NSUN5/TET2-directed chromatin-associated RNA modification of 5-methylcytosine to 5-hydroxymethylcytosine governs glioma immune evasion.

Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates ß-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of ß-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy.

The Metal-Insulator Transition in Vanadium Oxide Nanofilms Enables Microkelvin-Resolution Thermometry.

High-resolution thermometry is critical for probing nanoscale energy transport. Here, we demonstrate how high-resolution thermometry can be accomplished using vanadium oxide (VOx), which features a sizable temperature-dependence of its resistance at room temperature and an even stronger dependence at its metal-insulator-transition (MIT) temperature. We microfabricate VOx nanofilm-based electrical resistance thermometers that undergo a metal-insulator-transition at ∼337 K and systematically quantify their temperature-dependent resistance, noise characteristics, and temperature resolution. We show that VOx sensors can achieve, in a bandwidth of ∼16 mHz, a temperature resolution of ∼5 µK at room temperature (∼300 K) and a temperature resolution of ∼1 µK at the MIT (∼337 K) when the amplitude of temperature perturbations is in the microkelvin range, which, in contrast to larger perturbations, is found to avoid hysteric resistance responses. These results demonstrate that VOx-based thermometers offer a ∼10-50-fold improvement in resolution over widely used Pt-based thermometers.

Electrical Conductance and Thermopower of ß-Substituted Porphyrin Molecular Junctions─Synthesis and Transport.

Molecular junctions offer significant potential for enhancing thermoelectric power generation. Quantum interference effects and associated sharp features in electron transmission are expected to enable the tuning and enhancement of thermoelectric properties in molecular junctions. To systematically explore the effect of quantum interferences, we designed and synthesized two new classes of porphyrins, P1 and P2, with two methylthio anchoring groups in the 2,13- and 2,12-positions, respectively, and their Zn complexes, Zn-P1 and Zn-P2. Past theory suggests that P1 and Zn-P1 feature destructive quantum interference in single-molecule junctions with gold electrodes and may thus show high thermopower, while P2 and Zn-P2 do not. Our detailed experimental single-molecule break-junction studies of conductance and thermopower, the latter being the first ever performed on porphyrin molecular junctions, revealed that the electrical conductance of the P1 and Zn-P1 junctions is relatively close, and the same holds for P2 and Zn-P2, while there is a 6 times reduction in the electrical conductance between P1 and P2 type junctions. Further, we observed that the thermopower of P1 junctions is slightly larger than for P2 junctions, while Zn-P1 junctions show the largest thermopower and Zn-P2 junctions show the lowest. We relate the experimental results to quantum transport theory using first-principles approaches. While the conductance of P1 and Zn-P1 junctions is robustly predicted to be larger than those of P2 and Zn-P2, computed thermopowers depend sensitively on the level of theory and the single-molecule junction geometry. However, the predicted large difference in conductance and thermopower values between Zn-P1 and Zn-P2 derivatives, suggested in previous model calculations, is not supported by our experimental and theoretical findings.

Surface Phonon Polariton-Mediated Near-Field Radiative Heat Transfer at Cryogenic Temperatures.

Recent experiments, at room temperature, have shown that near-field radiative heat transfer (NFRHT) via surface phonon polaritons (SPhPs) exceeds the blackbody limit by several orders of magnitude. Yet, SPhP-mediated NFRHT at cryogenic temperatures remains experimentally unexplored. Here, we probe thermal transport in nanoscale gaps between a silica sphere and a planar silica surface from 77-300 K. These experiments reveal that cryogenic NFRHT has strong contributions from SPhPs and does not follow the T^{3} temperature (T) dependence of far-field thermal radiation. Our modeling based on fluctuational electrodynamics shows that the temperature dependence of NFRHT can be related to the confinement of heat transfer to two narrow frequency ranges and is well accounted for by a simple analytical model. These advances enable detailed NFRHT studies at cryogenic temperatures that are relevant to thermal management and solid-state cooling applications.

