Distinct Signatures Research Articles

Predicting the First Steps of Evolution in Randomly Assembled Communities.

Microbial communities can self-assemble into highly diverse states with predictable statistical properties. However, these initial states can be disrupted by rapid evolution of the resident strains. When a new mutation arises, it competes for resources with its parent strain and with the other species in the community. This interplay between ecology and evolution is difficult to capture with existing community assembly theory. Here, we introduce a mathematical framework for predicting the first steps of evolution in large randomly assembled communities that compete for substitutable resources. We show how the fitness effects of new mutations and the probability that they coexist with their parent depends on the size of the community, the saturation of its niches, and the metabolic overlap between its members. We find that successful mutations are often able to coexist with their parent strains, even in saturated communities with low niche availability. At the same time, these invading mutants often cause extinctions of metabolically distant species. Our results suggest that even small amounts of evolution can produce distinct genetic signatures in natural microbial communities.

Paper and nylon based optical tongues with poly(p-phenyleneethynylene)-fluorophores efficiently discriminate nitroarene-based explosives and pollutants

Discrimination of nitroarenes with hydrophobic dyes in a polar (H2O) environment is difficult but possible via a lab-on-chip, with polymeric dyes immobilized on paper or nylon membranes. Here arrays of 12 hydrophobic poly(p-phenyleneethynylene)s (PPEs), are assembled into a chemical tongue to detect/discriminate nitroarenes in water. The changes in fluorescence image of the PPEs when interacting with solutions of the nitroarenes were recorded and converted into color difference maps, followed by cluster analysis methods. The variable selection method for both paper and nylon devices selects a handful of PPEs at different pH-values that discriminate nitroaromatics reliably. The paper-based chemical tongue could accurately discriminate all studied nitroarenes whereas the nylon-based devices represented distinguishable optical signature for picric acid and 2,4,6-trinitrotoluene (TNT) with high accuracy.

Low- and high-grade glioma-associated vascular cells differentially regulate tumor growth.

A key feature distinguishing high-grade glioma (HG) from low-grade glioma (LG) is the extensive neovascularization and endothelial hyperproliferation. Prior work has shown that tumor-associated vasculature from HG is molecularly and functionally distinct from normal brain vasculature and expresses higher levels of pro-tumorigenic factors that promote glioma growth and progression. However, it remains unclear whether vessels from LG also express pro-tumorigenic factors, and to what extent they functionally contribute to glioma growth. Here, we profile the transcriptomes of glioma-associated vascular cells (GVC) from IDH-mutant (mIDH) LG and IDH-wildtype (wIDH) HG and show that they exhibit significant molecular and functional differences. LG-GVC show enrichment of extracellular matrix-related gene sets and sensitivity to anti-angiogenic drugs, whereas HG-GVC display an increase in immune response-related gene sets and anti-angiogenic resistance. Strikingly, conditioned media from LG-GVC inhibits the growth of wIDH glioblastoma cells, whereas HG-GVC promotes growth. In vivo co-transplantation of LG-GVC with tumor cells reduces growth, whereas HG-GVC enhances tumor growth in orthotopic xenografts. We identify ASPORIN (ASPN), a small leucine-rich repeat proteoglycan, highly enriched in LG-GVC as a growth suppressor of wIDH glioblastoma cells in vitro and in vivo. Together, these findings indicate that GVC from LG and HG are molecularly and functionally distinct and differentially regulate tumor growth. Implications: This study demonstrated that vascular cells from IDH-mutant LG and IDH-wildtype HG exhibit distinct molecular signatures and have differential effects on tumor growth via regulation of ASPN-TGFβ1-GPM6A signaling.

Quantum-Geometry-Induced Anomalous Hall Effect in Nonunitary Superconductors and Application to Sr_{2}RuO_{4}.

