作者: Ugur, Berrak ; McAdow, Anthony R. ; Solnica-Krezel, Lilianna ; Su, Maohan ; Hanna, Michael G. ; Postlethwait, John ; De Camilli, Pietro ; Leonzino, Marianna ; Wilson, Catherine ; Wu, Yumei ; Bewersdorf, Joerg ; Shin, Jimann ; Schueder, Florian

Mutations in VPS13B, a member of a protein family implicated in bulk lipid transport between adjacent membranes, cause Cohen syndrome. VPS13B is known to be concentrated in the Golgi complex, but its precise location within this organelle and thus the site(s) where it achieves lipid transport remains unclear. Here, we show that VPS13B is localized at the interface between proximal and distal Golgi subcompartments and that Golgi complex reformation after Brefeldin A (BFA)–induced disruption is delayed in VPS13B KO cells. This delay is phenocopied by the loss of FAM177A1, a Golgi complex protein of unknown function reported to be a VPS13B interactor and whose mutations also result in a developmental disorder. In zebrafish, the vps13b ortholog, not previously annotated in this organism, genetically interacts with fam177a1. Collectively, these findings raise the possibility that bulk lipid transport by VPS13B may play a role in the dynamics of Golgi membranes and that VPS13B may be assisted in this function by FAM177A1.

2024-11-01·Journal of Allergy and Clinical Immunology

TH2 cell compensatory effect following benralizumab treatment for eosinophilic gastritis

Article

作者: Rochman, Yrina ; Kliewer, Kara ; Collins, Margaret H ; Bolton, Scott M ; Caldwell, Julie M ; Rothenberg, Marc E ; Mukkada, Vincent ; Putnam, Philip E ; Morgenstern, Netali Ben-Baruch

BACKGROUNDEosinophil accumulation is a main feature of eosinophilic gastritis (EoG) and is associated with its histologic diagnosis and pathology. However, a recent clinical trial has demonstrated that EoG endoscopic, noneosinophil histologic, and clinical features remain persistent despite complete eosinophil depletion.OBJECTIVEOur aim was to examine gastric T-cell composition and associated cytokine levels of patients with EoG following benralizumab-induced eosinophil depletion versus following administration of placebo.METHODSA cohort of subjects with EoG from a subset of subjects who participated in a recent phase 2 benralizumab trial was treated for 12 weeks with administration of 3 doses of benralizumab (anti-IL-5 receptor α antibody [n = 5]) or placebo (n = 4). Single-cell suspensions obtained by gastric biopsy were stimulated with phorbol 12,13-dibutyrate and ionomycin in the presence of brefeldin A and monensin. Harvested cells were fixed, stained, and analyzed by flow cytometry to examine T-cell populations and associated cytokines.RESULTSFollowing benralizumab treatment but not placebo, blood and gastric eosinophil levels decreased 16-fold and 10-fold, respectively. Whereas histologic score and features were significantly decreased, no change was observed in endoscopic score and features. Following complete eosinophil depletion with benralizumab, gastric T_H2 cell levels were 3-fold higher than the levels in the patients with EoG who were given placebo; and the levels of associated type 2 cytokine production of IL-4, IL-5, and IL-13 in the benralizumab-treated patients were, respectively, 4-, 5.5-, and 2.5-fold, higher than those in the placebo-treated patients.CONCLUSIONWe have identified a putative positive feedback loop whereby eosinophil depletion results in a paradoxic increase in levels of T_H2 cells and derived cytokines; this finding suggests an explanation for the limited success of eosinophil depletion as monotherapy in eosinophil-associated gastrointestinal disorders.

