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Mutations in the isocitrate dehydrogenase (IDH) 1 gene are commonly found in human glioma, with the majority of low-grade gliomas harboring a recurrent point mutation (IDH1 R132H). Mutant IDH reveals an altered enzymatic activity leading to the synthesis of 2-hydroxyglutarate, which has been implicated in epigenetic mechanisms of oncogenesis. Nevertheless, it is unclear exactly how IDH mutations drive glioma initiation and progression, and it is also not clear why tumors with this mutation generally have a better prognosis than IDH wild-type tumors. Recognition of the high frequency of IDH mutations in glioma [and also in other malignancies, including acute myeloid leukemia (AML) and cholangiocarcinoma] have led to the development of a number of targeted agents that can inhibit these enzymes. Enasidenib and ivosidenib have both gained regulatory approval for IDH mutant AML. Both agents are still in early clinical phases for glioma therapy, as are a number of additional candidates (including AG-881, BAY1436032, and DS1001). A marked clinical problem in the development of these agents is overcoming the blood–brain barrier. An alternative approach to target the IDH1 mutation is by the induction of synthetic lethality with compounds that target poly (ADP-ribose) polymerase (PARP), glutamine metabolism, and the Bcl-2 family of proteins. We conclude that within the last decade, several approaches have been devised to therapeutically target the IDH1 mutation, and that, potentially, both IDH1 inhibitors and synthetic lethal approaches might be relevant for future therapies.

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification. Diet intervention is emerging as an option to improve cancer therapy. Here, the authors show that a diet with restrictive cysteine and methionine synergizes with a ferroptosis inducer to increase cell death and survival in glioma preclinical models.

Sinking particulate organic carbon out of the surface ocean sequesters carbon on decadal to millennial timescales. Predicting the particulate carbon flux is therefore critical for understanding both global carbon cycling and the future climate. Microbes play a crucial role in particulate organic carbon degradation, but the impact of depth-dependent microbial dynamics on ocean-scale particulate carbon fluxes is poorly understood. Here we scale-up essential features of particle-associated microbial dynamics to understand the large-scale vertical carbon flux in the ocean. Our model provides mechanistic insight into the microbial contribution to the particulate organic carbon flux profile. We show that the enhanced transfer of carbon to depth can result from populations struggling to establish colonies on sinking particles due to diffusive nutrient loss, cell detachment, and mortality. These dynamics are controlled by the interaction between multiple biotic and abiotic factors. Accurately capturing particle-microbe interactions is essential for predicting variability in large-scale carbon cycling. Micro-scale microbial community dynamics can substantially alter the fate of sinking particulates in the ocean thus playing a key role in setting the vertical flux of particulate carbon in the ocean.

Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies. Glioblastoma patients are treated with Aurora kinase A (AURKA) inhibitors but resistance can occur. Here, the authors show that AURKA inhibition induces metabolic reprogramming, which leads to increased mitochondrial activity and inhibition of oxidative metabolism sensitizes glioblastoma cells to AURKA inhibition.

Maximal safe surgical resection remains a critical component of glioblastoma (GBM) management, improving both survival and quality of life. However, complete tumor removal is hindered by the infiltrative nature of GBM and its proximity to eloquent brain regions. Fluorescence-guided surgery (FGS) has emerged as a valuable tool to enhance intraoperative tumor visualization and optimize resection outcomes. Currently used fluorophores such as 5-aminolevulinic acid (5-ALA), fluorescein sodium (FS), and indocyanine green (ICG) have distinct advantages but are limited by suboptimal specificity, shallow tissue penetration, and technical constraints. 5-ALA and SF often yield unreliable signals in low-grade tumors or infiltrative regions and also pose challenges such as phototoxicity and poor depth resolution. In contrast, near-infrared (NIR) fluorescence imaging represents a promising next-generation approach, providing superior tissue penetration, reduced autofluorescence, and real-time delineation of tumor margins. This review explores the mechanisms, clinical applications, and limitations of currently approved FGS agents and highlights future directions in image-guided neurosurgery.

