We report the identification of three structurally diverse compounds - compound 4, GC376, and MAC-5576 - as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex ...with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors.
Somatic gain-of-function mutations in isocitrate dehydrogenases (
) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (
)-2-hydroxyglutarate ...(2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.
studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human
mutation-positive acute myeloid leukemia (AML) cells
and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2
-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with
mutation-positive advanced hematologic malignancies.
Mutations in
are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development.
.
Drought and salt tolerances are complex traits and controlled by multiple genes, environmental factors and their interactions. Drought and salt stresses can result in more than 50% yield loss in ...Upland cotton (
Gossypium hirsutum
L.).
G. barbadense
L. (the source of Pima cotton) carries desirable traits such as tolerance to abiotic and biotic stress along with high fiber quality. However, few studies have been reported on mapping quantitative trait loci (QTL) for abiotic stress tolerance using a permanent bi-parental population in multiple tests. The transfer of drought and salt tolerance from Pima to Upland cotton has been a challenge due to interspecific hybrid breakdown. This issue may be overcome by using introgression lines with genes transferred from Pima to Upland cotton. In this study, four replicated tests were conducted in the greenhouse each for drought and salt tolerance along with another test conducted in a field for drought tolerance using an Upland recombinant inbred line population of TM-1/NM24016 that has a stable introgression from Pima cotton. The objectives of the study were to investigate the genetic basis of drought and salt tolerance and to identify genetic markers associated with the abiotic stress tolerance. A total of 1004 polymorphic DNA marker loci including RGA-AFLP, SSR and GBS-SNP markers were used to construct a genetic map spanning 2221.28 cM. This population together with its two parents was evaluated for morphological, physiological, yield and fiber quality traits. The results showed that drought under greenhouse and field conditions and salt stress in the greenhouse reduced cotton plant growth at the seedling stage, and decreased lint yield and fiber quality traits in the field. A total of 165 QTL for salt and drought tolerance were detected on most of the cotton chromosomes, each explaining 5.98–21.43% of the phenotypic variation. Among these, common QTL for salt and drought tolerance were detected under both the greenhouse and field conditions. This study represents the first study to report consistent abiotic stress tolerance QTL from multiple tests in the greenhouse and the field that will be useful to understand the genetic basis of drought and salt tolerance and to breeding for abiotic stress tolerance using molecular marker-assisted selection in cotton.
Cotton has been cultivated and used to make fabrics for at least 7000 years. Two allotetraploid species of great commercial importance, Gossypium hirsutum and Gossypium barbadense, were domesticated ...after polyploidization and are cultivated worldwide. Although the overall genetic diversity between these two cultivated species has been studied with limited accessions, their population structure and genetic variations remain largely unknown.
We resequence the genomes of 147 cotton accessions, including diverse wild relatives, landraces, and modern cultivars, and construct a comprehensive variation map to provide genomic insights into the divergence and dual domestication of these two important cultivated tetraploid cotton species. Phylogenetic analysis shows two divergent groups for G. hirsutum and G. barbadense, suggesting a dual domestication processes in tetraploid cottons. In spite of the strong genetic divergence, a small number of interspecific reciprocal introgression events are found between these species and the introgression pattern is significantly biased towards the gene flow from G. hirsutum into G. barbadense. We identify selective sweeps, some of which are associated with relatively highly expressed genes for fiber development and seed germination.
We report a comprehensive analysis of the evolution and domestication history of allotetraploid cottons based on the whole genomic variation between G. hirsutum and G. barbadense and between wild accessions and modern cultivars. These results provide genomic bases for improving cotton production and for further evolution analysis of polyploid crops.
Despite remarkable advances in our knowledge of epigenetically mediated transcriptional programming of cell differentiation in plants, little is known about chromatin topology and its functional ...implications in this process.
To interrogate its significance, we establish the dynamic three-dimensional (3D) genome architecture of the allotetraploid cotton fiber, representing a typical single cell undergoing staged development in plants. We show that the subgenome-relayed switching of the chromatin compartment from active to inactive is coupled with the silencing of developmentally repressed genes, pinpointing subgenome-coordinated contribution to fiber development. We identify 10,571 topologically associating domain-like (TAD-like) structures, of which 25.6% are specifically organized in different stages and 75.23% are subject to partition or fusion between two subgenomes. Notably, dissolution of intricate TAD-like structure cliques showing long-range interactions represents a prominent characteristic at the later developmental stage. Dynamic chromatin loops are found to mediate the rewiring of gene regulatory networks that exhibit a significant difference between the two subgenomes, implicating expression bias of homologous genes.
This study sheds light on the spatial-temporal asymmetric chromatin structures of two subgenomes in the cotton fiber and offers a new insight into the regulatory orchestration of cell differentiation in plants.
