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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 1,045 records · Page 58
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding

Compared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due to the often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity allosteric kinase inhibitors exist. Cyclin-dependent kinase 2 (CDK2) is a target for many therapeutic indications, including non-hormonal contraception. However, an inhibitor against this kinase with exquisite selectivity has not reached the market because of the structural similarity between CDKs. In this paper, we describe the development and mechanism of action of type III inhibitors that bind CDK2 with nanomolar affinity. Notably, these anthranilic acid inhibitors exhibit a strong negative cooperative relationship with cyclin binding, which remains an underexplored mechanism for CDK2 inhibition. Furthermore, the binding profile of these compounds in both biophysical and cellular assays demonstrate the promise of this series for further development into a therapeutic selective for CDK2 over highly similar kinases like CDK1. The potential of these inhibitors as contraceptive agents is seen by incubation with spermatocyte chromosome spreads from mouse testicular explants, where they recapitulate Cdk2 -/- and Spdya -/- phenotypes.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Structure and growth of plant cell walls

Plant cells build nanofibrillar walls that are central to plant growth, morphogenesis and mechanics. Starting from simple sugars, three groups of polysaccharides, namely, cellulose, hemicelluloses and pectins, with very different physical properties are assembled by the cell to make a strong yet extensible wall. Here, this Review describes the physics of wall growth and its regulation by cellular processes such as cellulose production by cellulose synthase, modulation of wall pH by plasma membrane H + -ATPase, wall loosening by expansin and signalling by plant hormones such as auxin and brassinosteroid. In addition, this Review discusses the nuanced roles, properties and interactions of cellulose, matrix polysaccharides and cell wall proteins and describes how wall stress and wall loosening cooperatively result in cell wall growth.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

A Targeted Mass Spectrometric Assay for Reliable Sensitive Hepcidin Quantification

Hepcidin, a cysteine-rich peptide hormone, secreted mainly by the liver, plays a central role in iron metabolism regulation. Emerging evidence suggests that disordered iron metabolism is a risk factor for various types of diseases including cancers. However, it remains challenging to apply current mass spectrometry (MS)-based hepcidin assays for precise quantification due to the low fragmentation efficiency of intact hepcidin as well as synthesis difficulties for the intact hepcidin standard. To address these issues we recently developed a reliable sensitive targeted MS assay for hepcidin quantification that uses fully alkylated rather than intact hepcidin as the internal standard. Limits of detection and quantification were determined to be <0.5 ng/mL and 1 ng/mL, respectively, which are better than those from currently available MS-based hepcidin assays. Application of the alkylated hepcidin assay to 70 clinical plasma samples (42 normal and 28 ovarian cancer patient samples) enabled reliable detection of endogenous hepcidin from the plasma samples, as well as conditioned culture media. The hepcidin concentrations ranged from 0.0 to 95.6 ng/mL across normal and cancer plasma specimens. Interestingly, cancer patients were found to have significantly higher hepcidin concentrations compared to normal patients (mean: 20.6 ng/ml for cancer; 5.94 ng/ml for normal) with the p value of <0.001. Our results demonstrate that the newly developed hepcidin assay has better sensitivity and quantification accuracy than current MS-based hepcidin assays without the challenges in synthesis of intact hepcidin standard and accurately determining its absolute amount.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Global analysis of SBP gene family in Brachypodium distachyon reveals its association with spike development

SQUAMOSA-promoter binding like proteins (SBPs/SPLs) are plant specific transcription factors targeted by miR156 and involved in various biological pathways, playing multi-faceted developmental roles. This gene family is not well characterized in Brachypodium. We identified a total of 18 SBP genes in B. distachyon genome. Phylogenetic analysis revealed that SBP gene family in Brachypodium expanded through large scale duplication. A total of 10 BdSBP genes were identified as targets of miR156. Transcript cleavage analysis of selected BdSBPs by miR156 confirmed their antagonistic connection. Alternative splicing was observed playing an important role in BdSBPs and miR156 interaction. Characterization of T-DNA Bdsbp9 mutant showed reduced plant growth and spike length, reflecting its involvement in the spike development. Expression of a majority of BdSBPs elevated during spikelet initiation. Specifically, BdSBP1 and BdSBP3 differentially expressed in response to vernalization. Differential transcript abundance of BdSBP1, BdSBP3, BdSBP8, BdSBP9, BdSBP14, BdSBP18 and BdSBP23 genes was observed during the spike development under high temperature. Co-expression network, protein–protein interaction and biological pathway analysis indicate that BdSBP genes mainly regulate transcription, hormone, RNA and transport pathways. Our work reveals the multi-layered control of SBP genes and demonstrates their association with spike development and temperature sensitivity in Brachypodium.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Expression profiling of MADS-box gene family revealed its role in vegetative development and stem ripening in S. spontaneum