The polar Kerr effect and the closely related anomalous charge Hall effect are among the most distinguishing signatures of the superconducting state in Sr_{2}RuO_{4}, as well as in several other compounds. These effects are often thought to be derived from chiral superconducting pairing, and different mechanisms have been invoked for the explanation. However, the intrinsic mechanisms proposed previously often involve unrealistically strong interband Cooper pairing. We show in this Letter that, even without interband pairing, nonunitary superconducting states can support the intrinsic anomalous charge Hall effect, thanks to the quantum geometric properties of the Bloch electrons. The key here is to have a normal-state spin Hall effect, for which a nonzero spin-orbit coupling is essential. A finite charge Hall effect then naturally arises at the onset of a spin-polarized nonunitary superconducting pairing. It depends on both the spin polarization and the normal-state electron Berry curvature, the latter of which is the imaginary part of the quantum geometric tensor of the Bloch states. Applying our results to the weakly paired Sr_{2}RuO_{4} we conclude that, if the reported Kerr effect is of intrinsic origin, the superconducting state is most likely nonunitary and has odd parity. Our theory may be generalized to other superconductors that exhibit the polar Kerr effect.

A commercially viable solution process to control long-chain branching in polyethylene.

In polyolefins, long-chain branching is introduced through an energy-intensive, high-pressure radical process to form low-density polyethylene (LDPE). In the current work, we demonstrated a ladder-like polyethylene architecture through solution polymerization of ethylene and less than 1 mole % of α,ω-dienes, using a dual-chain catalyst. The ladder-branching mechanism requires catalysts with two growing polymer chains on the same metal center, thus enchaining the diene without the requirement of a steady-state concentration of pendant vinyl groups. Molecular weight distributions lacking a high-molecular weight tail, distinctive Mark-Houwink signatures, nuclear magnetic resonance characterization, and shear and extensional rheology consistent with highly branched polyethylene architectures are described. This approach represents an industrially viable solution-polymerization process capable of producing controlled long-chain branched polyethylene with rheological properties comparable to those of LDPE or its blends with linear low-density polyethylene (LLDPE).

Type I interferon pathway activation across the antiphospholipid syndrome spectrum: associations with disease subsets and systemic antiphospholipid syndrome presentation.

While the type I interferon (IFN-I) pathway is crucial in autoimmunity, its role in antiphospholipid antibody (aPL)-positive subjects, including aPL carriers and antiphospholipid syndrome (APS) patients, is poorly understood. This study aims at characterizing IFN-I pathway activation within the spectrum of aPL-positive subsets. A total of 112 patients [29 aPL carriers, 31 primary APS (PAPS), 25 secondary APS (SAPS), 27 systemic lupus erythematosus (SLE) patients without aPL, and 44 healthy controls (HCs)] were recruited. IFI6, IFI44, IFI44L, MX1, IFI27, OAS1, and RSAD2 gene expression was evaluated in whole blood, and a composite index (IFN score) was calculated. An overall activation of the IFN-I pathway was observed across the entire APS spectrum, with differences among genes based on the specific disease subset. The composite score revealed quantitative differences across subsets, being elevated in aPL carriers and PAPS patients compared to HCs (both p < 0.050) and increasing in SAPS (p < 0.010) and SLE patients (p < 0.001). An unsupervised cluster analysis identified three clusters, and correspondence analyses revealed differences in clusters usage across APS subsets (p < 0.001). A network analysis revealed different patterns characterizing different subsets. The associations between IFN-I pathway activation and clinical outcomes differed across APS subsets. Although no differences in gene expression were observed in systemic APS, the network analyses revealed specific gene-gene patterns, and a distinct distribution of the clusters previously identified was noted (p = 0.002). IFN-I pathway activation is a common hallmark among aPL-positive individuals. Qualitative and quantitative differences across the APS spectrum can be identified, leading to the identification of distinct IFN-I signatures with different clinical values beyond traditional categorization.

Distinct neural signatures of pulvinar in C9orf72 amyotrophic lateral sclerosis mutation carriers and noncarriers.