Comprehensive Analysis of Ferroptosis Regulators with Regard to PD-L1 and Immune Infiltration in Low-Grade Glioma.

The prognosis of low-grade glioma (LGG) is highly variable and requires more accurate predictors. Ferroptosis, a newly discovered programmed cell death, has been demonstrated to play a crucial role in some types of tumors. However, prognostic prediction based on ferroptosis-related genes (FRGs) and the influence on the tumor microenvironment (TME) in LGG remains elusive. We derived expression profiles for LGG from public databases. Based on the expression of 25 FRGs in LGG, two independent subtypes and a risk model were successfully constructed. Different methods were applied to assess the tumor heterogeneity, tumor microenvironment, and the prognostic value. In addition, a competing endogenous RNA (ceRNA) regulatory axis was constructed. The subtypes had independent tumor heterogeneity, tumor microenvironments, and prognoses. LPCAT3, SLC1A5, HSPA5, and NFE2L2 were identified as the potential prognostic FRGs. Based on these four FRGs, our risk model possesses excellent potential to predict prognosis and varied immune infiltration abundance. The ceRNA regulatory axis provides a potential therapeutic target for LGG. Our molecular subtypes, risk model, and ceRNA regulatory axis have strong immune prediction and prognostic prediction capabilities which could guide LGG treatment.

A nanoscale photonic thermal transistor for sub-second heat flow switching.

Control of heat flow is critical for thermal logic devices and thermal management and has been explored theoretically. However, experimental progress on active control of heat flow has been limited. Here, we describe a nanoscale radiative thermal transistor that comprises of a hot source and a cold drain (both are ~250 nm-thick silicon nitride membranes), which are analogous to the source and drain electrodes of a transistor. The source and drain are in close proximity to a vanadium oxide (VOx)-based planar gate electrode, whose dielectric properties can be adjusted by changing its temperature. We demonstrate that when the gate is located close ( < ~1 µm) to the source-drain device and undergoes a metal-insulator transition, the radiative heat transfer between the source and drain can be changed by a factor of three. More importantly, our nanomembrane-based thermal transistor features fast switching times ( ~ 500 ms as opposed to minutes for past three-terminal thermal transistors) due to its small thermal mass. Our experiments are supported by detailed calculations that highlight the mechanism of thermal modulation. We anticipate that the advances reported here will open new opportunities for designing thermal circuits or thermal logic devices for advanced thermal management.

How substituents tune quantum interference in meta-OPE3 molecular junctions to control thermoelectric transport.

Quantum interference (QI) can strongly affect electric and thermoelectric properties of molecular junctions (MJs). So far, however, a limited number of experimental studies have explored the influence of QI on thermoelectric transport in MJs. To address this open point, we synthesized derivatives of meta-OPE3 with an electron-withdrawing nitro (-NO2) substituent or an electron-donating N,N-dimethyl amine (-NMe2) substituent, attached at two different positions of the central phenylene ring, and systematically studied the electrical conductance and thermopower of the corresponding gold-molecule-gold junctions. We show that (i) the electrical conductance of MJs depends weakly on the polarity of the substituents but strongly on the substitution position and (ii) MJs with the N,N-dimethyl amine group feature a higher thermopower than MJs with the nitro group. We also present calculations based on first principles, which explain these trends and show that the transport properties are highly sensitive to microscopic details in junctions, exhibiting destructive QI features.

HSV-1-induced N6-methyladenosine reprogramming via ICP0-mediated suppression of METTL14 potentiates oncolytic activity in glioma.