Sugarcane is the most important sugar and biofuel crop. MADS-box genes encode transcription factors that are involved in developmental control and signal transduction in plants. Systematic analyses of MADS-box genes have been reported in many plant species, but its identification and characterization were not possible until a reference genome of autotetraploid wild type sugarcane specie, Saccharum spontaneum is available recently. We identified 182 MADS-box sequences in the S. spontaneum genome, which were annotated into 63 genes, including 6 (9.5%) genes with four alleles, 21 (33.3%) with three, 29 (46%) with two, 7 (11.1%) with one allele. Paralogs (tandem duplication and disperse duplicated) were also identified and characterized. These MADS-box genes were divided into two groups; Type-I (21 Mα, 4 Mβ, 4 Mγ) and Type-II (32 MIKCc, 2 MIKC*) through phylogenetic analysis with orthologs in Arabidopsis and sorghum. Structural diversity and distribution of motifs were studied in detail. Chromosomal localizations revealed that S. spontaneum MADS-box genes were randomly distributed across eight homologous chromosome groups. The expression profiles of these MADS-box genes were analyzed in leaves, roots, stem sections and after hormones treatment. Important alleles based on promoter analysis and expression variations were dissected. qRT-PCR analysis was performed to verify the expression pattern of pivotal S. spontaneum MADS-box genes and suggested that flower timing genes ( SOC1 and SVP ) may regulate vegetative development.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Lysosomal enzyme binding to the cation-independent mannose 6-phosphate receptor is regulated allosterically by insulin-like growth factor 2

The cation-independent mannose 6-phosphate receptor (CI-MPR) is clinically significant in the treatment of patients with lysosomal storage diseases because it functions in the biogenesis of lysosomes by transporting mannose 6-phosphate (M6P)-containing lysosomal enzymes to endosomal compartments. CI-MPR is multifunctional and modulates embryonic growth and fetal size by downregulating circulating levels of the peptide hormone insulin-like growth factor 2 (IGF2). The extracellular region of CI-MPR comprises 15 homologous domains with binding sites for M6P-containing ligands located in domains 3, 5, 9, and 15, whereas IGF2 interacts with residues in domain 11. How a particular ligand affects the receptor’s conformation or its ability to bind other ligands remains poorly understood. To address these questions, we purified a soluble form of the receptor from newborn calf serum, carried out glycoproteomics to define the N-glycans at its 19 potential glycosylation sites, probed its ability to bind lysosomal enzymes in the presence and absence of IGF2 using surface plasmon resonance, and assessed its conformation in the presence and absence of IGF2 by negative-staining electron microscopy and hydroxyl radical protein footprinting studies. Together, our findings support the hypothesis that IGF2 acts as an allosteric inhibitor of lysosomal enzyme binding by inducing global conformational changes of CI-MPR.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Characterization of DWARF14 Genes in Populus

Strigolactones are a new class of plant hormones regulating shoot branching and symbiotic interactions with arbuscular mycorrhizal fungi. Studies of branching mutants in herbaceous plants have identified several key genes involved in strigolactone biosynthesis or signaling. The strigolactone signal is perceived by a member of the α/β-fold hydrolase superfamily, known as DWARF14 (D14). However, little is known about D14 genes in the woody perennial plants. Here we report the identification of D14 homologs in the model woody plant Populus trichocarpa. We showed that there are two D14 homologs in P. trichocarpa, designated as PtD14a and PtD14b that are over 95% similar at the amino acid level. Expression analysis indicated that the transcript level of PtD14a is generally more abundant than that of PtD14b. However, only PtD14a was able to complement Arabidopsis d14 mutants, suggesting that PtD14a is the functional D14 ortholog. Amino acid alignment and structural modeling revealed substitutions of several highly conserved amino acids in the PtD14b protein including a phenylalanine near the catalytic triad of D14 proteins. Ultimately, we find this study lays a foundation for further characterization of strigolactone pathway and its functions in the woody perennial plants.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Folding propensity of intrinsically disordered proteins by osmotic stress