Thalamic alterations have been reported as a major feature in presymptomatic and symptomatic patients carrying the C9orf72 mutation across the frontotemporal dementia-amyotrophic lateral sclerosis (ALS) spectrum. Specifically, the pulvinar, a high-order thalamic nucleus and timekeeper for large-scale cortical networks, has been hypothesized to be involved in C9orf72-related neurodegenerative diseases. We investigated whether pulvinar volume can be useful for differential diagnosis in ALS C9orf72 mutation carriers and noncarriers and how underlying functional connectivity changes affect this region. We studied 19 ALS C9orf72 mutation carriers (ALSC9+) accurately matched with wild-type ALS (ALSC9-) and ALS mimic (ALSmimic) patients using structural and resting-state functional magnetic resonance imaging data. Pulvinar volume was computed using automatic segmentation. Seed-to-voxel functional connectivity analyses were performed using seeds from a pulvinar functional parcellation. Pulvinar structural integrity had high discriminative values for ALSC9+ patients compared to ALSmimic (area under the curve [AUC] = 0.86) and ALSC9- (AUC = 0.77) patients, yielding a volume cutpoint of approximately 0.23%. Compared to ALSmimic, ALSC9- showed increased anterior, inferior, and lateral pulvinar connections with bilateral occipital-temporal-parietal regions, whereas ALSC9+ showed no differences. ALSC9+ patients when compared to ALSC9- patients showed reduced pulvinar-occipital connectivity for anterior and inferior pulvinar seeds. Pulvinar volume could be a differential biomarker closely related to the C9orf72 mutation. A pulvinar-cortical circuit dysfunction might play a critical role in disease progression and development, in both the genetic phenotype and ALS wild-type patients.

Byrd Ice Core Debris Constrains the Sediment Provenance Signature of Central West Antarctica

AbstractProvenance records from sediments deposited offshore of the West Antarctic Ice Sheet (WAIS) can help identify past major ice retreat, thus constraining ice‐sheet models projecting future sea‐level rise. Interpretations from such records are, however, hampered by the ice obscuring Antarctica's geology. Here, we explore central West Antarctica's subglacial geology using basal debris from within the Byrd ice core, drilled to the bed in 1968. Sand grain microtextures and a high kaolinite content (∼38–42%) reveal the debris consists predominantly of eroded sedimentary detritus, likely deposited initially in a warm, pre‐Oligocene, subaerial environment. Detrital hornblende 40Ar/39Ar ages suggest proximal late Cenozoic subglacial volcanism. The debris has a distinct provenance signature, with: common Permian‐Early Jurassic mineral grains; absent early Ross Orogeny grains; a high kaolinite content; and high 143Nd/144Nd and low 87Sr/86Sr ratios. Detecting this “fingerprint” in Antarctic sedimentary records could imply major WAIS retreat, revealing the WAIS's sensitivity to future warming.

Accounting for the microbial assembly of each process in wastewater treatment plants (WWTPs): study of four WWTPs receiving similar influent streams.

We evaluated a unique model in which four full-scale wastewater treatment plants (WWTPs) with the same treatment schematic and fed with similar influent wastewater were tracked over an 8-month period to determine whether the community assembly would differ in the activated sludge (AS) and sand filtration (SF) stages. For each WWTP, AS and SF achieved an average of 1-log10 (90%) and <0.02-log10 (5%) reduction of total cells, respectively. Despite the removal of cells, both AS and SF had a higher alpha and beta diversity compared to the influent microbial community. Using the Sloan neutral model, it was observed that AS and SF were individually dominated by different assembly processes. Specifically, microorganisms from influent to AS were predominantly determined by the selective niche process for all WWTPs, while the microbial community in the SF was relatively favored by a stochastic, random migration process, except two WWTPs. AS also contributed more to the final effluent microbial community compared with the SF. Given that each WWTP operates the AS independently and that there is a niche selection process driven mainly by the chemical oxygen demand concentration, operational taxonomic units unique to each of the WWTPs were also identified. The findings from this study indicate that each WWTP has its distinct microbial signature and could be used for source-tracking purposes.IMPORTANCEThis study provided a novel concept that microorganisms follow a niche assembly in the activated sludge (AS) tank and that the AS contributed more than the sand filtration process toward the final microbial signature that is unique to each treatment plant. This observation highlights the importance of understanding the microbial community selected by the AS stage, which could contribute toward source-tracking the effluent from different wastewater treatment plants.

