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Molecular Cell Jun 2024The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its...
The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction. This restriction is eliminated by nuclear receptor (NR) binding to CKM-MED, which enables CTD binding in a MED26-dependent manner. Cryoelectron microscopy (cryo-EM) and crosslinking-mass spectrometry (XL-MS) revealed that the structural basis for modulation of CTD interaction with MED relates to a large intrinsically disordered region (IDR) in CKM subunit MED13 that blocks MED26 and CTD interaction with MED but is repositioned upon NR binding. Hence, NRs can control transcription initiation by priming CKM-MED for MED26-dependent RNA Pol II interaction.
PubMed: 38955181
DOI: 10.1016/j.molcel.2024.06.006 -
Cell Reports. Medicine Jun 2024Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of...
Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).
PubMed: 38955178
DOI: 10.1016/j.xcrm.2024.101630 -
Current Biology : CB Jun 2024Organisms experience constant nutritional flux. Mechanisms at the interface of opposing nutritional states-scarcity and surplus-enable organismal energy homeostasis....
Organisms experience constant nutritional flux. Mechanisms at the interface of opposing nutritional states-scarcity and surplus-enable organismal energy homeostasis. Contingent on nutritional stores, adipocytes secrete adipokines, such as the fat hormone leptin, to signal nutrient status to the central brain. Increased leptin secretion underlies metabolic dysregulation during common obesity, but the molecular mechanisms regulating leptin secretion from human adipocytes are poorly understood. Here, we report that Atg8/LC3 family proteins, best known for their role in autophagy during nutrient scarcity, play an evolutionarily conserved role during nutrient surplus by promoting adipokine secretion. We show that in a well-fed state, Atg8/LC3 promotes the secretion of the Drosophila functional leptin ortholog unpaired 2 (Upd2) and leptin from human adipocytes. Proteomic analyses reveal that LC3 directs leptin to a secretory pathway in human cells. We identified LC3-dependent extracellular vesicle (EV) loading and secretion (LDELS) as a required step for leptin release, highlighting a unique secretory route adopted by leptin in human adipocytes. In Drosophila, mutations to Upd2's Atg8 interaction motif (AIM) result in constitutive adipokine retention. Atg8-mediated Upd2 retention alters lipid storage and hunger response and rewires the bulk organismal transcriptome in a manner conducive to starvation survival. Thus, Atg8/LC3's bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively. We posit that decoding how bidirectional molecular switches-such as Atg8/LC3-operate at the nexus of nutritional scarcity and surplus will inform therapeutic strategies to tackle chronic metabolic disorders.
PubMed: 38955177
DOI: 10.1016/j.cub.2024.06.005 -
Microbial Physiology Jul 2024The global poultry industry produces millions of tons of waste feathers every year, which can be degraded to make feed, fertilizer, and daily chemicals. However, feather...
INTRODUCTION
The global poultry industry produces millions of tons of waste feathers every year, which can be degraded to make feed, fertilizer, and daily chemicals. However, feather degradation is a complex process that is not yet fully understood. This results in low degradation efficiency and difficulty in industrial applications. Omics-driven system biology research offers an effective solution to quickly and comprehensively understand the molecules and mechanisms involved in a metabolic pathway.
METHODS
In the early stage of this process, feathers are hydrolyzed into water-soluble keratin monomers. In this study, we used high-throughput RNA-seq technology to analyze the genes involved in the internalization and degradation of keratin monomers in S. maltophilia DHHJ strain cells. Moreover, we used Co-IP with LC-MS/MS technology to search for proteins that interact with recombinant keratin monomers.
RESULTS
We discovered TonB transports and molecular chaperones associating with the keratin monomer, which may play a crucial role in the transmembrane transport of keratin. Meanwhile, multiple proteases belonging to distinct families were identified as binding partners of keratin monomers, among which ATPases associated with diverse cellular activities (AAA+) family proteases are overrepresented. Four genes, including JJL50_15620, JJL50_17955 (TonB-dependent receptors), JJL50_03260 (ABC transporter ATP-binding protein), and JJL50_20035 (ABC transporter substrate-binding protein), were selected as representatives for determining their expressions under different culture conditions using qRT-PCR and they were found to be upregulated in response to keratin degradation consistent with the data from RNA-seq and Co-IP.
CONCLUSION
This study highlights the complexity of keratin biodegradation in S. maltophilia DHHJ, in which multiple pathways are involved such as protein folding, protein transport, and several protease systems. Our findings provide new insights into the mechanism of feather degradation.