Proteins imparted with intrinsic disorder conduct a range of essential cellular functions. To better understand the folding and hydration properties of intrinsically disordered proteins (IDPs), we used osmotic stress to induce conformational changes in nuclear co-activator binding domain (NCBD) and activator for thyroid hormone and retinoid receptor (ACTR). Osmotic stress was applied by the addition of small and polymeric osmolytes, where we discovered that water contributions to NCBD folding always exceeded those for ACTR. Both NCBD and ACTR were found to gain a-helical structure with increasing osmotic stress, consistent with their folding upon NCBD/ACTR complex formation. Using small-angle neutron scattering (SANS), we further characterized NCBD structural changes with the osmolyte ethylene glycol. Here a large reduction in overall size initially occurred before substantial secondary structural change. In conclusion, by focusing on folding propensity, and linked hydration changes, we uncover new insights that may be important for how IDP folding contributes to binding.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Lipid bilayer thickness determines cholesterol's location in model membranes

Cholesterol is an essential biomolecule of animal cell membranes, and an important precursor for the biosynthesis of certain hormones and vitamins. It is also thought to play a key role in cell signaling processes associated with functional plasma membrane microdomains (domains enriched in cholesterol), commonly referred to as rafts. In all of these diverse biological phenomena, the transverse location of cholesterol in the membrane is almost certainly an important structural feature. Using a combination of neutron scattering and solid-state 2 H NMR, we have determined the location and orientation of cholesterol in phosphatidylcholine (PC) model membranes having fatty acids of different lengths and degrees of unsaturation. The data establish that cholesterol reorients rapidly about the bilayer normal in all the membranes studied, but is tilted and forced to span the bilayer midplane in the very thin bilayers. The possibility that cholesterol lies flat in the middle of bilayers, including those made from PC lipids containing polyunsaturated fatty acids (PUFAs), is ruled out. Finally, these results support the notion that hydrophobic thickness is the primary determinant of cholesterol's location in membranes.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2016

Role of Assay Type in Determining Free 25-Hydroxyvitamin D Levels in Diverse Populations

Serum 25-hydroxyvitamin D (25OHD) is the most frequently used marker of vitamin D status. Low 25OHD is associated with bone loss, fractures {Cauley, 2010 #1516;Ensrud, 2009 #1517}, and other adverse health outcomes {Theodoratou, 2014 #1518}. Most extra renal tissues only have access to free 25OHD, and free 25OHD concentration is thus a plausible biomarker of 25OHD availability and function {Johnsen, 2014 #1443;Chun, 2014 #1343}. Stronger associations with free or bioavailable 25OHD than with total 25OHD were reported for serum calcium, parathyroid hormone (PTH) {Bhan, 2012 #1124} and bone mineral density (BMD) {Powe, 2011 #1129}. These findings have led to the suggestion that free or bioavailable 25OHD may provide a more clinically relevant measure of tissue 25OHD availability and vitamin D status {Powe, 2013 #1369; Holick NEJM 2013 editorial}. The US Preventive Services Task Force (LeFevre 2015) recently pointed to the gap in research regarding bioavailable and free 25OHD and noted the possibility that these may be better markers of tissue 25OHD availability. Free 25OHD is conventionally calculated from the concentrations of total 25OHD, vitamin D binding protein (DBP) and albumin, with or without a factor accounting for DBP genotype-specific binding affinities {Bouillon, 1981 #1207;Chun, 2012 #1143; Powe, 2011 #1129;Johnsen, 2014 #1443}. DBP—or Group specific component (GC) {Hirschfeld, 1959 #1468}—polymorphisms (rs4588 and rs7041) give rise to three major polymorphic isoforms of DBP, GC-1F, GC-1S and GC-2, the frequencies of which differ globally, with GC-1F alleles more common in populations of African descent {Kambou, 1986 #1122}. Although DBP is a primary component of free and bioavailable 25OHD calculations, substantial variation in DBP between assays has been noted (Powe suggest to cite here previous publications as in previous version of this Ms). Using DBP measured by a monoclonal antibody Powe et al. {Powe, 2013 #1369} concluded that calculated free 25OHD in African-Americans was equal or higher than in US whites, questioning the implications of low total 25OHD concentrations in African Americans (Holick 2013). This idea gained widespread attention in medical and lay press {LeFevre, 2015 #1598; Bhan, 2014 #1485; Durazo-Arvizu, 2014 #1519}, and many others) and may have important implications for nutrional supplementation policy. To better understand the importance of free 25OHD estimates, and its racial differences, we conducted studies in cohorts based in the US, UK and The Gambia that included participants of African and European ancestry known to differ in GC genotype distribution. We characterized the molecular forms of circulating DBP through comparison of several DBP assays and DBP peptide proteomic analysis, to obtain both calculated and directly measured free 25OHD by geographical region, race and GC genotype.