Textiles made from cotton fibers are flammable and thus often include flame retardant additives for consumer safety. Transgressive segregation in multi-parent populations facilitates new combinations ...of alleles of genes and can result in traits that are superior to those of any of the parents. A screen of 257 recombinant inbred lines from a multi-parent advanced generation intercross (MAGIC) population for naturally enhance flame retardance (FR) was conducted. All eleven parents, like all conventional white fiber cotton cultivars produce flammable fabric. MAGIC recombinant inbred lines (RILs) that produced fibers with significantly lower heat release capacities (HRC) as measured by microscale combustion calorimetry (MCC) were identified and the stability of the phenotypes of the outliers were confirmed when the RILs were grown at an additional location. Of the textiles fabricated from the five superior RILs, four exhibited the novel characteristic of inherent flame resistance. When exposed to open flame by standard 45° incline flammability testing, these four fabrics self-extinguished. To determine the genetic architecture of this novel trait, linkage, epistatic and multi-locus genome wide association studies (GWAS) were conducted with 473k SNPs identified by whole genome sequencing (WGS). Transcriptomes of developing fiber cells from select RILs were sequenced (RNAseq). Together, these data provide insight into the genetic mechanism of the unexpected emergence of flame-resistant cotton by transgressive segregation in a breeding program. The incorporation of this trait into global cotton germplasm by breeding has the potential to greatly reduce the costs and impacts of flame-retardant chemicals.
The number of cotton (Gossypium sp.) ovule epidermal cells differentiating into fiber initials is an important factor affecting cotton yield and fiber quality. Despite extensive efforts in ...determining the molecular mechanisms regulating fiber initial differentiation, only a few genes responsible for fiber initial differentiation have been discovered. To identify putative genes directly involved in the fiber initiation process, we used a cotton ovule culture technique that controls the timing of fiber initial differentiation by exogenous phytohormone application in combination with comparative expression analyses between wild type and three fiberless mutants. The addition of exogenous auxin and gibberellins to pre-anthesis wild type ovules that did not have visible fiber initials increased the expression of genes affecting auxin, ethylene, ABA and jasmonic acid signaling pathways within 1 h after treatment. Most transcripts expressed differentially by the phytohormone treatment in vitro were also differentially expressed in the ovules of wild type and fiberless mutants that were grown in planta. In addition to MYB25-like, a gene that was previously shown to be associated with the differentiation of fiber initials, several other differentially expressed genes, including auxin/indole-3-acetic acid (AUX/IAA) involved in auxin signaling, ACC oxidase involved in ethylene biosynthesis, and abscisic acid (ABA) 8'-hydroxylase an enzyme that controls the rate of ABA catabolism, were co-regulated in the pre-anthesis ovules of both wild type and fiberless mutants. These results support the hypothesis that phytohormonal signaling networks regulate the temporal expression of genes responsible for differentiation of cotton fiber initials in vitro and in planta.
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in ...the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.
Personalized treatment choices would increase the effectiveness of internet-based cognitive behavioral therapy (iCBT) for depression to the extent that patients differ in interventions that better ...suit them.
To provide personalized estimates of short-term and long-term relative efficacy of guided and unguided iCBT for depression using patient-level information.
We searched PubMed, Embase, PsycInfo, and Cochrane Library to identify randomized clinical trials (RCTs) published up to January 1, 2019.
Eligible RCTs were those comparing guided or unguided iCBT against each other or against any control intervention in individuals with depression. Available individual patient data (IPD) was collected from all eligible studies. Depression symptom severity was assessed after treatment, 6 months, and 12 months after randomization.
We conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD network meta-regression.
Patient Health Questionnaire-9 (PHQ-9) scores.
Of 42 eligible RCTs, 39 studies comprising 9751 participants with depression contributed IPD to the IPD network meta-analysis, of which 8107 IPD were synthesized. Overall, both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-9 scores than control treatments over the short term and the long term. Guided iCBT was associated with more effectiveness than unguided iCBT (mean difference MD in posttreatment PHQ-9 scores, -0.8; 95% CI, -1.4 to -0.2), but we found no evidence of a difference at 6 or 12 months following randomization. Baseline depression was found to be the most important modifier of the relative association for efficacy of guided vs unguided iCBT. Differences between unguided and guided iCBT in people with baseline symptoms of subthreshold depression (PHQ-9 scores 5-9) were small, while guided iCBT was associated with overall better outcomes in patients with baseline PHQ-9 greater than 9.
In this network meta-analysis with IPD, guided iCBT was associated with more effectiveness than unguided iCBT for individuals with depression, benefits were more substantial in individuals with moderate to severe depression. Unguided iCBT was associated with similar effectiveness among individuals with symptoms of mild/subthreshold depression. Personalized treatment selection is entirely possible and necessary to ensure the best allocation of treatment resources for depression.
PDF
