A method for predicting drugs that can boost the efficacy of immune checkpoint blockade.

Combination therapy is a promising therapeutic strategy to enhance the efficacy of immune checkpoint blockade (ICB); however, predicting drugs for effective combination is challenging. Here we developed a general data-driven method called CM-Drug for screening compounds that can boost ICB treatment efficacy based on core and minor gene sets identified between responsive and nonresponsive samples in ICB therapy. The CM-Drug method was validated using melanoma and lung cancer mouse models, with combined therapeutic efficacy demonstrated in eight of nine predicted compounds. Among these compounds, taltirelin had the strongest synergistic effect. Mechanistic analysis and experimental verification demonstrated that taltirelin can stimulate CD8+ T cells and is mediated by the induction of thyroid-stimulating hormone. This study provides an effective and general method for predicting and evaluating drugs for combination therapy and identifies candidate compounds for future ICB combination therapy.

PTEN inhibition enhances sensitivity of ovarian cancer cells to the poly (ADP-ribose) polymerase inhibitor by suppressing the MRE11-RAD50-NBN complex.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPis) can effectively treat ovarian cancer patients with defective homologous recombination (HR). Loss or dysfunction of PTEN, a typical tumour suppressor, impairs double-strand break (DSB) repair. Hence, we explored the possibility of inhibiting PTEN to induce HR deficiency (HRD) for PARPi application. METHODS: Functional studies using PTEN inhibitor VO-OHpic and PARPi olaparib were performed to explore the molecular mechanisms in vitro and in vivo. RESULTS: In this study, the combination of VO-OHpic with olaparib exhibited synergistic inhibitory effects on ovarian cancer cells was demonstrated. Furthermore, VO-OHpic was shown to enhance DSBs by reducing nuclear expression of PTEN and inhibiting HR repair through the modulation of MRE11-RAD50-NBN (MRN) complex, critical for DSB repair. TCGA and GTEx analysis revealed a strong correlation between PTEN and MRN in ovarian cancer. Mechanistic studies indicated that VO-OHpic reduced expression of MRN, likely by decreasing PTEN/E2F1-mediated transcription. Moreover, PTEN-knockdown inhibited expression of MRN, increased sensitivities to olaparib, and induced DSBs. In vivo experiments showed that the combination of VO-OHpic with olaparib exhibited enhanced inhibitory effects on tumour growth. CONCLUSIONS: Collectively, this study highlights the potential of PTEN inhibitors in combination therapy with PARPis to create HRD for HRD-negative ovarian cancers.

Rotationally Invariant Circuits: Universality with the Exchange Interaction and Two Ancilla Qubits.

Universality of local unitary transformations is one of the cornerstones of quantum computing with many applications and implications that go beyond this field. However, it has recently been shown that this universality does not hold in the presence of continuous symmetries: generic symmetric unitaries on a composite system cannot be implemented, even approximately, using local symmetric unitaries on the subsystems. In this Letter, we show that, despite these constraints, any SU(2) rotationally invariant unitary can be realized with the Heisenberg exchange interaction, which is 2-local and rotationally invariant, provided that the system interacts with a pair of ancilla qubits. We also show that a single ancilla is not enough to achieve universality. Furthermore, we study qubit circuits formed from k-local rotationally invariant unitaries and fully characterize the constraints imposed by locality on the realizable unitaries. We also find an interpretation of these constraints in terms of the average energy of states with a fixed angular momentum.

Spatiotemporal Utilization of Latent Heat in Erythritol-based Phase Change Materials as Solar Thermal Fuels.

Solar thermal fuels (STFs) have been particularly concerned as sustainable future energy due to their impressive ability to store solar energy in chemical bonds and controllably release thermal energy. However, currently studied STFs mainly focus on molecule-based materials with high photochemical activity, toxicity, and compromised features, which greatly restricts their applications in practical scenarios of solar energy utilization. Herein, we present a novel erythritol-based composite phase change material (PCM) as a new type of STFs with an outstanding capability to store solar energy as latent heat in its stable supercooling state and release thermal energy as needed. This composite PCM with stored thermal energy can be maintained stably at room temperature and subsequently release latent heat as high as 224.9 J/g during the crystallization process triggered by thermal stimuli. Remarkably, solar energy can be converted into latent heat stored in the composite PCM over months. Through mechanical stimulations, the released latent heat can increase the temperature of the composite up to 91 °C. This work presents a new concept of using spatiotemporal storage and release of latent heat in PCMs for solar energy utilization, making it a potential candidate as STFs for developing future clean energy techniques.

Intrinsically Flexible Phase Change Fibers for Intelligent Thermal Regulation.