Melanoma is an aggressive cancer with rising incidence, particularly among older individuals. Despite advancements in targeted therapies for BRAF and MEK proteins and immunotherapies, many patients either fail to respond or develop resistance. For those progressing on immunotherapy, limited treatment options remain. The Cyclin D–CDK4/6–RB pathway is commonly dysregulated in melanoma, with up to 90% of cases showing alterations that activate it. Although targeting Cyclin–CDK complexes has shown promise in preclinical models, clinical responses have been suboptimal. This review explores the molecular mechanisms behind Cyclin–CDK dysregulation in melanoma and the challenges of targeting this pathway. It also discusses strategies to improve the efficacy of CDK4/6 inhibitors, including combination therapies to overcome resistance and enhance patient outcomes. Understanding these mechanisms can guide the development of more effective treatments for melanoma.

This study explores how images of the past have been deployed to set up current arrangements of leadership and institutional identity by considering the career and teachings of Thích Thanh Từ in connection with his “revived” Buddhist tradition in Vietnam. Promoted as a continuation of the unique and pure Vietnamese Buddhist meditation tradition and associated with the Vietnamese national identity, the contemporary Trúc Lâm (Bamboo Grove) is a pride of many Vietnamese Buddhists. The original Trúc Lâm is claimed to be founded by the heroic King-turned-monk Trần Nhân Tông in the thirteenth century. The tradition was supposedly transmitted through the next two generations and died out. In the twentieth century, a Southern Vietnamese monk, Thích Thanh Từ (1924–), who had quit Pure Land (Tịnh Độ, C. Jingtu 淨土) Buddhism to self-learn and practice meditation, decided to reinvent the medieval Trúc Lâm tradition and became the founder of the contemporary Trúc Lâm. Despite growing up during French colonization and American war, Thanh Từ was not politically involved; instead, he focused on setting up new monasteries, taught meditation, and discouraged his followers from political and social engagement. This paper examines how successful Thích Thanh Từ and his disciples are in popularizing Trúc Lâm in Vietnam, given that the majority of Vietnamese Buddhists follow Pure Land devotional practices. More importantly, it describes how Thích Thanh Từ combines the teachings attributed to Trần Nhân Tông and two Chinese Chan masters, Huike 慧可 (the Second Patriarch) and Huineng 惠能 (the Sixth Patriarch), to form Trúc Lâm’s philosophical views and meditation techniques. With the clear-cut distinction between the delusional mind of sentient beings and the perfect mind of enlightened beings, Thích Thanh Từ presents the goal of Trúc Lâm practice as attaining the state of no-thought and sharpening it to perfection to perceive the “buddha nature” (phật tính, S. buddhadhātu, C. foxing 佛性) understood as the pure mind of nonduality and nonform. Outlining that process, he emphasizes the importance of “sudden awakening” (đốn ngộ, C. dunwu 頓悟) followed by “gradual cultivation” (tiệm tu, C. jianxiu 漸修). His meditation manual for ordinary practitioners with no experience of sudden awakening contains key techniques of (1) stabilizing the mind by counting and then observing breaths, (2) recognizing the “true mind” (chân tâm, C. zhenxin 真心) through practicing “no abiding in thoughts” (biết vọng không theo), “no mind for the externals” (đối cảnh vô tâm), “no dualistic discrimination” (không kẹt hai bên), and then proceeding to the stage of permanently abiding in the nature of true mind. These meditation methods are pertinent to Trúc Lâm’s view that all phenomena that emerge via speculative thoughts are unreal and illusory, and that only the true mind is real. The first section of this paper explores historical connections between Vietnamese and Chinese forms of Buddhism, shedding light on why Trúc Lâm embraces Thiền Tông, which is transmitted from Chinese Chan zong, and how Thích Thanh Từ builds connections between Thiền Tông and the Vietnamese national identity. The second section focuses on Thích Thanh Từ’s own life story, on how he practiced meditation and suddenly experienced “unlearned wisdom” (trí vô sư/vô sư trí, C. wushi zhi 無師智, an alternative term for true mind and buddha nature as a result of his practice) and how he succeeded in spreading the “revived” Trúc Lâm. With the first two sections as a background, in the third section, this paper explores Thích Thanh Từ’s views and practices and critically analyzes those views and practices in the conclusion. Overall, I argue that Thích Thanh Từ’s instructions on meditation are closely intertwined with his view of reality, which in turn is based on the mainstream Chan zong ideas.

