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1.
Cell Chem Biol ; 31(6): 1101-1117, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38876100

ABSTRACT

RNA-targeting small molecules (rSMs) have become an attractive modality to tackle traditionally undruggable proteins and expand the druggable space. Among many innovative concepts, RNA-targeting chimeras (RNATACs) represent a new class of multispecific, induced proximity small molecules that act by chemically bringing RNA targets into proximity with an endogenous RNA effector, such as a ribonuclease (RNase). Depending on the RNA effector, RNATACs can alter the stability, localization, translation, or splicing of the target RNA. Although still in its infancy, this new modality has the potential for broad applications in the future to treat diseases with high unmet need. In this review, we discuss potential advantages of RNATACs, recent progress in the field, and challenges to this cutting-edge technology.


Subject(s)
RNA , Small Molecule Libraries , Humans , RNA/metabolism , RNA/chemistry , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Animals , Ribonucleases/metabolism
2.
bioRxiv ; 2024 May 17.
Article in English | MEDLINE | ID: mdl-38798351

ABSTRACT

Background: Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB subtype accounts for about 25% of MB diagnoses and is associated with the most unfavorable outcomes. Herein, we report that more than half of group 3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are tumor antigens, expressed in several types of adult cancers and associated with poorer prognosis and therapy resistance; however, their expression in pediatric cancers is mostly unknown. The aim of this study was to determine whether MAGEs are activated in pediatric MB. Methods: To determine MAGE frequency in pediatric MB, we obtained formalin-fixed paraffin-embedded tissue (FFPE) samples of 34 patients, collected between 2008 - 2015, from the Children's Medical Center Dallas pathology archives and applied our validated reverse transcription quantitative PCR (RT-qPCR) assay to measure the relative expression of 23 MAGE cancer-testis antigen genes. To validate our data, we analyzed several published datasets from pediatric MB patients and patient-derived orthotopic xenografts, totaling 860 patients. We then examined how MAGE expression affects the growth and oncogenic potential of medulloblastoma cells by CRISPR-Cas9- and siRNA-mediated gene depletion. Results: Our RT-qPCR analysis suggested that MAGEs were expressed in group 3/4 medulloblastoma. Further mining of bulk and single-cell RNA-sequencing datasets confirmed that 50-75% of group 3 tumors activate a subset of MAGE genes. Depletion of MAGEAs, B2, and Cs alter MB cell survival, viability, and clonogenic growth due to decreased proliferation and increased apoptosis. Conclusions: These results indicate that targeting MAGEs in medulloblastoma may be a potential therapeutic option for group 3 medulloblastomas. Key Points: Several Type I MAGE CTAs are expressed in >60% of group 3 MBs. Type I MAGEs affect MB cell proliferation and apoptosis. MAGEs are potential biomarkers and therapeutic targets for group 3 MBs. Importance of the Study: This study is the first comprehensive analysis of all Type I MAGE CTAs ( MAGEA , -B , and -C subfamily members) in pediatric MBs. Our results show that more than 60% of group 3 MBs express MAGE genes, which are required for the viability and growth of cells in which they are expressed. Collectively, these data provide novel insights into the antigen landscape of pediatric MBs. The activation of MAGE genes in group 3 MBs presents potential stratifying and therapeutic options.

3.
Adv Sci (Weinh) ; 11(26): e2309883, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38687196

ABSTRACT

The design of high-entropy single-atom catalysts (HESAC) with 5.2 times higher entropy compared to single-atom catalysts (SAC) is proposed, by using four different metals (FeCoNiRu-HESAC) for oxygen reduction reaction (ORR). Fe active sites with intermetallic distances of 6.1 Å exhibit a low ORR overpotential of 0.44 V, which originates from weakening the adsorption of OH intermediates. Based on density functional theory (DFT) findings, the FeCoNiRu-HESAC with a nitrogen-doped sample were synthesized. The atomic structures are confirmed with X-ray photoelectron spectroscopy (XPS), X-ray absorption (XAS), and scanning transmission electron microscopy (STEM). The predicted high catalytic activity is experimentally verified, finding that FeCoNiRu-HESAC has overpotentials of 0.41 and 0.37 V with Tafel slopes of 101 and 210 mVdec-1 at the current density of 1 mA cm-2 and the kinetic current densities of 8.2 and 5.3 mA cm-2, respectively, in acidic and alkaline electrolytes. These results are comparable with Pt/C. The FeCoNiRu-HESAC is used for Zinc-air battery applications with an open circuit potential of 1.39 V and power density of 0.16 W cm-2. Therefore, a strategy guided by DFT is provided for the rational design of HESAC which can be replaced with high-cost Pt catalysts toward ORR and beyond.