Rare earth elements distribution in the Gulf of Cádiz (SW Spain): geogenic vs. anthropogenic influence

There is a current interest in the study of the geochemical behavior of the rare earth elements (REE) in aquatic systems since their identification as potential microcontaminants in natural waters. In this context, here we report the concentrations and patterns of dissolved REE (dREE) in the waters of the Gulf of Cádiz (GoC) and its major estuaries (Guadiana, Tinto-Odiel and Guadalquivir). Contamination in this area by metals has been extensively reported, linked to acid-mine inputs resulting from the mineralization of the Iberian Pyrite Belt, discharged mainly to the Tinto-Odiel river. However, the impact of these inputs on the concentrations and distribution of the dREE in the coastal waters of the GoC has not been addressed yet. Accordingly, elevated concentrations of dREE were obtained in the Tinto-Odiel estuary compared to the Guadiana and Guadalquivir, reflecting the impact of acid-mine drainage on this system. Only a significant fraction of anthropogenic gadolium (Gd) was observed in the Guadalquivir estuary, as a result of the input from major urban areas, where anthropogenic Gd fractions higher than 70% over the total dissolved pool were obtained for the freshwater end-member. Regarding the surface waters of the GoC, typical NE Atlantic distribution patterns of dREEs were obtained, but modified by two different end-members within this region. Accordingly, and despite the low water discharge of the Tinto-Odiel river, its elevated concentrations lead to an increase in the concentrations of dREEs in the nearshore waters of the GoC and producing a distinctive signature as observed for the MREE anomalies and HREE/LREE ratios. At the easternmost stations, close to the Strait of Gibraltar, these signals are also impacted by the inflow of Mediterranean waters and also by the discharge of the Guadalquivir river.

Cell-free DNA methylation reveals cell-specific tissue injury and correlates with disease severity and patient outcomes in COVID-19

BackgroundThe recently identified methylation patterns specific to cell type allows the tracing of cell death dynamics at the cellular level in health and diseases. This study used COVID-19 as a disease model to investigate the efficacy of cell-specific cell-free DNA (cfDNA) methylation markers in reflecting or predicting disease severity or outcome.MethodsWhole genome methylation sequencing of cfDNA was performed for 20 healthy individuals, 20 cases with non-hospitalized COVID-19 and 12 cases with severe COVID-19 admitted to intensive care unit (ICU). Differentially methylated regions (DMRs) and gene ontology pathway enrichment analyses were performed to explore the locus-specific methylation difference between cohorts. The proportion of cfDNA derived from lung and immune cells to a given sample (i.e. tissue fraction) at cell-type resolution was estimated using a novel algorithm, which reflects lung injuries and immune response in COVID-19 patients and was further used to evaluate clinical severity and patient outcome.ResultsCOVID‑19 patients had globally reduced cfDNA methylation level compared with healthy controls. Compared with non-hospitalized COVID-19 patients, the cfDNA methylation pattern was significantly altered in severe patients with the identification of 11,156 DMRs, which were mainly enriched in pathways related to immune response. Markedly elevated levels of cfDNA derived from lung and more specifically alveolar epithelial cells, bronchial epithelial cells, and lung endothelial cells were observed in COVID-19 patients compared with healthy controls. Compared with non-hospitalized patients or healthy controls, severe COVID-19 had significantly higher cfDNA derived from B cells, T cells and granulocytes and lower cfDNA from natural killer cells. Moreover, cfDNA derived from alveolar epithelial cells had the optimal performance to differentiate COVID-19 with different severities, lung injury levels, SOFA scores and in-hospital deaths, with the area under the receiver operating characteristic curve of 0.958, 0.941, 0.919 and 0.955, respectively.ConclusionSevere COVID-19 has a distinct cfDNA methylation signature compared with non-hospitalized COVID-19 and healthy controls. Cell type-specific cfDNA methylation signature enables the tracing of COVID-19 related cell deaths in lung and immune cells at cell-type resolution, which is correlated with clinical severities and outcomes, and has extensive application prospects to evaluate tissue injuries in diseases with multi-organ dysfunction.