2024-11-01·Journal of Plant Physiology

NHX5/NHX6/SPY22 complex regulates BRI1 and brassinosteroid signaling in Arabidopsis

Article

作者: Shang, Jun ; Qiao, Feng ; Zhang, Xiao ; Shen, Wei ; Mu, Guoxiu ; Qi, Yuting ; Xie, Yujie ; Ge, Mingrui ; Qiu, Quan-Sheng ; He, Yu

NHX5 and NHX6, Arabidopsis endosomal antiporters, play a vital role in facilitating ion and pH homeostasis in endosomal compartments. Studies have found that NHX5 and NHX6 are essential for protein trafficking, auxin homeostasis, and plant growth and development. Here, we report the role of NHX5 and NHX6 in brassinosteroid (BR) signaling. We found that hypocotyl growth was enhanced in nhx5 nhx6 under epibrassinolide (eBR) treatment. nhx5 nhx6 bri1 was insensitive to eBR treatment, indicating that NHX5 and NHX6 are downstream of the BRI1 receptor in BR signaling. Moreover, confocal observation with both hypocotyls and root tips showed that BRI1-YFP localization in the plasma membrane (PM) was reduced in nhx5 nhx6. Interestingly, brefeldin A (BFA) treatment showed that formation of the BFA bodies containing BRI1 and their disassembling were disrupted in nhx5 nhx6. Further genetic analysis showed that NHX5/NHX6 and SYP22 may act coordinately in BR signaling. NHX5 and NHX6 may regulate SYP22 function by modulating cellular K⁺ and pH homeostasis. Importantly, NHX5 and NHX6 colocalize and interact with SYP22, but do not interact with BRI1. In summary, our findings indicate that NHX5/NHX6/SYP22 complex is essential for the regulation of BRI1 recycling and PM localization. The H⁺-leak facilitated by NHX5 and NHX6 offers a means of controlling BR signaling in plants.

项与 Brefeldin A 相关的新闻（医药）

2024-06-24

·Science Daily

Removal of excess chloride ions by plants when subjected to salt stress

Researchers have discovered a salt adaptation mechanism in plants that facilitates chloride removal from the roots and enhancing salinity tolerance. A research team has uncovered a novel mechanism of plant adaptation to salt stress involving the NaCl-induced translocation of a specific chloride channel protein, AtCLCf. National University of Singapore (NUS) researchers have discovered a salt adaptation mechanism in plants that facilitates chloride removal from the roots and enhancing salinity tolerance. Soil salinity is one of the most deleterious environmental stress factors and increased salinity poses a growing challenge for crop production and adversely affects crop yields worldwide. The excess accumulation of soluble salts, especially sodium chloride (NaCl), in the root zone severely impedes plant growth, reducing crop productivity. Although chloride ions (Cl-) are essential nutrients for plants at low concentrations, their excessive accumulation is toxic to the plant cells. Plants have evolved various strategies to cope with such environmental stresses by employing various channels and transporters for maintaining ion balance (ion homeostasis) in their cells. While there is a better understanding of the sodium ion homeostasis under salt stress, removal of chloride ions is not well understood. To address this, a research team led by Professor Prakash KUMAR from the NUS Department of Biological Sciences has uncovered a novel mechanism of plant adaptation to salt stress involving the NaCl-induced translocation of a specific chloride channel protein, AtCLCf. Their work revealed that the AtCLCf protein is made and stored in the endomembrane system (the Golgi apparatus) under normal growth conditions. When the root cells are treated with salt, AtCLCf translocates to the plasma membrane, where it helps to remove the excess chloride ions. This represents a novel mechanism to increase the plant's salinity tolerance. The research is a collaboration with Dr Ji?í FRIML from the Institute of Science and Technology, Austria and Professor XU Jian from Radboud University, The Netherlands. This work was recently published in Nature Communications on 10 May 2024. The study also identified a transcription factor, AtWRKY9, that directly regulates the expression of the AtCLCf gene when the plant is under salt stress. NaCl causes the AtCLCf protein to move from inside the cell (the Golgi) to the cell surface with the help of another protein called AtRABA1b/BEX5. If this movement is blocked by an inhibitor (brefeldin-A) or by modifying the BEX5 gene, it results in high salt sensitivity in plants. Transgenic plants designed to produce additional AtCLCf gene showed increased salt tolerance in mutant forms of Arabidopsis plants lacking the CLCf gene. Collectively, these findings proved that AtCLCf is involved in the removal of excess chloride ions from root tissues to increase the salt tolerance of plants. To understand how AtCLCf functions in plant cells, the researchers used several techniques such as fluorimetric measurement of liposomes incorporated with recombinant AtCLCf protein and chloride ion sensitive dye, as well as electrophysiological studies (patch clamp). These studies showed that AtCLCf works like a pump that swaps chloride ions with hydrogen ions, helping to remove excess chloride ions from the cells. Prof Kumar said, "This represents an essential and previously unknown salt tolerance mechanism in Arabidopsis plants. This knowledge could be used to improve the salinity tolerance of crop plants in the future."