4.
Science ; 383(6689): 1318-1325, 2024 Mar 22.
Article in English | MEDLINE | ID: mdl-38513014

ABSTRACT

Plants are constantly exposed to volatile organic compounds (VOCs) that are released during plant-plant communication, within-plant self-signaling, and plant-microbe interactions. Therefore, understanding VOC perception and downstream signaling is vital for unraveling the mechanisms behind information exchange in plants, which remain largely unexplored. Using the hormone-like function of volatile terpenoids in reproductive organ development as a system with a visual marker for communication, we demonstrate that a petunia karrikin-insensitive receptor, PhKAI2ia, stereospecifically perceives the (-)-germacrene D signal, triggering a KAI2-mediated signaling cascade and affecting plant fitness. This study uncovers the role(s) of the intermediate clade of KAI2 receptors, illuminates the involvement of a KAI2ia-dependent signaling pathway in volatile communication, and provides new insights into plant olfaction and the long-standing question about the nature of potential endogenous KAI2 ligand(s).


Subject(s)
Furans , Hydrolases , Petunia , Pyrans , Volatile Organic Compounds , Hydrolases/genetics , Hydrolases/metabolism , Signal Transduction , Volatile Organic Compounds/metabolism , Petunia/physiology , Furans/metabolism , Pyrans/metabolism , Sesquiterpenes, Germacrane/metabolism
5.
J Wildl Dis ; 60(2): 327-338, 2024 04 01.
Article in English | MEDLINE | ID: mdl-38385992

ABSTRACT

Products of parturition are the predominant source of Brucella abortus for transmission in bison (Bison bison). Our objective was to assess whether preventing pregnancy in Brucella-seropositive bison reduced B. abortus shedding. Brucella-seropositive and -seronegative bison from Yellowstone National Park, Wyoming, USA were used in a replicated experiment. Each of two replicates (rep1, rep2) included a group of seropositive females treated with a single dose of gonadotropin-releasing hormone-based immunocontraceptive (Treatment rep1, n=15; Treatment rep2, n=20) and an untreated group (Control rep1, n=14; Control rep2, n=16) housed separately. Seronegative sentinel females were placed in each group to monitor horizontal transmission. Seronegative males were co-mingled for breeding each year. Pregnant females were removed from treatment groups in the first year, but not thereafter. Each January-June we monitored for B. abortus shedding events-any parturition associated with culture-positive fluids or tissues. We analyzed probability of shedding events using a negative binomial generalized linear mixed model fit by maximum likelihood using Laplace approximation. Over 5 yr, we observed zero shedding events in Treatment rep1 vs. 12 in Control rep1. All five Control rep1 sentinels but zero (0/5) Treatment rep1 sentinels seroconverted. In the second replicate, Treatment rep2 had two shedding events over 3 yr and Control rep2 had five events over 2 yr. Sentinels in both Control rep2 (3/6) and Treatment rep2 (5/6) seroconverted by trial endpoint. Treatment rep1 showed a reduced shedding probability relative to Control rep1, Treatment rep2, and Control rep2 (log odds value -25.36 vs. -1.71, -1.39, and -0.23, respectively). Fixed effect predictor covariates, year and age, had no explanatory value. These data suggest that successful contraception of brucellosis-seropositive female bison prevents shedding of B. abortus by individual animals. However, contraceptive treatment may or may not sufficiently reduce disease transmission to reduce brucellosis prevalence in an affected herd.


