (JAK2) NOTCH pathways in CNC cells, we used RNAseq to analyze transcriptional pathways activated in CNC cells treated with JAG1±DAPT, a NOTCH-canonical pathway inhibitor. JAG1 upregulated expression of multiple NOTCH canonical pathway genes (Hes1), which were downregulated in the presence of DAPT. JAG1 also induced bone chemokines (Cxcl1), regulators of cytoskeletal organization and cell migration (Rhou), signaling targets (STAT5), promoters of early osteoblast cell proliferation (Prl2c2, Smurf1 and Esrra), and, inhibitors of osteoclasts (Id1). In the presence of DAPT, expression levels of Hes1 and Cxcl1 were decreased, whereas, Prl2c2, Smurf1, Esrra, Rhou and Id1 remain elevated, suggesting that JAG1 induces osteoblast proliferation through these non-canonical genes. Pathway analysis of JAG1+DAPT-treated CNC cells revealed significant upregulation of multiple non-canonical pathways, including the cell cycle, tubulin pathway, regulators of Runx2 initiation and phosphorylation of STAT5 pathway. In total, our data show that JAG1 upregulates multiple pathways involved in osteogenesis, independent of the NOTCH canonical pathway. Moreover, our findings suggest that JAG1 delivery using a synthetic hydrogel, is a bone-regenerative approach with powerful translational potential.