Systematic characterization of p53-regulated long non-coding RNAs across human cancers reveals remarkable heterogeneity among different tumor types.

The p53 tumor suppressor protein, a sequence specific DNA binding transcription factor, regulates the expression of a large number of genes, in response to various forms of cellular stress. While the protein coding target genes of p53 have been well studied, less is known about its role in regulating long non-coding genes and their functional relevance to cancer. Here we report the genome-wide identification of a large set (>1000) of long non-coding RNAs(lncRNAs) that are putative p53 targets in a colon cancer cell line and in human patient datasets from five different common types of cancer. These lncRNAs have not been annotated by other studies of normal unstressed systems. In the colon cancer cell line a high proportion of these lncRNAs are uniquely induced by different chemotherapeutic agents that activate p53, while others are induced by more than one agent tested. Further, subsets of these lncRNAs independently predict overall and disease-free survival of patients across the five different common cancer types. Interestingly, both genetic alterations and patient survival associated with different lncRNAs are unique to each cancer tested, indicating extraordinary tissue-specific variability in the p53 non-coding response. The newly identified non-coding p53 target genes have allowed us to construct a classifier for tumor diagnosis and prognosis. Implications: Our results not only identify myriad p53-regulated lncRNAs, they also reveal marked drug-induced, as well as tissue- and tumor-specific heterogeneity in these putative p53 targets and our findings have enabled the construction of robust classifiers for diagnosis and prognosis.

Co3O4 nanoparticle modified N, P co-doped carbon paper as sodium carrier to construct stable anodes for Na-metal batteries.

Sodium (Na) metal batteries such as Na-ion batteries and Na-CO2 batteries are considered to be excellent alternatives to lithium batteries in terms of their potential applications because of their high specific capacity and low cost. However, the sodium anode showed low efficiency and poor cycling in Na-metal battery performance due to the formation of sodium dendrites and serious corrosion. In this work, nitrogen (N), phosphorus (P) co-doped carbon paper (NP-CP) modified with cobalt tetroxide (Co3O4) nanoparticles was prepared as the Na anode carrier (Co3O4@NP-CP), and a sodium-based composite anode (Na-Co@NP-CP) was further prepared by electrodepositing sodium. The experimental results indicate that the N, P and Co3O4 multi-doped carbon paper has good sodiophilicity, which can induce the uniform plating/stripping of Na+ ions and inhibit the growth of Na dendrites. The N, P doped carbon paper provides a high surface area and tremendous three-dimensional (3D) framework to effectively reduce the areal current density, facilitate the transfer of electrons, and enhance battery life. Therefore, Na-Co@NP-CP based symmetric cells exhibit stable cycling of over 1100 hours at current densities of 1 mA cm-2 and fixed capacity of 1 mA h cm-2. When the Na-Co@NP-CP anode couples with CO2, the assembled batteries can deliver a stable cycling of 165 cycles at current densities of 500 mA g-1 and limited capacity of 500 mA h g-1. When Na-Co@NP-CP anode couples with Na3V2(PO4)3 (NVP) cathode, the assembled cells exhibit lower hysteresis and batter cycling performance.

Acid-Doped Pyridine-Based Polybenzimidazole as a Positive Triboelectric Material with Superior Charge Retention Capability.

The energy conversion efficiency of a triboelectric nanogenerator (TENG) is severely limited by the charge density of triboelectric materials, while drastic and unavoidable charge decay happens during contact due to the insufficient charge retention capacity of positive triboelectric materials. Here, elaborately synthesized acid-ion-doped pyridine-based polybenzimidazole processing with strong charge retention capability is demonstrated to couple with negatively corona-polarized electrets. As illustrated by thermal stimulation and an ion mass spectrometer, the formation of acid-ion chimerism processes high activation energy for stored charges, and the selective anion migration can compensate the escape of polarized charge. Accordingly, the charge density can reach up to 596 µC m-2 and the charge retention rate reaches 49.7%, which is so far the highest intrinsic charge density obtained in the open air. Thus, the ionic chimerism strategy provides an effective way to suppress the charge escaping in the open air and gives a great expandable avenue for the material challenges of TENG's practical deployment.

Characterization of the SF3B1-SUGP1 interface reveals how numerous cancer mutations cause mRNA missplicing.