Subject(s)
Bison , Brucellosis , Animals , Female , Pregnancy , Brucella abortus , Brucellosis/epidemiology , Brucellosis/prevention & control , Brucellosis/veterinary , Wyoming
6.
New Phytol ; 241(4): 1829-1839, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38058220

ABSTRACT

The biosynthesis of specialized metabolites is strictly regulated by environmental inputs such as the day-night cycle, but the underlying mechanisms remain elusive. In Petunia hybrida cv. Mitchell flowers, the biosynthesis and emission of volatile compounds display a diurnal pattern with a peak in the evening to attract nocturnal pollinators. Using petunia flowers as a model system, we found that chromatin level regulation, especially histone acetylation, plays an essential role in mediating the day-night oscillation of the biosynthetic gene network of specialized metabolites. By performing time-course chromatin immunoprecipitation assays for histone modifications, we uncovered that a specific group of genes involved in the regulation, biosynthesis, and emission of floral volatile compounds, which displays the greatest magnitude in day-night oscillating gene expression, is associated with highly dynamic histone acetylation marks H3K9ac and H3K27ac. Specifically, the strongest oscillating genes featured a drastic removal of histone acetylation marks at night, potentially to shut down the biosynthesis of floral volatile compounds during the morning when they are not needed. Inhibiting daytime histone acetylation led to a compromised evening induction of these genes. Overall, our study suggested an active role of chromatin modification in the diurnal oscillation of specialized metabolic network.


Subject(s)
Histones , Petunia , Histones/metabolism , Acetylation , Metabolic Networks and Pathways , Protein Processing, Post-Translational , Chromatin/metabolism , Flowers/physiology , Petunia/metabolism , Gene Expression Regulation, Plant
7.
Chembiochem ; 25(4): e202300712, 2024 02 16.
Article in English | MEDLINE | ID: mdl-38015747

ABSTRACT

Chemically induced proximity (CIP) refers to co-opting naturally occurring biological pathways using synthetic molecules to recruit neosubstrates that are not normally encountered or to enhance the affinity of naturally occurring interactions. Leveraging proximity biology through CIPs has become a rapidly evolving field and has garnered considerable interest in basic research and drug discovery. PROteolysis TArgeting Chimera (PROTAC) is a well-established CIP modality that induces the proximity between a target protein and an E3 ubiquitin ligase, causing target protein degradation via the ubiquitin-proteasome system. Inspired by PROTACs, several other induced proximity modalities have emerged to modulate both proteins and RNA over recent years. In this review, we summarize the critical advances and opportunities in the field, focusing on protein degraders, RNA degraders and non-degrader modalities such as post-translational modification (PTM) and protein-protein interaction (PPI) modulators. We envision that these emerging proximity-based drug modalities will be valuable resources for both biological research and therapeutic discovery in the future.


Subject(s)
Tics , Humans , Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Proteolysis , Drug Discovery , RNA/metabolism , Biology , Ligands
8.
Commun Biol ; 6(1): 1225, 2023 12 04.
Article in English | MEDLINE | ID: mdl-38044380

ABSTRACT

Environmental stimuli trigger rapid transcriptional reprogramming of gene networks. These responses occur in the context of the local chromatin landscape, but the contribution of organ-specific dynamic chromatin modifications in responses to external signals remains largely unexplored. We treated tomato seedlings with a supply of nitrate and measured the genome-wide changes of four histone marks, the permissive marks H3K27ac, H3K4me3, and H3K36me3 and repressive mark H3K27me3, in shoots and roots separately, as well as H3K9me2 in shoots. Dynamic and organ-specific histone acetylation and methylation were observed at functionally relevant gene loci. Integration of transcriptomic and epigenomic datasets generated from the same organ revealed largely syngenetic relations between changes in transcript levels and histone modifications, with the exception of H3K27me3 in shoots, where an increased level of this repressive mark is observed at genes activated by nitrate. Application of a machine learning approach revealed organ-specific rules regarding the importance of individual histone marks, as H3K36me3 is the most successful mark in predicting gene regulation events in shoots, while H3K4me3 is the strongest individual predictor in roots. Our integrated study substantiates a view that during plant environmental responses, the relationships between histone code dynamics and gene regulation are highly dependent on organ-specific contexts.


Subject(s)
Histones , Solanum lycopersicum , Histones/genetics , Histones/metabolism , Histone Code , Solanum lycopersicum/genetics , Nitrates , Chromatin
9.
RSC Chem Biol ; 4(3): 192-215, 2023 Mar 08.
Article in English | MEDLINE | ID: mdl-36908699

ABSTRACT

Molecular glues are a class of small molecules that stabilize the interactions between proteins. Naturally occurring molecular glues are present in many areas of biology where they serve as central regulators of signaling pathways. Importantly, several clinical compounds act as molecular glue degraders that stabilize interactions between E3 ubiquitin ligases and target proteins, leading to their degradation. Molecular glues hold promise as a new generation of therapeutic agents, including those molecular glue degraders that can redirect the protein degradation machinery in a precise way. However, rational discovery of molecular glues is difficult in part due to the lack of understanding of the protein-protein interactions they stabilize. In this review, we summarize the structures of known molecular glue-induced ternary complexes and the interface properties. Detailed analysis shows different mechanisms of ternary structure formation. Additionally, we also review computational approaches for predicting protein-protein interfaces and highlight the promises and challenges. This information will ultimately help inform future approaches for rational molecular glue discovery.