Environmental Molecular Sciences Laboratory↗
DOE OSTI2010

ID-SERS Based Reference Method for Quantification of Large Biomolecules on a Single Chip

Accuracy and precision of quantitative SERS results have been significantly increased by applying a method based on the so-called isotope-dilution (ID) principle. In this ID-SERS approach, an isotopically labeled analogue of the target molecule (isotopologue) is spiked to the sample at a known concentration. Due to the slight difference in their molar masses, some Raman bands of the heavier isotopologue are red-shifted with respect to the same signals resulting from the unlabelled compound. As a result, spectra evaluation is reduced to the determination of intensity ratios rather than absolute intensities, and the unknown quantity of the analyte can be calculated from the known quantity of the standard. This procedure is of particular interest in the development of highly accurate reference procedures for metrology in chemistry. Because the sample is spiked prior to any further treatment, potential loss of material or matrix effects would equally affect both isotopologues, without influencing the final result. The method has been successfully applied for quantifying small diagnostic marker molecules like creatinine at their relevant serum concentration levels using silver colloids as SERS substrates. Now, the ID-SERS approach has been realized as a 'one-chip' approach using 'Bio-chips' made of intrinsically grown spherical silver nanoparticles with gaps less than 10 nm in between (Fig. 1). In addition, the scope of the method has been extended to larger biomolecules like peptides which will be shown using the example of the human growth-hormone (hGH) peptide T12 at physiologically relevant serum concentration levels (Fig. 2). Further developments towards the quantification of full proteins will also be reported.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2014

L-serine capped ZnS:Mn nanocrystals for plant cell biological studies and as a growth enhancing agent for micropropagation of Bacopa monnieri Linn. (Brahmi:Scrophulariaceae)

In the present work, the prospects of ZnS:Mn nanocrystals capped with L- serine, a bio-compatible amino acid, synthesized by wet chemical route, as efficient fluorescent probes for plant cell biological studies have been investigated. The present synthesis route using bio-compatible material is a low cost and easy to control method. The colloidal stability of the capped nano crystals is very good as they remain stable without settling down for long time. It is observed that L- serine significantly modifies the structural and optical characteristics of the ZnS:Mn nanocrystals and hence is suitable as a bio-compatible capping agent. The structural properties of L- serine capped nanocrystals were investigated by XRD technique. The size of the L- serine capped ZnS:Mn nanocrystals is found to be around 2 nm . The optical characterization of the nanocrystals was carried out on the basis of photoluminescence (PL) spectroscopic studies. The intense photoluminescence emission observed around 597nm for L-serine capped ZnS:Mn offers high prospects of applications in bio-imaging fields. The unique optical properties of nanoparticles make them appealing as in vivo and in vitro fluorophores in a variety of biological investigations. In the present study, L-serine capped ZnS:Mn nanocrystals were used as a staining dye in fluorescent microscope for observing cell division, cell structure etc. These nanocrystals were also incorporated into the culture media along with the normal auxin- cytokinin hormone combinations in Murashige and Skoog (MS) medium for micropropagation of Bacopa monnieri Linn. (Brahmi:Scrophulariaceae), an Ayurvedic medicine. The results suggest that L-serine capped ZnS:Mn nanocrystals can act as efficient enhancers towards quick callusing and shoot proliferation.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2014

Molecular ageing: Free radical initiated epimerization of thymopentin – A case study

The epimerization of amino acid residues increases with age in living organisms. In the present study, the structural consequences and thermodynamic functions of the epimerization of thymopentin (TP-5), the active site of the thymic hormone thymopoietin, were studied using molecular dynamics and density functional theory methods. The results show that free radical-initiated D-amino acid formation is energetically favoured (−130 kJmol{sup −1}) for each residue and induces significant changes to the peptide structure. In comparison to the wild-type (each residue in the L-configuration), the radius of gyration of the D-Asp{sup 3} epimer of the peptide decreased by 0.5 Å, and disrupted the intramolecular hydrogen bonding of the native peptide. Beyond establishing important structural, energetic and thermodynamic benchmarks and reference data for the structure of TP-5, these results disseminate the understanding of molecular ageing, the epimerization of amino acid residues.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2014