Linking Cause and Effect: Nanoscale Vibrational Spectroscopy of Space Weathering from Asteroid Ryugu

Airless bodies are subjected to space-weathering effects that modify the first few microns of their surface. Therefore, understanding their impact on the optical properties of asteroids is key to the interpretation of their color variability and infrared reflectance observations. The recent Hayabusa2 sample return mission to asteroid Ryugu offers the first opportunity to study these effects, in the case of the most abundant spectral type among the main-asteroid belt, C-type objects. This study employs vibrational electron energy-loss spectroscopy in the transmission electron microscope to achieve the spatial resolution required to measure the distinct mid-infrared spectral signature of Ryugu's space-weathered surface. The comparison with the spectrum of the pristine underlying matrix reveals the loss of structural -OH and C-rich components in the space-weathered layers, providing direct experimental evidence that exposure to the space environment tends to mask the optical signatures of phyllosilicates and carbonaceous matter. Our findings should contribute to rectifying potential underestimations of water and carbon content of C-type asteroids when studied through remote sensing with new-generation telescopes.

A 2D Cryptographic Hash Function Incorporating Homomorphic Encryption for Secure Digital Signatures.

User authentication is a critical aspect of any information exchange systemwhich verifies the identities of individuals seeking access to sensitive information. Conventionally, this approachrelies on establishing robust digital signature protocolswhich employ asymmetric encryption techniques involving a key pair consisting of a public key and its matching private key. In this article, a user verification platform constructed using integrated circuits (ICs) with atomically thin two-dimensional (2D) monolayer molybdenum disulfide (MoS2 ) memtransistors is presented. First, generation of secure cryptographic keys is demonstrated by exploiting the inherent stochasticity of carrier trapping and detrapping at the 2D/oxide interface trap sites. Subsequently, the ability to manipulate the functionality of logical NOR is leveraged to create a secure one-way hash function which when homomorphically operated upon with NAND, XOR, OR, NOT, and AND logic circuits generate distinct digital signatures. These signatures when subsequently decrypted, verify the authenticity of the receiver while ensuring complete preservation of data integrity and confidentiality as the underlying information is never revealed. Finally, the advantages of implementing a NOR-based hashing techniques in comparison to the conventional XOR-based encryption method are established. This demonstration highlights the potential of 2D-based ICs in developing critical hardware information security primitives.

Distinct neural signatures underlying information maintenance and manipulation in working memory.

Previous working memory research has demonstrated robust stimulus representations during memory maintenance in both voltage and alpha-band activity in electroencephalography. However, the exact functions of these 2 neural signatures have remained controversial. Here we systematically investigated their respective contributions to memory manipulation. Human participants either maintained a previously seen spatial location, or manipulated the location following a mental rotation cue over a delay. Using multivariate decoding, we observed robust location representations in low-frequency voltage and alpha-band oscillatory activity with distinct spatiotemporal dynamics: location representations were most evident in posterior channels in alpha-band activity, but were most prominent in the more anterior, central channels in voltage signals. Moreover, the temporal emergence of manipulated representation in central voltage preceded that in posterior alpha-band activity, suggesting that voltage might carry stimulus-specific source signals originated internally from anterior cortex, whereas alpha-band activity might reflect feedback signals in posterior cortex received from higher-order cortex. Lastly, while location representations in both signals were coded in a low-dimensional neural subspace, location representation in central voltage was higher-dimensional and underwent a representational transformation that exclusively predicted memory behavior. Together, these results highlight the crucial role of central voltage in working memory, and support functional distinctions between voltage and alpha-band activity.