Upon infection with herpes simplex virus 1 (HSV-1), the virus deploys multiple strategies to evade the host's innate immune response. However, the mechanisms governing this phenomenon remain elusive. Here, we find that HSV-1 leads to a decrease in overall m6A levels by selectively reducing METTL14 protein during early infection in glioma cells. Specifically, the HSV-1-encoded immediate-early protein ICP0 interacts with METTL14 within ND10 bodies and serves as an E3 ubiquitin protein ligase, targeting and ubiquitinating METTL14 at the lysine 156 and 162 sites. Subsequently, METTL14 undergoes proteasomal degradation. Furthermore, METTL14 stabilizes ISG15 mRNA mediated by IGF2BP3 to promote antiviral effects. Notably, METTL14 suppression significantly enhances the anti-tumor effect of oncolytic HSV-1 (oHSV-1) in mice bearing glioma xenografts. Collectively, these findings establish that ICP0-guided m6A modification controls the antiviral immune response and suggest that targeting METTL14/ISG15 represents a potential strategy to enhance the oncolytic activity of oHSV-1 in glioma treatment.

Overcoming therapeutic resistance in oncolytic herpes virotherapy by targeting IGF2BP3-induced NETosis in malignant glioma.

Oncolytic virotherapy holds promise for cancer treatment, but the factors determining its oncolytic activity remain unclear. Neutrophil extracellular traps (NETs) are associated with cancer progression, yet their formation mechanism and role in oncolytic virotherapy remain elusive. In this study, we demonstrate that, in glioma, upregulation of IGF2BP3 enhances the expression of E3 ubiquitin protein ligase MIB1, promoting FTO degradation via the ubiquitin-proteasome pathway. This results in increased m6A-mediated CSF3 release and NET formation. Oncolytic herpes simplex virus (oHSV) stimulates IGF2BP3-induced NET formation in malignant glioma. In glioma models in female mice, a BET inhibitor enhances the oncolytic activity of oHSV by impeding IGF2BP3-induced NETosis, reinforcing virus replication through BRD4 recruitment with the CDK9/RPB-1 complex to HSV gene promoters. Our findings unveil the regulation of m6A-mediated NET formation, highlight oncolytic virus-induced NETosis as a critical checkpoint hindering oncolytic potential, and propose targeting NETosis as a strategy to overcome resistance in oncolytic virotherapy.

The Tick-Borne Pathogens: An Overview of China's Situation.

BACKGROUND: Ticks are important medical arthropods that can transmit hundreds of pathogens, such as parasites, bacteria, and viruses, leading to serious public health burdens worldwide. Unexplained fever is the most common clinical manifestation of tick-borne diseases. Since the emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the surge of coronavirus disease 2019 (COVID-19) cases led to the hospital overload and fewer laboratory tests for tick-borne diseases. Therefore, it is essential to review the tick-borne pathogens and further understand tick-borne diseases. PURPOSE: The geographic distribution and population of ticks in the Northern hemisphere have expanded while emerging tick-borne pathogens have been introduced to China continuously. This paper focused on the tick-borne pathogens that are threatening public health in the world. Their medical significant tick vectors, as well as the epidemiology, clinical manifestations, diagnosis, treatment, prevention, and control measures, are emphasized in this document. METHODS: In this study, all required data were collected from articles indexed in English databases, including Scopus, PubMed, Web of Science, Science Direct, and Google Scholar. RESULTS: Ticks presented a great threat to the economy and public health. Although both infections by tick-borne pathogens and SARS-CoV-2 have fever symptoms, the history of tick bite and its associated symptoms such as encephalitis or eschar could be helpful for the differential diagnosis. Additionally, as a carrier of vector ticks, migratory birds may play a potential role in the geographical expansion of ticks and tick-borne pathogens during seasonal migration. CONCLUSION: China should assess the risk score of vector ticks and clarify the potential role of migratory birds in transmitting ticks. Additionally, the individual and collective protection, vector control, comprehensive surveillance, accurate diagnosis, and symptomatic treatment should be carried out, to meet the challenge.

Quantitative Mapping of Unmodulated Temperature Fields with Nanometer Resolution.