Investigating the roles of MicroRNAs in biotic stress response induced by Rhizoctonia solani in rice

Sheath blight disease, caused by Rhizoctonia solani 1802/KB was screened on two rice varieties, Oryza sativaindica cultivar MR219 and Oryza sativa indica cultivar UKMRC9. The disease symptom was severe in MR219 compared to UKMRC9. Total RNA from R. solani 1802/KB, infected rice leaves of MR219 and infected rice leaves of UKMRC9 were extracted using TRIzol reagent, purified and sent for small RNA sequencing. Three miRNA libraries were generated and analyzed. The libraries generated 65 805, 78 512 and 81 325 known miRNAs respectively. The structure of miRNA of these samples was predicted. The up-regulated and down-regulated of miRNAs target gene prediction and its target functions were discovered and were mainly related to the growth and development of metabolism, protein transport, transcriptional regulation, stress response, and hormone signaling and electron transfer. Sheath blight-induced differential expression of known miRNAs tends to targetMYB transcription factor, F-box proteins, NBS-LRR, leucine-rich repeat receptor protein kinases and zinc finger proteins. Detecting new miRNAs and measuring the expression profiles of known miRNAs is an important tasks required for a better understanding of various biological conditions. Therefore, further analysis using Gene Ontology Slim will be conducted to deduce some biological information from the datasets obtained.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2021

Metabolic profiling of epidermal and mesophyll tissues under water-deficit stress in Opuntia ficus-indica reveals stress-adaptive metabolic responses

Cactus pear (Opuntia ficus-indica) is a high productivity species within the Cactaceae grown in many semiarid parts of the world for food, fodder, forage, and biofuels. O. ficus-indica utilises obligate crassulacean acid metabolism (CAM), an adaptation that greatly improves water-use efficiency (WUE) and reduces crop water usage. To better understand CAM-related metabolites and water-deficit stress responses of O. ficus-indica, comparative metabolic profiling was performed on mesophyll and epidermal tissues collected from well-watered and water-deficit stressed cladodes at 50% relative water content (RWC). Tissues were collected over a 24-h period to identify metabolite levels throughout the diel cycle and analysed using a combination of acidic/basic ultra-high-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) and gas chromatography/mass spectrometry (GC/MS) platforms. A total of 382 metabolites, including 210 (55%) named and 172 (45%) unnamed compounds, were characterised across both tissues. Most tricarboxylic acid (TCA) cycle and glycolysis intermediates were depleted in plants undergoing water-deficit stress indicative of CAM idling or post-idling, while the raffinose family oligosaccharides (RFO) accumulated in both mesophyll and epidermal tissues as osmoprotectants. Levels of reduced glutathione and other metabolites of the ascorbate cycle as well as oxylipins, stress hormones such as traumatic acid, and nucleotide degradation products were increased under water-deficit stress conditions. Notably, tryptophan accumulation, an atypical response, was significantly (24-fold) higher during all time points in water-deficit stressed mesophyll tissue compared with well-watered controls. Many of the metabolite increases were indicative of a highly oxidising environment under water-deficit stress. A total of 34 unnamed metabolites also accumulated in response to water-deficit stress indicating that such compounds might play important roles in water-deficit stress tolerance.

Plant Sciences↗
DOE OSTI2015

An early secretory pathway mediated by GNOM-LIKE 1 and GNOM is essential for basal polarity establishment in Arabidopsis thaliana