The spliceosomal gene SF3B1 is frequently mutated in cancer. While it is known that SF3B1 hotspot mutations lead to loss of splicing factor SUGP1 from spliceosomes, the cancer-relevant SF3B1-SUGP1 interaction has not been characterized. To address this issue, we show by structural modeling that two regions flanking the SUGP1 G-patch make numerous contacts with the region of SF3B1 harboring hotspot mutations. Experiments confirmed that all the cancer-associated mutations in these regions, as well as mutations affecting other residues in the SF3B1-SUGP1 interface, not only weaken or disrupt the interaction but also alter splicing similarly to SF3B1 cancer mutations. Finally, structural modeling of a trimeric protein complex reveals that the SF3B1-SUGP1 interaction "loops out" the G-patch for interaction with the helicase DHX15. Our study thus provides an unprecedented molecular view of a protein complex essential for accurate splicing and also reveals that numerous cancer-associated mutations disrupt the critical SF3B1-SUGP1 interaction.

Identifying predictors of glioma evolution from longitudinal sequencing.

Clonal evolution drives cancer progression and therapeutic resistance. Recent studies have revealed divergent longitudinal trajectories in gliomas, but early molecular features steering posttreatment cancer evolution remain unclear. Here, we collected sequencing and clinical data of initial-recurrent tumor pairs from 544 adult diffuse gliomas and performed multivariate analysis to identify early molecular predictors of tumor evolution in three diffuse glioma subtypes. We found that CDKN2A deletion at initial diagnosis preceded tumor necrosis and microvascular proliferation that occur at later stages of IDH-mutant glioma. Ki67 expression at diagnosis was positively correlated with acquiring hypermutation at recurrence in the IDH-wild-type glioma. In all glioma subtypes, MYC gain or MYC-target activation at diagnosis was associated with treatment-induced hypermutation at recurrence. To predict glioma evolution, we constructed CELLO2 (Cancer EvoLution for LOngitudinal data version 2), a machine learning model integrating features at diagnosis to forecast hypermutation and progression after treatment. CELLO2 successfully stratified patients into subgroups with distinct prognoses and identified a high-risk patient group featured by MYC gain with worse post-progression survival, from the low-grade IDH-mutant-noncodel subtype. We then performed chronic temozolomide-induction experiments in glioma cell lines and isogenic patient-derived gliomaspheres and demonstrated that MYC drives temozolomide resistance by promoting hypermutation. Mechanistically, we demonstrated that, by binding to open chromatin and transcriptionally active genomic regions, c-MYC increases the vulnerability of key mismatch repair genes to treatment-induced mutagenesis, thus triggering hypermutation. This study reveals early predictors of cancer evolution under therapy and provides a resource for precision oncology targeting cancer dynamics in diffuse gliomas.

Targeting alternative splicing in cancer immunotherapy.

Tumor immunotherapy has made great progress in cancer treatment but still faces several challenges, such as a limited number of targetable antigens and varying responses among patients. Alternative splicing (AS) is an essential process for the maturation of nearly all mammalian mRNAs. Recent studies show that AS contributes to expanding cancer-specific antigens and modulating immunogenicity, making it a promising solution to the above challenges. The organoid technology preserves the individual immune microenvironment and reduces the time/economic costs of the experiment model, facilitating the development of splicing-based immunotherapy. Here, we summarize three critical roles of AS in immunotherapy: resources for generating neoantigens, targets for immune-therapeutic modulation, and biomarkers to guide immunotherapy options. Subsequently, we highlight the benefits of adopting organoids to develop AS-based immunotherapies. Finally, we discuss the current challenges in studying AS-based immunotherapy in terms of existing bioinformatics algorithms and biological technologies.

Eye tracking and eye expression decoding based on transparent, flexible and ultra-persistent electrostatic interface.

Eye tracking provides valuable insight for analyzing visual attention and underlying thinking progress through the observation of eye movements. Here, a transparent, flexible and ultra-persistent electrostatic sensing interface is proposed for realizing active eye tracking (AET) system based on the electrostatic induction effect. Through a triple-layer structure combined with a dielectric bilayer and a rough-surface Ag nanowire (Ag NW) electrode layer, the inherent capacitance and interfacial trapping density of the electrostatic interface has been strongly enhanced, contributing to an unprecedented charge storage capability. The electrostatic charge density of the interface reached 1671.10 µC·m-2 with a charge-keeping rate of 96.91% after 1000 non-contact operation cycles, which can finally realize oculogyric detection with an angular resolution of 5°. Thus, the AET system enables real-time decoding eye movements for customer preference recording and eye-controlled human-computer interaction, supporting its limitless potentiality in commercial purpose, virtual reality, human computer interactions and medical monitoring.

L-shaped association of serum 25-hydroxyvitamin D with all-cause and cardiovascular mortality in older people with chronic kidney disease: results from the NHANES database prospective cohort study.

