A Type I Photosensitizer-Polymersome Boosts Reactive Oxygen Species Generation by Forcing H-Aggregation for Amplifying STING Immunotherapy.

Activation of the innate immune Stimulator of Interferon Genes (STING) pathway potentiates antitumor immunity. However, delivering STING agonists systemically to tumors presents a formidable challenge, and resistance to STING monotherapy has emerged in clinical trials with diminishing natural killer (NK) cell proliferation. Here, we encapsulated the STING agonist diABZI within polymersomes containing a Type I photosensitizer (NBS), creating a nanoagonist (PNBS/diABZI) for highly responsive tumor immunotherapy.

Clathrin mediates membrane fission and budding by constricting membrane pores.

Membrane budding, which underlies fundamental processes like endocytosis, intracellular trafficking, and viral infection, is thought to involve membrane coat-forming proteins, including the most observed clathrin, to form Ω-shape profiles and helix-forming proteins like dynamin to constrict Ω-profiles' pores and thus mediate fission. Challenging this fundamental concept, we report that polymerized clathrin is required for Ω-profiles' pore closure and that clathrin around Ω-profiles' base/pore region mediates pore constriction/closure in neuroendocrine chromaffin cells. Mathematical modeling suggests that clathrin polymerization at Ω-profiles' base/pore region generates forces from its intrinsically curved shape to constrict/close the pore.

Visualization of Exo- and Endocytosis Membrane Dynamics with Super-Resolution STED Microscopy.

Recent advances in stimulated emission depletion (STED) microscopy offer an unparalleled avenue to study membrane dynamics of exo- and endocytosis, such as fusion pore opening, pore expansion, constriction, and closure, as well as the membrane transformation from flat-shaped to round-shaped vesicles in real time. Here we depict a method of using the state-of-the-art STED microscopy to image these membrane dynamics in bovine chromaffin cells. This method can potentially be applied to study other membrane structure dynamics in other cell model system.

Effectiveness of Different Washing Strategies on Pesticide Residue Removal: The First Comparative Study on Leafy Vegetables.

Leafy vegetables are used in various cuisines worldwide; however, as they cannot be peeled and their leaf surface area is large, the risk of retaining pesticide residues on these vegetables is relatively higher than on others. To our knowledge, this is the first comparative study to reveal the effect of removing pesticide residues from five artificially contaminated leafy vegetables (lettuce, perilla leaves, spinach, crown daisy, and ssamchoo (Brassica lee ssp. namai)) using different removal methods.

Real-time visualization of exo- and endocytosis membrane dynamics with confocal and super-resolution microscopy.

Real-time confocal and super-resolution imaging reveals membrane dynamics of exo- and endocytosis, including hemi-fusion, fusion pore opening, expansion, constriction, closure (kiss-and-run), fused-vesicle shrinking (shrink fusion), and flat membrane transition to vesicles via intermediate Λ- and Ω-shape structures. Here, we describe a protocol for imaging these membrane dynamics, including primary culture of bovine adrenal chromaffin cells, fluorescent probe application, patch-clamp to deliver depolarization and evoke exo- and endocytosis, electron microscopy (EM), and real-time confocal and stimulated emission depletion (STED) microscopy. For complete details on the use and execution of this protocol, please refer to Zhao et al.

Confocal Microscopy to Measure Three Modes of Fusion Pore Dynamics in Adrenal Chromaffin Cells.

Dynamic fusion pore opening and closure mediate exocytosis and endocytosis and determine their kinetics. Here, it is demonstrated in detail how confocal microscopy was used in combination with patch-clamp recording to detect three fusion modes in primary culture bovine adrenal chromaffin cells. The three fusion modes include 1) close-fusion (also called kiss-and-run), involving fusion pore opening and closure, 2) stay-fusion, involving fusion pore opening and maintaining the opened pore, and 3) shrink-fusion, involving shrinkage of the fusion-generated Ω-shape profile until it merges completely at the plasma membrane.

Pesticide Residues and Risk Assessment from Monitoring Programs in the Largest Production Area of Leafy Vegetables in South Korea: A 15-Year Study.

Leafy vegetables are widely consumed in South Korea, especially in the form of kimchi and namul (seasoned vegetables) and are used for wrapping meat. Therefore, the management of pesticide residues in leafy vegetables is very important. A total of 17,977 samples (49 leafy vegetables) were mainly collected in the largest production area of leafy vegetables (Gwangju Metropolitan City and Chonnam Province) in South Korea.

Neurog2 directly converts astrocytes into functional neurons in midbrain and spinal cord.

Conversion of astrocytes into neurons in vivo offers an alternative therapeutic approach for neuronal loss after injury or disease. However, not only the efficiency of the conversion of astrocytes into functional neurons by single Neurog2, but also the conundrum that whether Neurog2-induced neuronal cells (Neurog2-iNs) are further functionally integrated into existing matured neural circuits remains unknown. Here, we adopted the AAV(2/8) delivery system to overexpress single factor Neurog2 into astrocytes and found that the majority of astrocytes were successfully converted into neuronal cells in multiple brain regions, including the midbrain and spinal cord.