Spatial regulation of the plant hormone indole-3-acetic acid (IAA, or auxin) is essential for plant development. Auxin gradient establishment is mediated by polarly localized auxin transporters, including PIN-FORMED (PIN) proteins. Their localization and abundance at the plasma membrane are tightly regulated by endomembrane machinery, especially the endocytic and recycling pathways mediated by the ADP ribosylation factor guanine nucleotide exchange factor (ARF-GEF) GNOM. We assessed the role of the early secretory pathway in establishing PIN1 polarity in Arabidopsis thaliana by pharmacological and genetic approaches. We identified the compound endosidin 8 (ES8), which selectively interferes with PIN1 basal polarity without altering the polarity of apical proteins. ES8 alters the auxin distribution pattern in the root and induces a strong developmental phenotype, including reduced root length. The ARF-GEF–defective mutants gnom-like 1 ( gnl1-1 ) and gnom ( van7 ) are significantly resistant to ES8. The compound does not affect recycling or vacuolar trafficking of PIN1 but leads to its intracellular accumulation, resulting in loss of PIN1 basal polarity at the plasma membrane. In conclusion, our data confirm a role for GNOM in endoplasmic reticulum (ER)–Golgi trafficking and reveal that a GNL1/GNOM-mediated early secretory pathway selectively regulates PIN1 basal polarity establishment in a manner essential for normal plant development.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Genomics of sorghum local adaptation to a parasitic plant

Host–parasite coevolution can maintain high levels of genetic diversity in traits involved in species interactions. In many systems, host traits exploited by parasites are constrained by use in other functions, leading to complex selective pressures across space and time. Here, we study genome-wide variation in the staple crop Sorghum bicolor (L.) Moench and its association with the parasitic weed Striga hermonthica (Delile) Benth., a major constraint to food security in Africa. We hypothesize that geographic selection mosaics across gradients of parasite occurrence maintain genetic diversity in sorghum landrace resistance. Suggesting a role in local adaptation to parasite pressure, multiple independent loss-of-function alleles at sorghum LOW GERMINATION STIMULANT 1 (LGS1) are broadly distributed among African landraces and geographically associated with S. hermonthica occurrence. However, low frequency of these alleles within S. hermonthica-prone regions and their absence elsewhere implicate potential trade-offs restricting their fixation. LGS1 is thought to cause resistance by changing stereochemistry of strigolactones, hormones that control plant architecture and below-ground signaling to mycorrhizae and are required to stimulate parasite germination. Consistent with trade-offs, we find signatures of balancing selection surrounding LGS1 and other candidates from analysis of genome-wide associations with parasite distribution. Experiments with CRISPR–Cas9-edited sorghum further indicate that the benefit of LGS1-mediated resistance strongly depends on parasite genotype and abiotic environment and comes at the cost of reduced photosystem gene expression. Our study demonstrates long-term maintenance of diversity in host resistance genes across smallholder agroecosystems, providing a valuable comparison to both industrial farming systems and natural communities.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Identification of potent inhibitors of JUN N-terminal kinases for treatment of endometriosis and associated pain

Endometriosis, defined as the ectopic growth of endometrial tissue outside of the uterine cavity, is an inflammatory and hormone-dependent disease that causes excruciating pelvic pain, infertility, and significantly decreases quality of life in affected patients. The JUN N-terminal kinases (JNKs) are a leading class of nonhormonal therapeutic targets that have been validated in preclinical models of endometriosis and in a Phase 1/2 clinical trial. Despite their therapeutic potential, JNK inhibitors with increased potency and specificity are needed to address the inflammatory pathology of endometriosis and to prevent disease progression. Leveraging a DNA-encoded chemical library collection of ~4 billion compounds, we identified lead inhibitor CDD-2428 and optimized derivatives, CDD-2728 and CDD-3013, with excellent binding affinity to JNK1-3 (K d = 0.12 to 3.7 nM), enhanced selectivity, metabolic stability, and cellular permeability. Crystallographic and biochemical studies confirmed that CDD-3013 exhibited superior kinase selectivity with improved efficacy compared to existing JNK inhibitors. In primary endometriosis cell models, CDD-2728 and CDD-3013 suppressed JNK-dependent inflammatory signaling, dampening pathways linked to pain, invasion, angiogenesis, and macrophage recruitment. In an endometriosis mouse model, both CDD-2728 and CDD-3013 reduced endometriotic lesion size, macrophage infiltration, and cellular proliferation, showing in vivo efficacy. When tested in a lipopolysaccharide-induced hyperalgesia model, CDD-2728 and CDD-3013 decreased markers of induced pain, as measured by changes in a dynamic weight bearing test and Grimace scores. These findings nominate CDD-2728 and CDD-3013 as potent, nonhormonal therapeutic candidates for endometriosis with broad anti-inflammatory and analgesic activity, addressing a critical unmet clinical need.

Madasu, Chandrashekhar [Department of Pathology an↗