BACKGROUND: This study was conducted to assess the association of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cardiovascular disease (CVD) mortality in older people with chronic kidney disease (CKD) in the United States. METHODS: We identified 3230 CKD participants aged ≥ 60 years from the National Health and Nutrition Examination Survey (2001-2018). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Mortality outcomes were determined by linkage to National Death Index (NDI) records through December 31, 2019. Restricted cubic spline based on Cox regression models were utilized to elucidate the nonlinear relationship between serum 25(OH)D concentrations and mortality in patients with CKD. RESULTS: During median 74 months of follow-up, 1615 all-cause death and 580 CVD death were recorded. We found an L-shaped association between serum 25(OH)D concentrations and all-cause and CVD mortality, reaching a plateau at 90 nmol/L. Accordingly, per one-unit increment in natural log-transformed 25(OH)D was associated with a 32% and 33% reduced risk of all-cause mortality (hazard ratio [HR] 0.68; 95%CI, 0.56 to 0.83) and CV mortality (HR 0.69; 95%CI, 0.49 to 0.97) in participants with serum 25(OH)D < 90 nmol/L, but no considerable difference was observed in participants with serum 25(OH)D ≥ 90 nmol/L. Compared with those in the deficiency group (< 50 nmol/L), insufficient (50 to < 75 nmol/L) and sufficient group (≥ 75 nmol/L) were significantly associated with lower all-cause mortality (HR,0.83; 95%CI, 0.71 to 0.97 and HR, 0.75; 95%CI, 0.64 to 0.89) and CV mortality (HR,0.87; 95%CI, 0.68 to 1.10 and HR, 0.77; 95%CI, 0.59 to < 1.0), respectively. CONCLUSION: An L-shaped relationship between serum 25(OH)D levels with all-cause and CVD mortality was observed in elderly CKD patients in the United States. A 25(OH)D concentration of 90 nmol/L may be the target to reduce the risk of premature death.

Large and Tunable Ranking Shift in Triboelectric Series of Polymers by Introducing Phthalazinone Moieties.

Regulating the ranking of polymer in triboelectric series over a wide range is of great help for material's selection of triboelectric nanogenerators (TENGs). Herein, fluorinated poly(phthalazinone ether)s (FPPEs) with tunable molecular structure and aggregate structure are synthesized by co-polycondensation, while the large positive ranking shift in the triboelectric series can be achieved by introducing phthalazinone moieties with strong electron donating capability. FPPE-5, which includes abundant phthalazinone moieties, is more positive than all of the previously reported triboelectric polymers. Hence, the regulating range of FPPEs in this work updates a new record in triboelectric series, which is wider than that of previous works. A peculiar crystallization behavior, capable of trapping and storing more electrons, has been observed in FPPE-2 with 25% phthalazinone moieties. Correspondingly, FPPE-2 is more negative than FPPE-1 without a phthalazinone moiety, which is an unexpected shift against the common changing tendency in triboelectric series. With FPPEs films as the probing material, a tactile TENG sensor is applied to enable material identification via electrical signal polarity. Hence, this study demonstrates a strategy to regulate the series of triboelectric polymers by copolymerization using monomers with distinct electrification capabilities, where both the monomer ratio and the peculiar nonlinear behavior can control triboelectric performance.

RNA helicase DHX15 exemplifies a unique dependency in acute leukemia.

RNA-binding proteins (RBP) have emerged as essential regulators that control gene expression and modulate multiple cancer traits. T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy derived from transformation of T-cell progenitors that normally undergo discrete steps of differentiation in the thymus. The implications of essential RBP during T-cell neoplastic transformation remain largely unclear. Systematic evaluation of RBP identifies RNA helicase DHX15, which facilitates the disassembly of the spliceosome and release of lariat introns, as a T-ALL dependency factor. Functional analysis using multiple murine T-ALL models demonstrates the essential importance of DHX15 in tumor cell survival and leukemogenesis. Moreover, single-cell transcriptomics reveals that DHX15 depletion in T-cell progenitors hinders burst proliferation during the transition from doublenegative to double-positive cells (CD4-CD8- to CD4+CD8+). Mechanistically, abrogation of DHX15 perturbs RNA splicing and leads to diminished levels of SLC7A6 and SLC38A5 transcripts due to intron retention, thereby suppressing glutamine import and mTORC1 activity. We further propose a DHX15 signature modulator drug ciclopirox and demonstrate that it has prominent anti-T-ALL efficacy. Collectively, our data highlight the functional contribution of DHX15 to leukemogenesis through regulation of established oncogenic pathways. These findings also suggest a promising therapeutic approach, i.e., splicing perturbation by targeting spliceosome disassembly, may achieve considerable anti-tumor efficacy.