临床结果

2024-05-07

·BioSpace

ASGCT24: On the Ground in Baltimore

Pictured: Baltimore skyline with color treatment/Taylor Tieden for BioSpace The American Society of Gene & Cell Therapy’s 27th annual meeting kicks off Tuesday in Baltimore, with a record 2,000 abstracts to be presented. ASGCT President Jeffrey Chamberlain told BioSpace this year’s conference will be “the largest yet,” with an increasing number of approvals in the space. Stay tuned to BioSpace as we keep you updated on all of the biggest data and news from the conference. Updated: May 7, 5:20 p.m. EST Fresh off last week’s FDA clearance of a clinical trial for an ex vivo prime editing candidate in patients with a rare disease, Prime Medicine on Tuesday laid out its vision for the next generation of one-time curative gene editing therapies at the ASGCT 2024 annual meeting. At a Tuesday workshop on the delivery and development of precision genome editing technologies, the company presented preclinical data demonstrating the broad potential of prime editing technology. Prime Medicine’s approach leverages CRISPR technology to rewrite defective genes without breaking DNA double helix strands, while enabling a wide range of edits such as substitutions, insertions and deletions. According to Jonathan Levy, principal scientist for platform delivery innovation at Prime Medicine, prime editors have the capability to repair almost all types of genetic mutations and work in many different tissues, organs and cell types, with potential opportunities across thousands of indications. “Off-target editing is very low. In fact, for our lead programs, we show no detectable off-targets,” Levy said in his Tuesday presentation on the development and delivery of prime editors. The company is working on a pipeline of investigational therapeutic programs in hematology, immunology, liver, lung, ocular and neuromuscular diseases. Speakers from Roche, Spark Therapeutics, Oxford Biomedica and other biopharma firms on Tuesday afternoon discussed ongoing efforts to improve AAV purification and yield, aiming to improve both the safety and quality of these workhorse vectors of gene therapy. AAV manufacturing is 15 years from where monoclonal antibodies are, Cirsium Biosciences’ Daniel Gibbs told BioSpace earlier in the day. And while that lag time is not unexpected considering monoclonal antibodies entered the biopharma scene well before cell and gene therapies (CGTs), Gibbs said that improvements to AAV manufacturing must outpace advances in producing monoclonal antibodies. “[We have to] take those learnings and go exponentially faster,” he said. Presentations at the session addressed different approaches to improving separation of full capsids from empty ones and removing impurities. These included various chromatography methods and the use of additives such as brefeldin A. And while the results presented were positive, Roche’s Thuy Linh Do noted that there are often tradeoffs to consider. There’s a “balance between yield and quality,” she said. Neurogene’s gene therapy NGN-401 was “generally well-tolerated” by all three patients dosed in a Phase I/II trial for Rett syndrome, the New York–based biotech reported Tuesday. There were no signs or symptoms of overexpression-related toxicity reported in any of the patients, who were followed for nine, six and three months after dosing. NGN-401 was designed to “overcome the limitations of conventional gene therapy for Rett syndrome,” with Neurogene’s EXACTTM transgene regulation technology, which the company believes provides tolerable and therapeutic levels of protein expression to the key areas of the brain and nervous system that drive disease, Neurogene founder and CEO Rachel McMinn said in a statement. Neurogene is on track to share interim efficacy data from the trial’s first cohort in the fourth quarter of this year, McMinn said.

基因疗法临床研究

100 项与 Brefeldin A 相关的药物交易

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