Molecular Mechanisms Underlying Ascl1-Mediated Astrocyte-to-Neuron Conversion.

Direct neuronal reprogramming potentially provides valuable sources for cell-based therapies. Proneural gene Ascl1 converts astrocytes into induced neuronal (iN) cells efficiently both in vitro and in vivo. However, the underlying mechanisms are largely unknown.

Metabolic Landscape of a Genetically Engineered Mouse Model of IDH1 Mutant Glioma.

Understanding the metabolic reprogramming of aggressive brain tumors has potential applications for therapeutics as well as imaging biomarkers. However, little is known about the nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate from α-ketoglutarate.

Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation.

Recent studies have revealed an essential role for embryonic cortical development in the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). However, the genetic basis and underlying mechanisms remain unclear. Here, we generate mutant human embryonic stem cell lines (Mut hESCs) carrying an NR2F1-R112K mutation that has been identified in a patient with ASD features and investigate their neurodevelopmental alterations.

IDH mutation in glioma: molecular mechanisms and potential therapeutic targets.

Isocitrate dehydrogenase (IDH) enzymes catalyse the oxidative decarboxylation of isocitrate and therefore play key roles in the Krebs cycle and cellular homoeostasis. Major advances in cancer genetics over the past decade have revealed that the genes encoding IDHs are frequently mutated in a variety of human malignancies, including gliomas, acute myeloid leukaemia, cholangiocarcinoma, chondrosarcoma and thyroid carcinoma. A series of seminal studies further elucidated the biological impact of the IDH mutation and uncovered the potential role of IDH mutants in oncogenesis.

mTORC2/Rac1 Pathway Predisposes Cancer Aggressiveness in Mutated Glioma.

Isocitrate dehydrogenase () mutations are common genetic abnormalities in lower grade gliomas. The neomorphic enzyme activity of IDH mutants leads to tumor formation through epigenetic alteration, dysfunction of dioxygenases, and metabolic reprogramming. However, it remains elusive as to how IDH mutants regulate the pathways associated with oncogenic transformation and aggressiveness.

Conversion of Astrocytes and Fibroblasts into Functional Noradrenergic Neurons.

Dysfunction of noradrenergic (NA) neurons is associated with a number of neuronal disorders. Diverse neuronal subtypes can be generated by direct reprogramming. However, it is still unknown how to convert non-neuronal cells into NA neurons.

Brusatol, an NRF2 inhibitor for future cancer therapeutic.

Background: Natural products from herbal medicines have long been investigated for their potentials as cancer therapeutics. Besides the development of several herbal medicine-derived anti-cancer agents, such as paclitaxel, vincristine and podophyllotoxin, many recent laboratory findings demonstrated that brusatol, a quassinoid from the seeds of , exhibits potent tumor suppressing effect with improved disease outcome. Our recent finding further demonstrated that brusatol synergizes with the intrinsic metabolic burden in cancer cells.

APPBP2 enhances non-small cell lung cancer proliferation and invasiveness through regulating PPM1D and SPOP.

Background: The influence of amyloid protein-binding protein 2 (APPBP2) on lung cancer is unknown.

Methods: The function and mechanisms of APPBP2 were investigated in the NSCLC cell lines A549 and H1299. The ectopic expression of APPBP2, PPM1D and SPOP in NSCLS were examined in samples collected from ten pairs of human lung adenocarcinoma cancer tissues and adjacent normal lung tissues.

Ascl1 Converts Dorsal Midbrain Astrocytes into Functional Neurons In Vivo.

In vivo induction of non-neuronal cells into neurons by transcription factors offers potential therapeutic approaches for neural regeneration. Although generation of induced neuronal (iN) cells in vitro and in vivo has been reported, whether iN cells can be fully integrated into existing circuits remains unclear. Here we show that expression of achaete-scute complex homolog-like 1 (Ascl1) alone is sufficient to convert dorsal midbrain astrocytes of mice into functional iN cells in vitro and in vivo.

A pilot study of topical intrarectal application of amifostine for prevention of late radiation rectal injury.

Purpose: Clinical symptomatic late injury to the rectal wall occurs in about one-third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of the prostate to the anterior rectal wall. On the basis of our previous observations in an animal model that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall, a Phase I dose-escalation clinical trial was undertaken.

Intrarectal application of amifostine for the prevention of radiation-induced rectal injury.

Clinically symptomatic late injury to the rectal wall occurs in about one third of patients with prostate cancer treated with external beam irradiation. Reducing the physical dose to the anterior rectal wall without a similar reduction in the posterior peripheral zone is difficult because of the proximity of these structures. Based on our previous observations that intrarectal application of amifostine resulted in very high concentrations of amifostine and its active metabolite WR-1065 in the rectal wall of Copenhagen rats, the authors initiated a phase I clinical trial in 1998.