Abstract B012: Application of shallow whole genome sequencing to identify therapeutic opportunities in p53abn endometrial cancers

Abstract Background: Shallow whole genome sequencing (sWGS) can be used to detect copy number (CN) aberrations. In high-grade serous ovarian (HGSOC) it has been used to identify CN signatures to direct therapy, recognizing two signatures associated with homologous recombination deficiency (HRD). p53abn endometrial carcinomas (EC) represent the most lethal subtype of EC with molecular similarities to HGSOC. Recent data have shown improved outcomes in patients with p53abn EC when adjuvant chemotherapy is used in addition to radiation, however, overall prognosis is still poor and therapeutic advances are urgently needed. Our aim was to apply sWGS with targeted sequencing to assess CN signatures in a cohort of p53abn ECs to identify additional prognostic or predictive stratification. Methods: sWGS was performed on formalin fixed paraffin embedded (FFPE) tissue from 215 p53abn ECs and 188 samples had targeted panel sequencing for 275 cancer related genes. CN variations, common mutations and CN signatures were derived, and associations to clinicopathologic and outcomes data were assessed. Results: 187 p53abn ECs had sufficient quality DNA to generate CN signatures (including 96 serous, 39 endometrioid, 33 carcinosarcoma, 12 clear cell and 7 other), with 5 distinct CN signatures identified. Signature 5 was associated with HRD due to CN loss of BRCA1 and 2 and was found in 35 (19%) of patients. Signatures 3 and 4 were associated with whole genome duplications, with mutations in PIK3CA defining Signature 3. 28% of cases had CCNE1 amplification, and this was enriched with carcinosarcoma histotype (p= 0.0019). 34% of patients had either HER2 gene amplification or HER2 overexpression by immunohistochemistry (IHC), which was seen across all histotypes, and was associated with worse outcomes (p=0.017). The most common mutations beyond TP53 were PIK3CA (32%), PPP2R1A (29%), PIK3R1 (18%), FBXW7 (16%) and PTEN (16%). There was no significant difference in outcomes observed between the CN signatures (35% of patients had recurred and 22% had died from disease at 3 years in total cohort), nor in the distribution of histotypes across signatures. After adjusting for stage, there was no difference in outcomes between histotypes. sWGS in combination with selective sequencing and IHC identified targetable pathways in 84% of patients with p53abn EC (HRD-PARP inhibitors, HER2-anti HER2 therapy, CCNE1-Wee1 inhibitor, PPP2R1A/FBXW7-PKMYT1 inhibitor). Conclusions: sWGS is a relatively inexpensive tool that can be performed on standard FFPE material and identified therapeutic opportunities in 84% of p53abn EC patients. Outcomes were uniformly poor in this cohort of p53abn ECs highlighting the need for improved treatment options beyond surgery and conventional chemoradiation. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn ECs. Citation Format: Amy Jamieson, Juliana Sobral de Barros, Dawn R. Cochrane, Maxwell Douglas, Sameer Shankar, Samuel Leung, Branden Lynch, Janine Senz, Blake Gilks, David G. Huntsman, Jessica N. McAlpine. Application of shallow whole genome sequencing to identify therapeutic opportunities in p53abn endometrial cancers [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B012.

Anthracyclines induce cardiotoxicity through a shared gene expression response signature.

TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

Exogenous abscisic acid mitigates chilling injury in zucchini during cold storage by eliciting a time-dependent shaping of specialized metabolites

Chilling injury is a physiological disorder that appears when zucchini fruit is stored at low temperatures, causing a severe diminution of the quality and nutraceutical value. Abscisic acid (ABA) has been proven to be a key natural agent preventing low-temperature damage. This work aimed to elucidate the changes in exocarp metabolites of zucchini fruit during cold storage and the mechanisms underlying the protective effects of ABA through an untargeted metabolomics approach. A time-dependent metabolic modulation could be observed in response to cold storage, where exogenously applied ABA elicited distinct metabolomic signatures. Supervised statistics were then used to identify methyl jasmonate, heliespirone C, and (indol-3-yl)acetyl-L-phenylalanine as the key compounds in the fruit exocarp having the highest discriminant ability. Noteworthy, the untargeted phenolic profile of zucchini exocarps was also distinctively modulated amid the different treatments. Overall, the implication of ABA in accumulating specialized metabolites, having a dual role in chilling injury mitigation during cold stress and increasing the nutraceutical properties of zucchini fruits, was observed.

