Metabolic reprogramming fulfils increased nutrient demands and regulates numerous oncogenic processes in tumors, leading to tumor malignancy. Branched-chain amino acids (BCAAs, i.e., valine, leucine, ...and isoleucine) function as nitrogen donors to generate macromolecules such as nucleotides and are indispensable for human cancer cell growth. The cell-autonomous and non-autonomous roles of altered BCAA metabolism have been implicated in cancer progression and the key proteins in the BCAA metabolic pathway serve as possible prognostic and diagnostic biomarkers in human cancers. Here we summarize how BCAA metabolic reprogramming is regulated in cancer cells and how it influences cancer progression.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) acts as a DNA damage sensor. It recognizes DNA damage and facilitates DNA repair by recruiting DNA repair machinery to damage sites. Recent studies ...reported that PARP-1 also plays an important role in DNA replication by recognizing the unligated Okazaki fragments and controlling the speed of fork elongation. On the other hand, emerging evidence reveals that excessive activation of PARP-1 causes chromatin DNA fragmentation and triggers an intrinsic PARP-1-dependent cell death program designated parthanatos, which can be blocked by genetic deletion or pharmacological inhibition of PARP-1. Therefore, PARP-1 plays an essential role in maintaining genomic stability by either facilitating DNA repair/replication or triggering DNA fragmentation to kill cells. A group of structure-specific nucleases is crucial for executing DNA incision and fragmentation following PARP-1 activation. In this review, we will discuss how PARP-1 coordinates with its associated nucleases to maintain genomic integrity and control the decision of cell life and death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cell death is a key feature of neurological diseases, including stroke and neurodegenerative disorders. Studies in a variety of ischemic/hypoxic mouse models demonstrate that poly(ADP‐ribose) ...polymerase 1 (PARP‐1)‐dependent cell death, also named PARthanatos, plays a pivotal role in ischemic neuronal cell death and disease progress. PARthanatos has its unique triggers, processors, and executors that convey a highly orchestrated and programmed signaling cascade. In addition to its role in gene transcription, DNA damage repair, and energy homeostasis through PARylation of its various targets, PARP‐1 activation in neuron and glia attributes to brain damage following ischemia/reperfusion. Pharmacological inhibition or genetic deletion of PARP‐1 reduces infarct volume, eliminates inflammation, and improves recovery of neurological functions in stroke. Here, we reviewed the role of PARP‐1 and PARthanatos in stroke and their therapeutic potential.
We reviewed the multifaceted effects of poly(ADP‐ribose) polymerase 1 (PARP‐1) in stroke and its therapeutic potential. PARP‐1 hyperactivation leads to poly(ADP‐ribose) accumulation, which 1) enables nuclear–mitochondria cross talk and triggers PARP‐1‐dependent cell death (PARthanatos); 2) causes NAD+ depletion and regulates metabolic reprogramming; 3) regulates ion homeostasis and aggravates calcium influx leading to a vicious cycle of excess calcium influx and excitotoxicity; and 4) induces neuroinflammation by activating transcription factors and their downstream gene expression.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Pharmaceuticals and personal care products (PPCPs) are increasingly being scrutinized by the scientific community due to their environmental persistence. Therefore, the development of novel ...environmentally compatible and energy-efficient technologies for their removal is highly anticipated. In this work, a novel metal-free photocatalytic nanoreactor was successfully synthesized by anchoring carbon dots to hollow carbon nitride nanospheres (HCNS/CDs). The unique structure of these hollow nanospherical HCNS/CDs hybrids endowed them with a high population of reactive sites, while enhancing optical absorption due to internal light reflection. Simultaneously, the CDs served as “artificial antennas” to absorb and convert photons with low energy, due to their superior up-converting properties. Consequently, the HCNS/CDs demonstrated excellent photodegradation activities for the degradation of PPCPs under broad-spectrum irradiation. Remarkedly, 10 mg/L of naproxen (NPX) was completely degraded following 5 min of natural solar irradiation. It was further revealed that the O2•- played a significant role during the photocatalytic process, which could lead to the decomposition of NPX. The effects of natural water matrices and the degradation of trace PPCPs further supported that this photocatalytic system may be efficaciously applied for the remediation of PPCPs contamination in ambient waterways.