Owing to the significant latent heat generated at constant temperatures, phase change fibers (PCFs) have recently received much attention in the field of wearable thermal management. However, the phase change materials involved in the existing PCFs still experience a solid-liquid transition process, severely restricting their practicality as wearable thermal management materials. Herein, we, for the first time, developed intrinsically flexible PCFs (polyethylene glycol/4,4'-methylenebis(cyclohexyl isocyanate) fibers, PMFs) through polycondensation and wet-spinning process, exhibiting an inherent solid-solid phase transition property, adjustable phase transition behaviors, and outstanding knittability. The PMFs also present superior mechanical strength (28 MPa), washability (> 100 cycles), thermal cycling stability (> 2000 cycles), facile dyeability, and heat-induced recoverability, all of which are highly significant for practical wearable applications. Additionally, the PMFs can be easily recycled by directly dissolving them in solvents for reprocessing, revealing promising applications as sustainable materials for thermal management. Most importantly, the applicability of the PMFs was demonstrated by knitting them into permeable fabrics, which exhibit considerably improved thermal management performance compared with the cotton fabric. The PMFs offer great potential for intelligent thermal regulation in smart textiles and wearable electronics.

Combined effects of climate and land-use changes on the alpha and beta functional diversities of terrestrial mammals in China.

Climate and land-use changes are predicted to impact biodiversity, threatening ecosystem services and functions. However, their combined effects on the functional diversity of mammals at the regional scale remain unclear, especially at the beta level. Here, we use projected climate and land-use changes in China to investigate their potential effects on the alpha and beta functional diversities of terrestrial mammals under low- and high-emission scenarios. In the current projection, we showed strong positive spatial correlations between functional richness and species richness. Functional evenness (FEve), functional specialization (FSpe), and functional originality (FOri) decreased with species richness, and functional divergence (FDiv) increased first and then plateaued. Functional beta diversity was dominated by its nestedness component, in contrast to the taxonomic facet. Potential changes in species richness are more strongly influenced by land-use change under the low-emission scenario, while under the high-emission scenario, they are more strongly influenced by climate change. Changes in functional richness (FRic) were inconsistent with those in species richness, with a magnitude of decreases greater than predicted from species richness. Moreover, mammal assemblages showed potential functional differentiation (FD) across the country, and the trends exceeded those towards taxonomic differentiation (TD). Our findings help us understand the processes underlying biodiversity responses to global changes on multiple facets and provide new insight for conservation plans.

Predicting air pollutant emissions of the foundry industry: Based on the electricity big data.

Industrial enterprises are one of the largest sources of air pollution. However, the existing means of monitoring air pollutant emissions are narrow in coverage, high in cost, and low in accuracy. To bridge these gaps, this study explored a predicting model for air pollutant emissions from foundry industries based on high-accuracy electricity consumption data and continuous emission monitoring system (CEMS). The model has then been applied to the calculation of air pollutant emissions from foundries without CEMS and the optimization of air pollutant emission temporal allocation factors. The results reveal that electricity consumption and PM emissions during the 2022 Beijing Winter Olympics have the same ascending and descending relationship. Furthermore, a cubic polynomial model between electricity consumption and flue gas flow is established based on the whole year data of 2021 (R2 = 0.85). The relative errors between the PM emissions calculated by the model and the emission factor method are small (-17.09-24.12 %), and the results from the two methods revealed a strong correlation (r = 0.93, p < 0.01). In addition, the monthly PM emissions from foundries are mainly concentrated in spring and winter, and the daily emissions on weekends are significantly lower than those on workdays. These results can be useful for environmental regulation and optimization of air pollutant emission inventories of foundry industry.

Menin signaling and therapeutic targeting in breast cancer.

To date, mounting evidence have shown that patients with multiple endocrine neoplasia type 1 (MEN1) may face an increased risk for breast carcinogenesis. The product of the MEN1 gene, menin, was also indicated to be an important regulator in breast cancer signaling network. Menin directly interacts with MLL, EZH2, JunD, NF-κB, PPARγ, VDR, Smad3, ß-catenin and ERα to modulate gene transcriptions leading to cell proliferation inhibition. Moreover, interaction of menin-FANCD2 contributes to the enhancement of BRCA1-mediated DNA repair mechanism. Ectopic expression of menin causes Bax-, Bak- and Caspase-8-dependent apoptosis. However, despite numbers of menin inhibitors were exploited in other cancers, data on the usage of menin inhibitors in breast cancer treatment remain limited. In this review, we focused on the menin associated signaling pathways and gene transcription regulations, with the aim of elucidating its molecular mechanisms and of guiding the development of novel menin targeted drugs in breast cancer therapy.

Elasticity-controlled jamming criticality in soft composite solids.