Correlated IR-SEM-TEM studies of three different grains from Ryugu: From the initial material to post-accretional processes

In order to better constrain the alteration history of the Ryugu parent body, we performed a multi-analytical study combining scanning electron microscopy, transmission electron microscopy and infrared spectroscopy on sections extracted from the three fragments A0064-FO019, A0064-FO021 and C0002-FO019 returned from Ryugu by the Hayabusa2 space mission. The three sections show large differences in terms of structure, mineralogy and infrared signature. Section A0064-FO019 resembles the major Ryugu lithology with the presence of both fine-grained phyllosilicates (fg-phyllos) with embedded nanosulfides and coarse-grained phyllosilicates (cg-phyllos), whereas section C0002-FO019 belongs to the group of the less altered lithologies with the presence of anhydrous minerals embedded in a partially amorphous matrix. Section A0064-FO021 also belongs to this group but shows two different lithologies, a compact amorphous one and a more porous and very fractured one showing the presence of Na-rich phosphate, calcite and olivine. The two less altered lithologies (sections A0064-FO021 and C0002-FO019) show the presence of numerous mineralogical features similar to those observed in cometary interplanetary dust particles, ultra-carbonaceous Antarctic micrometeorites or in the CM Paris meteorite, i.e. amorphous and partially crystallized matrix with GEMS-like ghosts objects, whisker olivine, phosphide, or FeNi metal. This supports an outer solar system origin common with that of cometary material for the Ryugu parent body. Combined with the results of Nakamura et al. (2022b) reporting the presence of a lithology showing the presence of GEMS-like objects, we propose that section C0002-FO019 represents the onset of aqueous alteration of such primitive materials. The cg-phyllos and fg-phyllos of section A0064-FO019, i.e. of the major Ryugu lithology, representing the advanced stage of alteration, exhibit distinctive IR signatures with a higher abundance of oxygen-rich functional groups in the organic matter (OM) from the cg-phyllos. We thus suggest the following chronology of formation and evolution for Ryugu: (1) accretion of highly porous aggregate of GEMS-like units with fine-grained high-temperature anhydrous silicates, (2) onset of alteration with the dissolution of primary nanosulfides and development of amorphous/partially crystallized material in the pores, (3) crystallization of fg-phyllos with a second generation of sulfides, (4) later formation of cg-phyllos devoid of nanosulfides and their associated oxygen-rich OM in a more water-rich environment.

E-cadherin loss drives diffuse-type gastric tumorigenesis via EZH2-mediated reprogramming.

Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion compared with KrasG12D, Trp53 KO (KP). We also identified EZH2 as a key mediator promoting CDH1 loss-associated DGAC tumorigenesis. These findings highlight DGAC's molecular diversity and potential for personalized treatment in CDH1-inactivated patients.

Serum Lipidome Profiling Reveals a Distinct Signature of Ovarian Cancer in Korean Women.

Distinguishing ovarian cancer from other gynecological malignancies is crucial for patient survival yet hindered by non-specific symptoms and limited understanding of ovarian cancer pathogenesis. Accumulating evidence suggests a link between ovarian cancer and deregulated lipid metabolism. Most studies have small sample sizes, especially for early-stage cases, and lack racial/ethnic diversity, necessitating more inclusive research for improved ovarian cancer diagnosis and prevention. Here, we profiled the serum lipidome of 208 ovarian cancer, including 93 early-stage patients with ovarian cancer and 117 nonovarian cancer (other gynecological malignancies) patients of Korean descent. Serum samples were analyzed with a high-coverage liquid chromatography high-resolution mass spectrometry platform, and lipidome alterations were investigated via statistical and machine learning (ML) approaches. We found that lipidome alterations unique to ovarian cancer were present in Korean women as early as when the cancer is localized, and those changes increase in magnitude as the diseases progresses. Analysis of relative lipid abundances revealed specific patterns for various lipid classes, with most classes showing decreased abundance in ovarian cancer in comparison with other gynecological diseases. ML methods selected a panel of 17 lipids that discriminated ovarian cancer from nonovarian cancer cases with an AUC value of 0.85 for an independent test set. This study provides a systemic analysis of lipidome alterations in human ovarian cancer, specifically in Korean women. Here, we show the potential of circulating lipids in distinguishing ovarian cancer from nonovarian cancer conditions.