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•Carbon dots decorated hollow porous carbon nitride nanosphere was synthesized.•The hollow porous structures provided a high population of active sites.•The photocatalyst demonstrated remarkable degradation activity.•Effects of natural water constituents and water matrices were further investigated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hypoxia-inducible factors (HIFs) mediate metabolic reprogramming in response to hypoxia. However, the role of HIFs in branched-chain amino acid (BCAA) metabolism remains unknown. Here we show that ...hypoxia upregulates mRNA and protein levels of the BCAA transporter LAT1 and the BCAA metabolic enzyme BCAT1, but not their paralogs LAT2-4 and BCAT2, in human glioblastoma (GBM) cell lines as well as primary GBM cells. Hypoxia-induced LAT1 protein upregulation is mediated by both HIF-1 and HIF-2 in GBM cells. Although both HIF-1α and HIF-2α directly bind to the hypoxia response element at the first intron of the human
BCAT1
gene, HIF-1α is exclusively responsible for hypoxia-induced BCAT1 expression in GBM cells. Knockout of HIF-1α and HIF-2α significantly reduces glutamate labeling from BCAAs in GBM cells under hypoxia, which provides functional evidence for HIF-mediated reprogramming of BCAA metabolism. Genetic or pharmacological inhibition of BCAT1 inhibits GBM cell growth under hypoxia. Together, these findings uncover a previously unrecognized HIF-dependent metabolic pathway that increases GBM cell growth under conditions of hypoxic stress.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The coexistence of multiple types of interactions within social, technological, and biological networks has motivated the study of the multilayer nature of real-world networks. Meanwhile, identifying ...network structures from dynamical observations is an essential issue pervading over the current research on complex networks. This paper addresses the problem of structure identification for multilayer networks, which is an important topic but involves a challenging inverse problem. To clearly reveal the formalism, the simplest two-layer network model is considered and a new approach to identifying the structure of one layer is proposed. Specifically, if the interested layer is sparsely connected and the node behaviors of the other layer are observable at a few time points, then a theoretical framework is established based on compressive sensing and regularization. Some numerical examples illustrate the effectiveness of the identification scheme, its requirement of a relatively small number of observations, as well as its robustness against small noise. It is noteworthy that the framework can be straightforwardly extended to multilayer networks, thus applicable to a variety of real-world complex systems.
Poly(ADP-ribose) polymerase-1 (PARP-1) plays a pivotal role in multiple neurologic diseases by mediating caspase-independent cell death, which has recently been designated parthanatos to distinguish ...it from other forms of cell death such as apoptosis, necrosis and autophagy. Mitochondrial apoptosis-inducing factor (AIF) release and translocation to the nucleus is the commitment point for parthanatos. This process involves a pathogenic role of poly(ADP-ribose) (PAR) polymer. It generates in the nucleus and translocates to the mitochondria to mediate AIF release following lethal PARP-1 activation. PAR polymer itself is toxic to cells. Thus, PAR polymer signaling to mitochondrial AIF is the key event initiating the deadly crosstalk between the nucleus and the mitochondria in parthanatos. Targeting PAR-mediated AIF release could be a potential approach for the therapy of neurologic disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract
TFBSshape (https://tfbsshape.usc.edu) is a motif database for analyzing structural profiles of transcription factor binding sites (TFBSs). The main rationale for this database is to be able ...to derive mechanistic insights in protein–DNA readout modes from sequencing data without available structures. We extended the quantity and dimensionality of TFBSshape, from mostly in vitro to in vivo binding and from unmethylated to methylated DNA. This new release of TFBSshape improves its functionality and launches a responsive and user-friendly web interface for easy access to the data. The current expansion includes new entries from the most recent collections of transcription factors (TFs) from the JASPAR and UniPROBE databases, methylated TFBSs derived from in vitro high-throughput EpiSELEX-seq binding assays and in vivo methylated TFBSs from the MeDReaders database. TFBSshape content has increased to 2428 structural profiles for 1900 TFs from 39 different species. The structural profiles for each TFBS entry now include 13 shape features and minor groove electrostatic potential for standard DNA and four shape features for methylated DNA. We improved the flexibility and accuracy for the shape-based alignment of TFBSs and designed new tools to compare methylated and unmethylated structural profiles of TFs and methods to derive DNA shape-preserving nucleotide mutations in TFBSs.
SAP30 is a core subunit of the transcriptional corepressor SIN3 complex, but little is known about its role in gene regulation and human cancer. Here, we show that SAP30 was a nonmutational ...oncoprotein upregulated in more than 50% of human breast tumors and correlated with unfavorable outcomes in patients with breast cancer. In various breast cancer mouse models, we found that SAP30 promoted tumor growth and metastasis through its interaction with SIN3A/3B. Surprisingly, the canonical gene silencing role was not essential for SAP30's tumor-promoting actions. SAP30 enhanced chromatin accessibility and RNA polymerase II occupancy at promoters in breast cancer cells, acting as a coactivator for genes involved in cell motility, angiogenesis, and lymphangiogenesis, thereby driving tumor progression. Notably, SAP30 formed a homodimer with 1 subunit binding to SIN3A and another subunit recruiting MLL1 through specific Phe186/200 residues within its transactivation domain. MLL1 was required for SAP30-mediated transcriptional coactivation and breast tumor progression. Collectively, our findings reveal that SAP30 represents a transcriptional dependency in breast cancer.
Query auto-completion (QAC) is widely used by modern search engines to assist users by predicting their intended queries. Most QAC approaches rely on deterministic batch learning algorithms trained ...from past query log data. However, query popularities keep changing all the time and QAC operates in a real-time scenario where users interact with the search engine continually. So, ideally, QAC must be timely and adaptive enough to reflect time-sensitive changes in an online fashion. Second, due to the vertical position bias, a query suggestion with a higher rank tends to attract more clicks regardless of user's original intention. Hence, in the long run, it is important to place some lower ranked yet potentially more relevant queries to higher positions to collect more valuable user feedbacks. In order to tackle these issues, we propose to formulate QAC as a ranked Multi-Armed Bandits (MAB) problem which enjoys theoretical soundness. To utilize prior knowledge from query logs, we propose to use Bayesian inference and Thompson Sampling to solve this MAB problem. Extensive experiments on large scale datasets show that our QAC algorithm has the capacity to adaptively learn temporal trends, and outperforms existing QAC algorithms in ranking qualities.
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