A curtain purification system based on a rabbit fur-based rotating triboelectric nanogenerator for efficient photocatalytic degradation of volatile organic compounds.

Efficient removal of air pollution caused by volatile organic compounds (VOCs) and particulate matter (PM) through distributed energy collected from the environment is an effective strategy to achieve both energy conservation and better air quality. Herein, a curtain purification system based on a rabbit fur-based rotary triboelectric nanogenerator (RR-TENG) and a collaborative photocatalysis technology was designed for indoor air purification. The high electrostatic field from RR-TENG enhances formaldehyde adsorption, while it can also efficiently adsorb PM2.5 simultaneously. More interestingly, the ultrahigh electric field provided by RR-TENG promotes the separation of photogenerated electron-hole pairs of the g-C3N4/TiO2 composite photocatalyst, generating more superoxide radicals (⋅O2-), hydroxyl radicals (⋅OH), and holes (h+) and thereby improving the photocatalytic efficiency. In a simulated reaction chamber of 9 L, the formaldehyde removal rate of the system can reach 79.2% within 90 min and RR-TENG rapidly reduces PM2.5 from 999 µg m-3 to 50 µg m-3 within 60 s. This study proposes a curtain purification system integrating the function of energy collection and photocatalytic purification, which can be applied for improving air quality and human health.

Human-Machine Interaction via Dual Modes of Voice and Gesture Enabled by Triboelectric Nanogenerator and Machine Learning.

With the development of science and technology, human-machine interaction has brought great benefits to the society. Here, we design a voice and gesture signal translator (VGST), which can translate natural actions into electrical signals and realize efficient communication in human-machine interface. By spraying silk protein on the copper of the device, the VGST can achieve improved output and a wide frequency response of 20-2000 Hz with a high sensitivity of 167 mV/dB, and the resolution of frequency detection can reach 0.1 Hz. By designing its internal structure, its resonant frequency and output voltage can be adjusted. The VGST can be used as a high-fidelity platform to effectively recover recorded music and can also be combined with machine learning algorithms to realize the function of speech recognition with a high accuracy rate of 97%. It also has good antinoise performance to recognize speech correctly even in noisy environments. Meanwhile, in gesture recognition, the triboelectric translator is able to recognize simple hand gestures and to judge the distance between hand and the VGST based on the principle of electrostatic induction. This work demonstrates that triboelectric nanogenerator (TENG) technology can have great application prospects and significant advantages in human-machine interaction and high-fidelity platforms.

ASCancer Atlas: a comprehensive knowledgebase of alternative splicing in human cancers.

Alternative splicing (AS) is a fundamental process that governs almost all aspects of cellular functions, and dysregulation in this process has been implicated in tumor initiation, progression and treatment resistance. With accumulating studies of carcinogenic mis-splicing in cancers, there is an urgent demand to integrate cancer-associated splicing changes to better understand their internal cross-talks and functional consequences from a global view. However, a resource of key functional AS events in human cancers is still lacking. To fill the gap, we developed ASCancer Atlas (https://ngdc.cncb.ac.cn/ascancer), a comprehensive knowledgebase of aberrant splicing in human cancers. Compared to extant databases, ASCancer Atlas features a high-confidence collection of 2006 cancer-associated splicing events experimentally proved to promote tumorigenesis, a systematic splicing regulatory network, and a suit of multi-scale online analysis tools. For each event, we manually curated the functional axis including upstream splicing regulators, splicing event annotations, downstream oncogenic effects, and possible therapeutic strategies. ASCancer Atlas also houses about 2 million computationally putative splicing events. Additionally, a user-friendly web interface was built to enable users to easily browse, search, visualize, analyze, and download all splicing events. Overall, ASCancer Atlas provides a unique resource to study the functional roles of splicing dysregulation in human cancers.

DHX15 is involved in SUGP1-mediated RNA missplicing by mutant SF3B1 in cancer.

SF3B1 is the most frequently mutated spliceosomal gene in cancer. Several hotspot mutations are known to disrupt the interaction of SF3B1 with another splicing factor, SUGP1, resulting in the RNA missplicing that characterizes mutant SF3B1 cancers. Properties of SUGP1, especially the presence of a G-patch motif, a structure known to function by activating DEAH-box RNA helicases, suggest the requirement of such an enzyme in SUGP1 function in splicing. However, the identity of this putative helicase has remained an important unanswered question. Here, using a variety of protein-protein interaction assays, we identify DHX15 as the critical helicase. We further show that depletion of DHX15 or expression of any of several DHX15 mutants, including one implicated in acute myeloid leukemia, partially recapitulates the splicing defects of mutant SF3B1. Moreover, a DHX15-SUGP1 G-patch fusion protein is able to incorporate into the spliceosome to rescue the splicing defects of mutant SF3B1. We also present the crystal structure of the human DHX15-SUGP1 G-patch complex, which reveals the molecular basis of their direct interaction. Our data thus demonstrate that DHX15 is the RNA helicase that functions with SUGP1 and additionally provide important insight into how mutant SF3B1 disrupts splicing in cancer.