Quantitative mapping of temperature fields with nanometric resolution is critical in various areas of scientific research and emerging technology, such as nanoelectronics, surface chemistry, plasmonic devices, and quantum systems. A key challenge in achieving quantitative thermal imaging with scanning thermal microscopy (SThM) is the lack of knowledge of the tip-sample thermal resistance (RTS), which varies with local topography and is critical for quantifying the sample temperature. Recent advances in SThM have enabled simultaneous quantification of RTS and topography in situations where the temperature field is modulated enabling quantitative thermometry even when topographical features cause significant variations in RTS. However, such an approach is not applicable to situations where the temperature modulation of the device is not readily possible. Here we show, using custom-fabricated scanning thermal probes (STPs) with a sharp tip (radius ∼25 nm) and an integrated heater/thermometer, that one can quantitatively map unmodulated temperature fields, in a single scan, with ∼7 nm spatial resolution and ∼50 mK temperature resolution in a bandwidth of 1 Hz. This is accomplished by introducing a modulated heat input to the STP and measuring the AC and DC responses of the probe's temperature which allow for simultaneous mapping of the tip-sample thermal resistance and sample surface temperature. The approach presented here─contact resistance resolved scanning thermal microscopy (CR-SThM)─can greatly facilitate temperature mapping of a variety of microdevices under practical operating conditions.

Heterogeneous irradiated-pristine polyethylene nanofiber junction as a high-performance solid-state thermal diode.

In this work, we demonstrate two types of heterogeneous irradiated-pristine polyethylene nanofiber junctions, 'heavily-irradiated-pristine' (HI-P) and 'lightly-irradiated-pristine' (LI-P) junctions, as high-performance solid-state thermal diodes. The HI-P junction rectifies heat flux in a single direction, while the LI-P junction shows dual-directional rectification under different working temperatures. We accurately model the phase transition of polyethylene nanofibers with a finite temperature range rather than a step function. The finite-temperature-range model suggests that the rectification factor increases with temperature bias and there is a minimum threshold of temperature bias for notable rectification. Besides, the finite-temperature-range model shows better prediction for the heat flow data from experiments, while the step function model tends to overestimate the rectification performance around the optimal length fraction of irradiation. Although both the models show that an optimal rectification occurs when the interface temperatures in the forward and the reverse biases are equal, the optimized rectification factor is determined by the temperature bias and the temperature range of phase transition. This work elucidates the influence of both the temperature bias and the temperature range of phase transition on thermal rectification performance, which could incredibly benefit the evaluation and design of thermal diodes.

Dual-mode solid-state thermal rectification.

Thermal rectification is an exotic thermal transport phenomenon which allows heat to transfer in one direction but block the other. We demonstrate an unusual dual-mode solid-state thermal rectification effect using a heterogeneous "irradiated-pristine" polyethylene nanofiber junction as a nanoscale thermal diode, in which heat flow can be rectified in both directions by changing the working temperature. For the nanofiber samples measured here, we observe a maximum thermal rectification factor as large as ~50%, which only requires a small temperature bias of <10 K. The tunable nanoscale thermal diodes with large rectification and narrow temperature bias open up new possibilities for developing advanced thermal management, energy conversion and, potentially thermophononic technologies.

High-contrast and reversible polymer thermal regulator by structural phase transition.

In comparison with the advancement of switchable, nonlinear, and active components in electronics, solid-state thermal components for actively controlling heat flow have been extremely rare. We demonstrate a high-contrast and reversible polymer thermal regulator based on the structural phase transition in crystalline polyethylene nanofibers. This structural phase transition represents a dramatic change in morphology from a highly ordered all-trans conformation to a combined trans and gauche conformation with rotational disorder, leading to an abrupt change in phonon transport along the molecular chains. For five nanofiber samples measured here, we observe an average thermal switching ratio of ~8× and maximum switching ratio of ~10×, which occurs in a narrow temperature range of 10 K across the structural phase transition. To the best of our knowledge, the ~10× switching ratio exceeds any reported experimental values for solid-solid and solid-liquid phase transitions of materials. There is no thermal hysteresis observed upon heating/cooling cycles.