10.
Methods Enzymol ; 681: 23-39, 2023.
Article in English | MEDLINE | ID: mdl-36764759

ABSTRACT

The discovery of new small molecule ligands for E3 ligases will enable the creation of novel proteolysis targeting chimeras (PROTACs) and molecular glues to tackle traditionally undruggable proteins. Diversifying both the chemical matter for each E3 ligase and the type of ligases will be important to fully capture the potential of these targeted protein degradation modalities. A key step in this process is to establish an integrated screening platform for the rapid identification and optimization of small molecule ligands for E3 ligases. Here, we provide a method to evaluate E3 ligase ligands using AlphaScreen technology. AlphaScreen allows for the evaluation of a wide array of molecular interactions and is utilized extensively in small molecule screening campaigns. This bead-based proximity technology offers facile development for interactions across a wide range of affinities and can be adapted to interrogate E3 ligase-degron interactions. In this protocol, we demonstrate the development of AlphaScreen for E3 ligase ligand competition assays toward the discovery of new ligands for E3 ligases.


Subject(s)
Proteins , Ubiquitin-Protein Ligases , Ligands , Proteins/metabolism , Ubiquitin-Protein Ligases/metabolism , Proteolysis
11.
Ann Vasc Surg ; 93: 174-184, 2023 Jul.
Article in English | MEDLINE | ID: mdl-36706948

ABSTRACT

BACKGROUND: Aneurysmal degeneration of aortic dissection portends significant morbidity and mortality consequences in the subacute and chronic phases of aortic dissection. This article describes the use of a multibranched stent graft system for the treatment of thoracoabdominal aneurysmal degeneration of dissections with visceral segment involvement and reports upon the 30-day and 1-year outcomes for the first 18 patients treated with this design configuration. METHODS: The in-hospital, 30-day and 1-year morbidity and mortality outcomes of 18 consecutive patients treated with the physician-assembled visceral manifold or unitary manifold stent graft systems between 2013 and 2022 were evaluated. RESULTS: A total of 18 patients were treated for aneurysmal changes after aortic dissection. A total of 71 visceral vessels were successfully stented. There were no acute procedural failures. There were no episodes of paraplegia, reinterventions for type I or III endoleaks, patency-related events or mortalities reported in the first 30 days following treatment. One-year, all-cause mortality demonstrated 2/11 (18.2%). CONCLUSIONS: The aneurysmal degeneration of aortic dissection poses significant risks to patients with medically managed aortic dissections and those under surveillance. When these aneurysms develop in the thoracoabdominal region, treatment becomes even more challenging given the problem of visceral vessel patency, as these vessels can originate off the true or false lumens. The physician-designed endovascular stent graft system reported upon here has been successfully deployed in 18 patients with no acute procedural failures and promising clinical results. This treatment modality may offer utility to vascular surgeons whose patients with thoracoabdominal aneurysmal degeneration following aortic dissection have historically had limited endovascular repair prospects.


Subject(s)
Aortic Aneurysm, Thoracic , Aortic Aneurysm, Thoracoabdominal , Aortic Dissection , Blood Vessel Prosthesis Implantation , Endovascular Procedures , Physicians , Humans , Blood Vessel Prosthesis/adverse effects , Aortic Aneurysm, Thoracic/diagnostic imaging , Aortic Aneurysm, Thoracic/etiology , Aortic Aneurysm, Thoracic/surgery , Blood Vessel Prosthesis Implantation/adverse effects , Risk Factors , Treatment Outcome , Postoperative Complications/diagnostic imaging , Postoperative Complications/etiology , Postoperative Complications/therapy , Endovascular Procedures/adverse effects , Stents/adverse effects , Aortic Dissection/diagnostic imaging , Aortic Dissection/etiology , Aortic Dissection/surgery , Prosthesis Design
12.
S D Med ; 75(7): 294-299, 2022 Jul.
Article in English | MEDLINE | ID: mdl-36542567