PubMed: 38955164
DOI: 10.1159/000540072 -
Laryngo- Rhino- Otologie Jul 2024
Topics: Sinusitis; Nasal Polyps; Humans; Rhinitis; Chronic Disease; Antibodies, Monoclonal, Humanized; Rhinosinusitis
PubMed: 38955159
DOI: 10.1055/a-2280-9363 -
Laryngo- Rhino- Otologie Jul 2024Allergies play a pivotal role in the daily practice of ENT specialists. Allergic symptoms induced by inhalant allergens are widespread in the population and can manifest... (Review)
Review
Allergies play a pivotal role in the daily practice of ENT specialists. Allergic symptoms induced by inhalant allergens are widespread in the population and can manifest through a wide range of symptoms, including rhinorrhea, sneezing, conjunctival redness, cough and dyspnea. Inconsistent diagnosis and treatment of allergic conditions can lead to reduced quality of life, decreased work performance, and socioeconomically significant secondary diseases. In addition to the medical history, the skin prick test and serological IgE diagnostics are the most important diagnostic procedure for detecting type-I allergies. To clarify clinical relevance, molecular diagnostics and nasal provocation testing may be employed. The key to effective treatment lies in a comprehensive allergological diagnosis coupled with a detailed patient history. General treatment recommendations such as allergen avoidance and nasal irrigation should complement pharmacological therapy. In the treatment of allergic rhinitis topical steroids are first line treatment options. The primary goal of treatment is symptom control, and if control is insufficient, causal therapy through specific allergen immunotherapy is recommended. Challenges in the ENT clinic involve selecting the necessary diagnostics and appropriate, effective treatments. Hence, using diagnostic and treatment algorithms, as well as standardized patient history questionnaires, can serve as invaluable tools in daily patient interactions, especially considering limited time availability.
Topics: Humans; Immunoglobulin E; Skin Tests; Desensitization, Immunologic; Referral and Consultation; Hypersensitivity
PubMed: 38955155
DOI: 10.1055/a-2073-9474 -
Laryngo- Rhino- Otologie Jul 2024
Topics: Humans; Dysphonia; Botulinum Toxins, Type A; Pain Perception; Injections, Intramuscular; Neuromuscular Agents
PubMed: 38955149
DOI: 10.1055/a-2226-0970 -
Laryngo- Rhino- Otologie Jul 2024
Topics: Humans; Dysphonia; Botulinum Toxins, Type A; Injections, Intramuscular; Pain Perception; Female; Middle Aged
PubMed: 38955148
DOI: 10.1055/a-2226-0626 -
Computers in Biology and Medicine Jul 2024This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and...
Inhibition of the Janus kinase protein (JAK1) by the A. Pyrethrum Root Extract for the treatment of Vitiligo pathology. Design, Molecular Docking, ADME-Tox, MD Simulation, and in-silico investigation.
This study delves into the therapeutic efficacy of A. pyrethrum in addressing vitiligo, a chronic inflammatory disorder known for inducing psychological distress and elevating susceptibility to autoimmune diseases. Notably, JAK inhibitors have emerged as promising candidates for treating immune dermatoses, including vitiligo. Our investigation primarily focuses on the anti-vitiligo potential of A. pyrethrum root extract, specifically targeting N-alkyl-amides, utilizing computational methodologies. Density Functional Theory (DFT) is deployed to meticulously scrutinize molecular properties, while comprehensive evaluations of ADME-Tox properties for each molecule contribute to a nuanced understanding of their therapeutic viability, showcasing remarkable drug-like characteristics. Molecular docking analysis probes ligand interactions with pivotal site JAK1, with all compounds demonstrating significant interactions; notably, molecule 6 exhibits the most interactions with crucial inhibition residues. Molecular dynamics simulations over 500ns further validate the importance and sustainability of these interactions observed in molecular docking, favoring energetically both molecules 6 and 1; however, in terms of stability, the complex with molecule 6 outperforms others. DFT analyses elucidate the distribution of electron-rich oxygen atoms and electron-poor regions within heteroatoms-linked hydrogens. Remarkably, N-alkyl-amides extracted from A. pyrethrum roots exhibit similar compositions, yielding comparable DFT and Electrostatic Potential (ESP) results with subtle distinctions. These findings underscore the considerable potential of A. pyrethrum root extracts as a natural remedy for vitiligo.
PubMed: 38955123
DOI: 10.1016/j.compbiomed.2024.108816 -
Food Chemistry May 2024Dried-bonito (Katsuobushi) exhibits a unique uniform "glass-like" texture after traditional smoke-drying. Herein, we developed a novel processing method for dried-bonito...
Dried-bonito (Katsuobushi) exhibits a unique uniform "glass-like" texture after traditional smoke-drying. Herein, we developed a novel processing method for dried-bonito and elucidated the mechanism of transformation of loose muscle into a "glass-like" texture in terms of texture, microstructure, and protein properties. Our findings showed that the unfolding and aggregation of proteins after thermal induction was a key factor in shaping the "glass-like" texture in bonito muscle. During processing, myofibrils aggregated, the originally alternating thick and thin filaments contracted laterally and aligned into a straight line, and protein cross-linking increased. Secondary structural analysis revealed a reduction in unstable β-turn content from 26.28% to 15.06%. Additionally, an increase in the content of SS bonds was observed, and the conformation changed from g-g-t to a stable g-g-g conformation, enhanced protein conformational stability. Taken together, our findings provide a theoretical basis for understanding the mechanism of formation of the uniform "glass-like" texture in dried-bonito.
PubMed: 38955120
DOI: 10.1016/j.foodchem.2024.139843