Accurate DNA replication and repair is essential for proper development, growth and tumor-free survival in all multicellular organisms. A key requirement for the maintenance of genomic integrity is ...the availability of adequate and balanced pools of deoxyribonucleoside triphosphates (dNTPs), the building blocks of DNA. Notably, dNTP pool alterations lead to genomic instability and have been linked to multiple human diseases, including mitochondrial disorders, susceptibility to viral infection and cancer. In this review, we discuss how a key regulator of dNTP biosynthesis in mammals, the enzyme ribonucleotide reductase (RNR), impacts cancer susceptibility and serves as a target for anti-cancer therapies. Because RNR-regulated dNTP production can influence DNA replication fidelity while also supporting genome-protecting DNA repair, RNR has complex and stage-specific roles in carcinogenesis. Nevertheless, cancer cells are dependent on RNR for de novo dNTP biosynthesis. Therefore, elevated RNR expression is a characteristic of many cancers, and an array of mechanistically distinct RNR inhibitors serve as effective agents for cancer treatment. The dNTP metabolism machinery, including RNR, has been exploited for therapeutic benefit for decades and remains an important target for cancer drug development.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Regulatory T cells (Treg cells) are essential for immune tolerance1, but also drive immunosuppression in the tumour microenvironment2. Therapeutic targeting of Treg cells in cancer will therefore ...require the identification of context-specific mechanisms that affect their function. Here we show that inhibiting lipid synthesis and metabolic signalling that are dependent on sterol-regulatory-element-binding proteins (SREBPs) in Treg cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral Treg cells. Moreover, deletion of SREBP-cleavage-activating protein (SCAP)-a factor required for SREBP activity-in these cells inhibits tumour growth and boosts immunotherapy that is triggered by targeting the immune-checkpoint protein PD-1. These effects of SCAP deletion are associated with uncontrolled production of interferon-у and impaired function of intratumoral Treg cells. Mechanistically, signalling through SCAP and SREBPs coordinates cellular programs for lipid synthesis and inhibitory receptor signalling in these cells. First, de novo fatty-acid synthesis mediated by fatty-acid synthase (FASN) contributes to functional maturation of Treg cells, and loss of FASN from Treg cells inhibits tumour growth. Second, Treg cells in tumours show enhanced expression ofthe PD-1 gene, through a process that depends on SREBP activity and signals via mevalonate metabolism to protein geranylgeranylation. Blocking PD-1 or SREBP signalling results in dysregulated activation of phosphatidylinositol-3-kinase in intratumoral Treg cells. Our findings show that metabolic reprogramming enforces the functional specialization of Treg cells in tumours, pointing to new ways of targeting these cells for cancer therapy.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Benign overfitting in linear regression Bartlett, Peter L.; Long, Philip M.; Lugosi, Gábor ...