Soft composite solids are made of inclusions dispersed within soft matrices. They are ubiquitous in nature and form the basis of many biological tissues. In the field of materials science, synthetic soft composites are promising candidates for building various engineering devices due to their highly programmable features. However, when the volume fraction of the inclusions increases, predicting the mechanical properties of these materials poses a significant challenge for the classical theories of composite mechanics. The difficulty arises from the inherently disordered, multi-scale interactions between the inclusions and the matrix. To address this challenge, we systematically investigated the mechanics of densely filled soft elastomers containing stiff microspheres. We experimentally demonstrate how the strain-stiffening response of the soft composites is governed by the critical scalings in the vicinity of a shear-jamming transition of the included particles. The proposed criticality framework quantitatively connects the overall mechanics of a soft composite with the elasticity of the matrix and the particles, and captures the diverse mechanical responses observed across a wide range of material parameters. The findings uncover a novel design paradigm of composite mechanics that relies on engineering the jamming properties of the embedded inclusions.

Precision engineering of nano-assemblies in superfluid helium by the use of van der Waals forces.

The ability to precisely engineer nanostructures underpins a wide range of applications in areas such as electronics, optics, and biomedical sciences. Here we present a novel approach for the growth of nanoparticle assemblies that leverages the unique properties of superfluid helium. Unlike viscous solvents at or near room temperature, superfluid helium provides an unperturbed and cold environment in which weak van der Waals interactions between molecular templates and metal atoms become significant and can define the spatial arrangement of nanoparticles. To demonstrate this concept, diol and porphyrin-based molecules are employed as templates to grow gold nanoparticle assemblies in superfluid helium droplets. After soft-landing on a solid surface to remove the helium, transmission electron microscopy (TEM) imaging shows the growth of gold nanoparticles at specific binding sites within the molecular templates where the interaction between gold atoms and the molecular template is at its strongest.

Deubiquitinase UCHL1 stabilizes KDM4B to augment VEGF signaling and confer bevacizumab resistance in clear cell renal cell carcinoma.

BACKGROUND: Bevacizumab resistance poses barriers to targeted therapy in clear cell renal cell carcinoma (ccRCC). Whether there exist epigenetic targets that modulate bevacizumab sensitivity in ccRCC remains indefinite. The focus of this study is to explore the role of UCHL1 in ccRCC. METHODS: Both in vitro and in vivo experiments were utilized to investigate the roles of UCHL1 in ccRCC. In vivo ubiquitination assays were performed to validate the posttranslational modification of KDM4B by UCHL1. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were utilized to explore KDM4B/VEGFA epigenetic regulations. RESULTS: UCHL1 was increased in ccRCC and associated with unfavorable survival outcomes in patients. UCHL1 was required for ccRCC growth and migration. Mechanistically, the wild-type UCHL1, but not C90A mutant, mediated the deubiquitination of KDM4B and thereby stabilized its proteins. KDM4B was up-regulated in ccRCC and potentiated cell growth. UCHL1 depended on KDM4B to augment ccRCC malignancies. Targeting UCHL1 suppressed tumor growth, colony formation, and migration abilities, which could be rescued by KDM4B. Furthermore, KDM4B was directly bound to the promoter region of VEGFA, abolishing repressive H3K9me3 modifications. KDM4B coordinated with HIF2α to activate VEGFA transcriptional levels. UCHL1-KDM4B axis governs VEGFA levels to sustain the angiogenesis phenotypes. Finally, a specific small-molecule inhibitor (6RK73) targeting UCHL1 remarkably inhibited ccRCC progression and further sensitized ccRCC to bevacizumab treatment. CONCLUSION: Overall, this study defined an epigenetic mechanism of UCHL1/KDM4B in activating VEGF signaling. The UCHL1-KDM4B axis represents a novel target for treating ccRCC and improving the efficacy of anti-angiogenesis therapy.

scMeFormer: a transformer-based deep learning model for imputing DNA methylation states in single cells enhances the detection of epigenetic alterations in schizophrenia.

DNA methylation (DNAm), a crucial epigenetic mark, plays a key role in gene regulation, mammalian development, and various human diseases. Single-cell technologies enable the profiling of DNAm states at cytosines within the DNA sequence of individual cells, but they often suffer from limited coverage of CpG sites. In this study, we introduce scMeFormer, a transformer-based deep learning model designed to impute DNAm states for each CpG site in single cells. Through comprehensive evaluations, we demonstrate the superior performance of scMeFormer compared to alternative models across four single-nucleus DNAm datasets generated by distinct technologies. Remarkably, scMeFormer exhibits high-fidelity imputation, even when dealing with significantly reduced coverage, as low as 10% of the original CpG sites. Furthermore, we applied scMeFormer to a single-nucleus DNAm dataset generated from the prefrontal cortex of four schizophrenia patients and four neurotypical controls. This enabled the identification of thousands of differentially methylated regions associated with schizophrenia that would have remained undetectable without imputation and added granularity to our understanding of epigenetic alterations in schizophrenia within specific cell types. Our study highlights the power of deep learning in imputing DNAm states in single cells, and we expect scMeFormer to be a valuable tool for single-cell DNAm studies.