Fabrication of triboelectric polymer films via repeated rheological forging for ultrahigh surface charge density.

Triboelectric polymer with high charge density is the foundation to promote the wide range of applications of triboelectric nanogenerators. This work develops a method to produce triboelectric polymer based on repeated rheological forging. The fluorinated ethylene propylene film fabricated by repeated forging method not only has excellent mechanical properties and good transmittance, but also can maintain an ultrahigh tribo-charge density. Based on the film with a thickness of 30 µm, the output charge density from contact-separation nanogenerator reaches 352 µC·m-2. Then, the same film is applied for the nanogenerator with air-breakdown mode and a charge density of 510 µC·m-2 is further achieved. The repeated forging method can effectively regulate the composition of surface functional groups, the crystallinity, and the dielectric constants of the fluorinated ethylene propylene, leading to the superior capability of triboelectrification. Finally, we summarize the key parameters for elevating the electrification performance on the basis of molecular structure and related fabrication crafts, which can guide the further development of triboelectric polymers.

Crystallization-Induced Shift in a Triboelectric Series and Even Polarity Reversal for Elastic Triboelectric Materials.

A stretchable triboelectric nanogenerator (TENG) can be a promising solution for the power supply of various flexible electronics. However, the detailed electrification mechanism of elastic triboelectric materials still needs to be clarified. In this work, we found crystallization behavior induced by strain and low temperature can lead to a shift in a triboelectric series for commonly used triboelectric elastomers and even reverse the triboelectric polarity. This effect is attributed to the notable rearrangement of surface electron cloud density happening along with the crystallization process of the molecular chain. This effect is significant with natural rubber, and silicone rubber can experience this effect at low temperature, which also leads to a shift in a triboelectric series, and an applied strain at low temperature can further enhance this shift. This study demonstrated that the electrification polarity of triboelectric materials should be re-evaluated under different strains and different temperatures, which provides a mechanism distinct from the general understanding of elastic triboelectric materials.

Monitoring the Degree of Comfort of Shoes In-Motion Using Triboelectric Pressure Sensors with an Ultrawide Detection Range.

Shoes play an important role in sports and human daily life. Here, an in-shoe sensor pad (ISSP) attached to the vamp lining is based on a triboelectric nanogenerator (TENG) for monitoring the real-time stress distribution on the top side of a foot. Each sensor unit on this ISSP is an air-capsule TENG (AC-TENG) consisting of activated carbon/polyurethane (AC/PU) and microsphere array electrodes. The detection range of each AC-TENG reaches 7.27 MPa, which is enough for monitoring the pressure change during different sports. This multifunctional ISSP can realize many typical functions of conventional smart shoes, including step counting and human-machine interaction. Moreover, it can also reveal special information, including the fitness of shoes, the stress concentration on toes, and the in-motion comfort degree. The signal processing and data transmission modules in the system have a hybrid power supply with wireless power transfer, while the real-time information about feet can be observed on a cell phone. Hence, this ISSP provides a potential approach to study the feet motion and comfort degree of shoes in long-term operations, which can guide both athlete training and the customized design of shoes.

Fish-Wearable Data Snooping Platform for Underwater Energy Harvesting and Fish Behavior Monitoring.

Conventional approaches to studying fish kinematics pose a great challenge for the real-time monitoring of fish motion kinematics. Here, a multifunctional fish-wearable data snooping platform (FDSP) for studying fish kinematics is demonstrated based on an air sac triboelectric nanogenerator (AS-TENG) with antibacterial coating. The AS-TENG not only can harvest energy from fish swimming but also serves as the self-powered sensory module to monitor the swimming behavior of the fish. The peak output power generated from each swing of the fishtail can reach 0.74 mW, while its output voltage can reflect the real-time behavior of the fishtail. The antibacterial coating on the FDSP can improve its biocompatibility and the elastic texture of the FDSP allows it to be tightly attached to fish. The wireless communication system is designed to transmit the sensory data to a cell phone, where the detailed parameters of fish motion can be obtained, including swing angle, swing frequency, and even the typical swing gestures. This FDSP has broad application prospects in underwater self-powered sensors, wearable tracking devices, and soft robots.