Proceedings of the National Academy of Sciences - PNAS,
12/2020, Volume:
117, Issue:
48
Journal Article
Peer reviewed
Open access
The phenomenon of benign overfitting is one of the key mysteries uncovered by deep learning methodology: deep neural networks seem to predict well, even with a perfect fit to noisy training data. ...Motivated by this phenomenon, we consider when a perfect fit to training data in linear regression is compatible with accurate prediction. We give a characterization of linear regression problems for which the minimum norm interpolating prediction rule has near-optimal prediction accuracy. The characterization is in terms of two notions of the effective rank of the data covariance. It shows that overparameterization is essential for benign overfitting in this setting: the number of directions in parameter space that are unimportant for prediction must significantly exceed the sample size. By studying examples of data covariance properties that this characterization shows are required for benign overfitting, we find an important role for finite-dimensional data: the accuracy of the minimum norm interpolating prediction rule approaches the best possible accuracy for a much narrower range of properties of the data distribution when the data lie in an infinite-dimensional space vs. when the data lie in a finite-dimensional space with dimension that grows faster than the sample size.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Abstract
Coronal loop oscillations are common phenomena in the solar corona, which are often classified as decaying and decayless oscillations. Using the high-resolution observation measured by the ...Extreme Ultraviolet Imager (EUI) on board the Solar Orbiter, we statistically investigate small-scale transverse oscillations with short periods (<200 s) of coronal loops in an active region (AR), i.e., NOAA AR 12965. A total of 111 coronal loops are identified in EUI 174 Å images, and they all reveal transverse oscillations without any significant decaying, regarded as decayless oscillations. Oscillatory periods are measured from ∼11 to ∼185 s, with a median period of 40 s. Thus, they are also termed short-period oscillations. The corresponding loop lengths are measured from ∼10.5 to ∼30.2 Mm, and a strong dependence of oscillatory periods on loop lengths is established, indicating that the short-period oscillations are standing kink-mode waves in nature. Based on the coronal seismology, kink speeds are measured to be ∼330–1910 km s
−1
, and magnetic field strengths in coronal loops are estimated to be ∼4.1–25.2 G, while the energy flux carried by decayless kink oscillations lies in the range from roughly 7 to 9220 W m
−2
. Our estimations suggest that the wave energy carried by short-period decayless kink oscillations cannot support the coronal heating in the AR.
Abstract
Regulatory T (T
reg
) cells derived from the thymus (tT
reg
) and periphery (pT
reg
) have central and distinct functions in immunosuppression, but mechanisms for the generation and ...activation of T
reg
subsets in vivo are unclear. Here, we show that mechanistic target of rapamycin (mTOR) unexpectedly supports the homeostasis and functional activation of tT
reg
and pT
reg
cells. mTOR signaling is crucial for programming activated T
reg
-cell function to protect immune tolerance and tissue homeostasis. T
reg
-specific deletion of mTOR drives spontaneous effector T-cell activation and inflammation in barrier tissues and is associated with reduction in both thymic-derived effector T
reg
(eT
reg
) and pT
reg
cells. Mechanistically, mTOR functions downstream of antigenic signals to drive IRF4 expression and mitochondrial metabolism, and accordingly, deletion of mitochondrial transcription factor A (Tfam) severely impairs T
reg
-cell suppressive function and eT
reg
-cell generation. Collectively, our results show that mTOR coordinates transcriptional and metabolic programs in activated T
reg
subsets to mediate tissue homeostasis.
Large-scale brain states or distributed patterns of brain activity modulate downstream processing and behavior. Sustained attention and memory retrieval states impact subsequent memory, yet how these ...states relate to one another is unclear. I hypothesize that internal attention is a central process of the retrieval state. The alternative is that the retrieval state specifically reflects a controlled, episodic retrieval mode, engaged only when intentionally accessing events situated within a spatiotemporal context. To test my hypothesis, I developed a mnemonic state classifier independently trained to measure retrieval state evidence and applied this classifier to a spatial attention task. I find that retrieval state evidence increases during delay and response intervals when participants are maintaining spatial information. Critically, retrieval state evidence is positively related to the amount of maintained spatial location information and predicts target detection reaction times. Together, these findings support the hypothesis that internal attention is a central process of the retrieval state.
The group of synthetic chemicals known as poly and per-fluoroalkyl substances (PFAS) are currently of high concern to environmental regulators and the public due to their widespread occurrence, ...resistance to degradation and reported toxicity. However, little data exists on the effects of exposure to PFAS at environmentally relevant concentrations and this hampers the effective management of these compounds. This paper reviews current research on the occurrence and ecotoxicology of PFAS at environmentally relevant doses to assess their potential biological impacts. Hazard Quotient (HQ) analysis was undertaken as part of this assessment. Most PFAS detected in the environment were found to have a HQ risk value of <1 meaning their reported concentrations are below their predicted no effect concentration. This indicates many reported toxic effects of PFAS are, theoretically, unlikely to occur outside the laboratory. However, lack of information on new PFAS as well as their precursors and degradation products, coupled with lack of knowledge of their mixture toxicity means our understanding of the risks of PFAS is incomplete, especially in regard to sub-lethal and/or chronic effects. It is proposed that the development of molecular markers for PFAS exposure are needed to aid in the development of environmental PFAS regulations that are effective in fully protecting the environment.