ABSTRACT

INTRODUCTION: The COVID-19 pandemic has ushered in a rapid evolution of regulations surrounding telemedicine and the public's need for affordable, accessible, high-quality care at a distance. This necessity led to a rise in telemedicine demand that forced health systems to adapt, and for providers to witness the potential benefits and limitations of such services. METHODS: In this analysis, Sanford Health EMR data was evaluated from Q2 of 2019 to Q2 of 2020 to compare specialty utilization of telemedicine and quantify percentage change within the midst of the COVID-19 pandemic. A survey was conducted to evaluate provider opinion within the Sanford Health system regarding demographics, usage, perceived benefits, and perceived barriers to this rapid adoption. RESULTS: Results suggest that Sanford Health experienced a significant, 1,600 percent increase of telemedicine usage. Additionally, with this increased usage of telemedicine, provider opinion of telemedicine and its potential has improved. During the pandemic, a greater percentage of providers believe telemedicine is highly beneficial to their practice and a majority believe telemedicine will continue to play a vital role in their practice in the future. However, the barriers found within the survey included limited patient access, technical difficulties, reimbursement, and insurance coverage. CONCLUSIONS: With the rapid increase in provider usage and the subsequent approval of providers, telemedicine has the potential to facilitate higher quality healthcare going forward. The COVID-19 pandemic has necessitated evolution and adoption of virtual media in medicine and has provided a unique glimpse into telemedicine's limitations and exceptional potential.


Subject(s)
COVID-19 , Telemedicine , Humans , COVID-19/epidemiology , South Dakota/epidemiology , Pandemics , Demography
13.
ACS Appl Mater Interfaces ; 14(41): 46471-46480, 2022 Oct 19.
Article in English | MEDLINE | ID: mdl-36197146

ABSTRACT

We demonstrate the use of the machine learning (ML) tools to rapidly and accurately predict the electric field as a guide for designing core-shell Au-silica nanoparticles to enhance 1O2 sensitization and selectivity of organic synthesis. Based on the feature importance analysis, obtained from a deep neural network algorithm, we found a general and linear dependent descriptor (θ ∝ aD0.25t-1, where a, D, and t are the shape constant, size of metal nanoparticles, and distance from the metal surface) for the electric field around the core-shell plasmonic nanoparticle. Directed by the new descriptor, we synthesized gold-silica nanoparticles and validated their plasmonic intensity using scanning transmission electron microscopy-electron energy loss spectroscopy (STEM-EELS) mapping. The nanoparticles with θ = 0.40 demonstrate an ∼3-fold increase in the reaction rate of photooxygenation of anthracene and 4% increase in the selectivity of photooxygenation of dihydroartemisinic acid (DHAA), a long-standing goal in organic synthesis. In addition, the combination of ML and experimental investigations shows the synergetic effect of plasmonic enhancement and fluorescence quenching, leading to enhancement for 1O2 generation. Our results from time-dependent density functional theory (TD-DFT) calculations suggest that the presence of an electric field can favor intersystem crossing (ISC) of methylene blue to enhance 1O2 generation. The strategy reported here provides a data-driven catalyst preparation method that can significantly reduce experimental cost while paving the way for designing photocatalysts for organic drug synthesis.

14.
Front Plant Sci ; 13: 1005077, 2022.
Article in English | MEDLINE | ID: mdl-36311072

ABSTRACT

Histone posttranslational modifications shape the chromatin landscape of the plant genome and affect gene expression in response to developmental and environmental cues. To date, the role of histone modifications in regulating plant responses to environmental nutrient availability, especially in agriculturally important species, remains largely unknown. We describe the functions of two histone lysine methyltransferases, SET Domain Group 33 (SDG33) and SDG34, in mediating nitrogen (N) responses of shoots and roots in tomato. By comparing the transcriptomes of CRISPR edited tomato lines sdg33 and sdg34 with wild-type plants under N-supplied and N-starved conditions, we uncovered that SDG33 and SDG34 regulate overlapping yet distinct downstream gene targets. In response to N level changes, both SDG33 and SDG34 mediate gene regulation in an organ-specific manner: in roots, SDG33 and SDG34 regulate a gene network including Nitrate Transporter 1.1 (NRT1.1) and Small Auxin Up-regulated RNA (SAUR) genes. In agreement with this, mutations in sdg33 or sdg34 abolish the root growth response triggered by an N-supply; In shoots, SDG33 and SDG34 affect the expression of photosynthesis genes and photosynthetic parameters in response to N. Our analysis thus revealed that SDG33 and SDG34 regulate N-responsive gene expression and physiological changes in an organ-specific manner, thus presenting previously unknown candidate genes as targets for selection and engineering to improve N uptake and usage in crop plants.