Telomere biology disorders (TBD) are a heterogeneous group of diseases arising from germline mutations affecting genes involved in telomere maintenance. Telomeres are DNA-protein structures at chromosome ends that maintain chromosome stability; their length affects cell replicative potential and senescence. A constellation of bone marrow failure, pulmonary fibrosis, liver cirrhosis and premature greying is suggestive, however incomplete penetrance results in highly variable manifestations, with idiopathic pulmonary fibrosis as the most common presentation. Currently, the true extent of TBD burden is unknown as there is no established diagnostic criteria and the disorder often is unrecognised and underdiagnosed. There is no gold standard for measuring telomere length and not all TBD-related mutations have been identified. There is no specific cure and the only treatment is organ transplantation, which has poor outcomes. This review summarises the current literature and discusses gaps in understanding and areas of need in managing TBD.

Acute lung injury (ALI), a common condition in critically ill patients, has limited treatments and high mortality. Aging is a risk factor for ALI. Sirtuins (SIRTs), central regulators of the aging process, decrease during normal aging and in aging-related diseases. We recently showed decreased SIRT7 expression in lung tissues and fibroblasts from patients with pulmonary fibrosis compared to controls. To gain insight into aging-related mechanisms in ALI, we investigated the effects of SIRT7 depletion on lipopolysaccharide (LPS)-induced inflammatory responses and endothelial barrier permeability in human primary pulmonary endothelial cells. Silencing SIRT7 in pulmonary artery or microvascular endothelial cells attenuated LPS-induced increases in ICAM1, VCAM1, IL8, and IL6 and induced endomesenchymal transition (EndoMT) with decreases in VE-Cadherin and PECAM1 and increases in collagen, alpha-smooth muscle actin, TGFβ receptor 1, and the transcription factor Snail. Loss of endothelial adhesion molecules was accompanied by increased F-actin stress fibers and increased endothelial barrier permeability. Together, these results show that an aging phenotype induced by SIRT7 deficiency promotes EndoMT with impaired inflammatory responses and dysfunction of the lung vascular barrier.

Virus genomes harbor compacted repertoires of genes and regulatory elements. Through long-read sequencing, we provide a comprehensive Epstein Barr virus (EBV) transcriptome analysis, identifying 1453 transcript isoforms and resolving the major isoform of all but one lytic reading frame. Further, we categorize each transcript according to their dependence on viral DNA replication. We show that the late gene viral preinitiation complex, vPIC also activates early promoters/genes, we identify active alternate promoters with distinct dependencies on viral DNA replication, we discover biphasic promoters with embedded features of both early and late promoters. Genetic and chromatin interaction studies identify an enhancer function for the viral lytic origin of replication (OriLyt). We also observe substantial viral read-through transcription that likely causes transcriptional interference and fine tuning of viral promoter activity. In some loci with same direction overlapping gene configurations, polyA read-through is necessary to facilitate transcription through entire ORFs while also giving rise to highly abundant viral lncRNAs due to the partial nature of read-through. Altogether, this study identifies extensive viral transcriptome diversity, it resolves the major isoforms for nearly all lytic ORFs, and it identifies the alternative regulatory modes driving the temporal regulation of EBV lytic gene expression. Here, the authors profile the EBV transcriptome during lytic replication and identify over 1,400 unique EBV transcript isoforms, resolving major isoforms of most lytic open reading frames, alternative and biphasic promoters and an enhancer function for the viral lytic origin of replication.