Display omitted
•Data on the effects of PFAS at environmentally relevant concentrations is limited.•Toxicity occurs at higher concentrations than PFAS occur in the environment.•Hazard Quotient Analysis generally gives values of <1 for PFOA and PFOS.•Unknown PFAS, their degradation products and precursors may be higher risk.•Molecular markers of sublethal PFAS exposure are needed for risk assessment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Regulatory T cells (T
cells) are essential for immune tolerance
, but also drive immunosuppression in the tumour microenvironment
. Therapeutic targeting of T
cells in cancer will therefore require ...the identification of context-specific mechanisms that affect their function. Here we show that inhibiting lipid synthesis and metabolic signalling that are dependent on sterol-regulatory-element-binding proteins (SREBPs) in T
cells unleashes effective antitumour immune responses without autoimmune toxicity. We find that the activity of SREBPs is upregulated in intratumoral T
cells. Moreover, deletion of SREBP-cleavage-activating protein (SCAP)-a factor required for SREBP activity-in these cells inhibits tumour growth and boosts immunotherapy that is triggered by targeting the immune-checkpoint protein PD-1. These effects of SCAP deletion are associated with uncontrolled production of interferon-γ and impaired function of intratumoral T
cells. Mechanistically, signalling through SCAP and SREBPs coordinates cellular programs for lipid synthesis and inhibitory receptor signalling in these cells. First, de novo fatty-acid synthesis mediated by fatty-acid synthase (FASN) contributes to functional maturation of T
cells, and loss of FASN from T
cells inhibits tumour growth. Second, T
cells in tumours show enhanced expression of the PD-1 gene, through a process that depends on SREBP activity and signals via mevalonate metabolism to protein geranylgeranylation. Blocking PD-1 or SREBP signalling results in dysregulated activation of phosphatidylinositol-3-kinase in intratumoral T
cells. Our findings show that metabolic reprogramming enforces the functional specialization of T
cells in tumours, pointing to new ways of targeting these cells for cancer therapy.
Full text
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Parkinson's disease (PD) is characterised by degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Inflammation may be associated with the neuropathology of PD due to the ...following accumulating evidence: excessive microglial activation and increased levels of the pro-inflammatory cytokines tumour necrosis factor-alpha and interleukin-1beta in the SNpc of patients with PD; the emergence of PD-like symptoms following influenza infection; the increased susceptibility to PD associated with bacterial vaginosis; the presence of inflammatory mediators and activators in animal models of PD; the ability of anti-inflammatory drugs to decrease susceptibility to PD; and the emerging possibility of the use of microglial activation inhibitors as a therapy in PD. In this review, we will discuss the role of inflammation in PD. We will focus on the influence of microglia in the pathogenesis of PD and discuss potential therapeutic interventions for PD, that target microglia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Understanding metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics in the clinic. Here, using transcriptomic ...data for 10,704 tumor and normal samples from The Cancer Genome Atlas, across 26 disease sites, we present a novel bioinformatics pipeline that distinguishes tumor from normal tissues, based on differential gene expression for 114 metabolic pathways. We confirm pathway dysregulation in separate patient populations, demonstrating the robustness of our approach. Bootstrapping simulations were then applied to assess the biological significance of these alterations. We provide distinct examples of the types of analysis that can be accomplished with this tool to understand cancer specific metabolic dysregulation, highlighting novel pathways of interest, and patterns of metabolic flux, in both common and rare disease sites. Further, we show that Master Metabolic Transcriptional Regulators explain why metabolic differences exist, can segregate patient populations, and predict responders to different metabolism-targeted therapeutics.
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