15.
Chem Soc Rev ; 51(14): 5740-5756, 2022 Jul 18.
Article in English | MEDLINE | ID: mdl-35587208

ABSTRACT

Targeted protein degradation (TPD) strategies have revolutionized how scientists tackle challenging protein targets deemed undruggable with traditional small molecule inhibitors. Many promising campaigns to inhibit proteins have failed due to factors surrounding inhibition selectivity and targeting of compounds to specific tissues and cell types. One of the major improvements that PROTAC (proteolysis targeting chimera) and molecular glue technology can exert is highly selective control of target inhibition. Multiple studies have shown that PROTACs can gain selectivity for their protein targets beyond that of their parent ligands via optimization of linker length and stabilization of ternary complexes. Due to the bifunctional nature of PROTACs, the tissue selective nature of E3 ligases can be exploited to uncover novel targeting mechanisms. In this review, we provide critical analysis of the recent progress towards making selective PROTAC molecules and new PROTAC technologies that will continue to push the boundaries of achieving selectivity. These efforts have wide implications in the future of treating disease as they will broaden the possible targets that can be addressed by small molecules, like undruggable proteins or broadly active targets that would benefit from degradation in specific tissue types.


Subject(s)
Proteolysis , Ubiquitin-Protein Ligases , Ligands , Ubiquitin-Protein Ligases/metabolism
16.
Plant J ; 109(5): 1134-1151, 2022 03.
Article in English | MEDLINE | ID: mdl-34863006

ABSTRACT

Scent bouquets produced by the flowers of Petunia spp. (petunia) are composed of a complex mixture of floral volatile benzenoid and phenylpropanoid compounds (FVBPs), which are specialized metabolites derived from phenylalanine (Phe) through an interconnected network of enzymes. The biosynthesis and emission of high levels of these volatiles requires coordinated transcriptional activation of both primary and specialized metabolic networks. The petunia R2R3-MYB transcription factor ODORANT 1 (ODO1) was identified as a master regulator of FVBP production and emission; however, our knowledge of the direct regulatory targets of ODO1 has remained limited. Using chromatin immunoprecipitation followed by sequencing (ChIP-seq) in petunia flowers, we identify genome-wide ODO1-bound genes that are enriched not only in genes involved in the biosynthesis of the Phe precursor, as previously reported, but also genes associated with the specialized metabolic pathways involved in generating phenylpropanoid intermediates for FVBPs. ODO1-bound genes are also involved in methionine and S-adenosylmethionine metabolism, which could modulate methyl group supplies for certain FVBPs. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and RNA-seq analysis in an ODO1 RNAi knockdown line revealed that ODO1-bound targets are expressed at lower levels when ODO1 is suppressed. A cis-regulatory motif, CACCAACCCC, was identified as a potential binding site for ODO1 in the promoters of genes that are both bound and activated by ODO1, which was validated by in planta promoter reporter assays with wild-type and mutated promoters. Overall, our work presents a mechanistic model for ODO1 controlling an extensive gene regulatory network that contributes to FVBP production to give rise to floral scent.


Subject(s)
Petunia , Flowers/genetics , Flowers/metabolism , Gene Expression Regulation, Plant , Metabolic Networks and Pathways , Petunia/genetics , Petunia/metabolism , Plant Proteins/metabolism
17.
Article in English | MEDLINE | ID: mdl-34921061

ABSTRACT

Pathogenic variants in CKAP2L have previously been reported in Filippi syndrome (FS), a rare autosomal recessive, craniodigital syndrome characterized by microcephaly, syndactyly, short stature, intellectual disability, and dysmorphic facial features. To date, fewer than 10 patients with pathogenic variants in CKAP2L associated with FS have been reported. All of the previously reported probands have presumed loss-of-function variants (frameshift, canonical splice site, starting methionine), and all but one have been homozygous for a pathogenic variant. Here we describe two brothers who presented with microcephaly, micrognathia, syndactyly, dysmorphic features, and intellectual disability. Whole-exome sequencing of the family identified a missense variant, c.2066G > A;p.(Arg689His), in trans with a frameshift variant, c.1169_1173del;p.(Ile390LysfsTer4), in CKAP2L To our knowledge, these are the first patients with FS to be reported with a missense variant in CKAP2L and only the second family to be reported with two variants in trans.


Subject(s)
Cytoskeletal Proteins , Intellectual Disability , Microcephaly , Nervous System Malformations , Syndactyly , Cytoskeletal Proteins/genetics , Facies , Growth Disorders , Humans , Intellectual Disability/genetics , Intellectual Disability/pathology , Male , Microcephaly/genetics , Nervous System Malformations/genetics , Pedigree , Siblings , Syndactyly/genetics
18.
Angew Chem Int Ed Engl ; 60(51): 26663-26670, 2021 12 13.
Article in English | MEDLINE | ID: mdl-34614283

ABSTRACT

Targeting cereblon (CRBN) is currently one of the most frequently reported proteolysis-targeting chimera (PROTAC) approaches, owing to favorable drug-like properties of CRBN ligands, immunomodulatory imide drugs (IMiDs). However, IMiDs are known to be inherently unstable, readily undergoing hydrolysis in body fluids. Here we show that IMiDs and IMiD-based PROTACs rapidly hydrolyze in commonly utilized cell media, which significantly affects their cell efficacy. We designed novel CRBN binders, phenyl glutarimide (PG) analogues, and showed that they retained affinity for CRBN with high ligand efficiency (LE >0.48) and displayed improved chemical stability. Our efforts led to the discovery of PG PROTAC 4 c (SJ995973), a uniquely potent degrader of bromodomain and extra-terminal (BET) proteins that inhibited the viability of human acute myeloid leukemia MV4-11 cells at low picomolar concentrations (IC50 =3 pM; BRD4 DC50 =0.87 nM). These findings strongly support the utility of PG derivatives in the design of CRBN-directed PROTACs.


Subject(s)
Adaptor Proteins, Signal Transducing/chemistry , Piperidones/chemistry , Ubiquitin-Protein Ligases/chemistry , Humans , Hydrolysis , Proteolysis
19.
J Surg Case Rep ; 2021(9): rjab389, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34512948

ABSTRACT

Ovarian vein thrombosis (OVT) is a rare condition most frequently associated with pelvic inflammatory disease (PID), malignancy or the immediate postpartum period. This case study reports on a 56-year-old woman who developed OVT 11 days after a positive COVID-19 diagnosis. Imaging including abdominal/pelvic computed tomography, transvaginal Doppler ultrasound and transabdominal pelvic ultrasound failed to definitively diagnose the thrombotic etiology of the patient's presentation. Ultimately, laparoscopic visualization and subsequent oophorectomy were necessary for diagnostic and therapeutic purposes. The patient did not have underlying malignancy, recent surgical history, history of PID or any history of previous thromboembolic events. Therefore, this report contributes further evidence to the growing knowledge of systemic manifestations associated with COVID-19 that may require surgical intervention.

20.
Pattern Recognit ; 119: 108083, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34121775

ABSTRACT

COVID-19 is an infectious disease caused by a newly discovered type of coronavirus called SARS-CoV-2. Since the discovery of this disease in late 2019, COVID-19 has become a worldwide concern, mainly due to its high degree of contagion. As of April 2021, the number of confirmed cases of COVID-19 reported to the World Health Organization has already exceeded 135 million worldwide, while the number of deaths exceeds 2.9 million. Due to the impacts of the disease, efforts in the literature have intensified in terms of studying approaches aiming to detect COVID-19, with a focus on supporting and facilitating the process of disease diagnosis. This work proposes the application of texture descriptors based on phylogenetic relationships between species to characterize segmented CT volumes, and the subsequent classification of regions into COVID-19, solid lesion or healthy tissue. To evaluate our method, we use images from three different datasets. The results are promising, with an accuracy of 99.93%, a recall of 99.93%, a precision of 99.93%, an F1-score of 99.93%, and an AUC of 0.997. We present a robust, simple, and efficient method that can be easily applied to 2D and/or 3D images without limitations on their dimensionality.

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