Cell-type-specific effects of age and sex on human cortical neurons.

Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes with advanced age. Using single-nucleus multi-omic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex from young adult and aged donors, we found widespread age- and sex-related variation in specific neuron types. The proportion of inhibitory SST- and VIP-expressing neurons was reduced in aged donors. Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells. Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in aged adults. Genes located in subtelomeric regions increased their expression with age and correlated with reduced telomere length. We further mapped cell-type-specific sex differences in gene expression and X-inactivation escape genes. Multi-omic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.

Cell type-specific enrichment of somatic aneuploidy in the mammalian brain.

Somatic mutations alter the genomes of a subset of an individual's brain cells1-3, impacting gene regulation and contributing to disease processes4,5. Mosaic single nucleotide variants have been characterized with single-cell resolution in the brain2,3, but we have limited information about large-scale structural variation, including whole-chromosome duplication or loss1,6,7. We used a dataset of over 415,000 single-cell DNA methylation and chromatin conformation profiles across the adult mouse brain to identify aneuploid cells comprehensively. Whole-chromosome loss or duplication occurred in <1% of cells, with rates up to 1.8% in non-neuronal cell types, including oligodendrocyte precursors and pericytes. Among all aneuploidies, we observed a strong enrichment of trisomy on chromosome 16, which is syntenic with human chromosome 21 and constitutively trisomic in Down syndrome. Chromosome 16 trisomy occurred in multiple cell types and across brain regions, suggesting that nondisjunction is a recurrent feature of somatic variation in the brain.

The relationship between behavior isotemporal substitution and depression among vocational school students with different moderate-to-vigorous physical activity durations / 中国学校卫生

Objective@#To explore the relationship between isotemporal substitution of 10 min/d of vigorous physical activity (VPA), moderate physical activity (MPA), walking, sedentary behavior (SB) and sleep (SLP) and depression among vocational school students with different duration of moderate-to-vigorous physical activity (MVPA), so as to provide time allocation suggestions for reducing depression levels.@*Methods@#The convenient cluster sampling method was adopted to conduct a questionnaire survey among 8 149 grade one to grade three students in 14 vocational schools in Shanghai and Jiangsu Province from December 2021 to January 2022. According to whether the MVPA reached 60 min/d, the vocational school students were divided into the MVPA standard group and the MVPA non-standard group, and the isotemporal substitution model was used for analysis.@*Results@#About 19.81% of students were in the MVPA standard group. In the MVPA non-standard group, substituting MPA for all other studied behaviors and substituting SLP for walking and SB were negatively correlated with depression ( β =-0.78, -0.90, -0.88, -0.83; -0.07 , -0.05, P <0.05), and the association of MPA substitution was much greater than that of SLP substitution. In the MVPA standard group, replacing VPA, walking and SB with SLP were all negatively associated with depression ( β =-0.23, -0.12, -0.10 ), whereas replacing MPA, SB and SLP with VPA was all positively associated with depression ( β =0.15, 0.13, 0.23) ( P <0.05).@*Conclusion@#The MVPA level of vocational school students is low. The effects of isotemporal substitution for VPA and MPA are different when MVPA duration is up to standard and when MVPA duration is not up to standard. Appropriate time allocation suggestions should be provided based on the characteristics of adolescents with different MVPA durations.

Construction of nutrition health educational guidance outline for primary and secondary school students in Shanghai / 中国学校卫生

Objective@#Develop a nutrition health educational guidance outline for primary and secondary school students which is adapted to the characteristics of Shanghai and meets the cognitive level of students at different levels, so as to provide a reference for planning the content and target of nutrition health education among students of different school stages.@*Methods@#Through literature search and qualitative interviews, the framework of nutrition health education for primary and secondary school students in Shanghai was developed, and 21 experts in the fields of nutrition, school health and health education were invitied to conduct a Delphi consultation, and determined the content of nutrition and health education for students in each school section based on the consultation results.@*Results@#The recall rate for both rounds of consultation was 100%, the degree of expert authority was 0.74 and 0.89 , and the coordination coefficients were 0.31 and 0.33( P <0.01), suggesting high credibility of expert opinion. The resulting guidance outline included 2 first level entries, 6 second level entries, 60 third level entries and corresponding entry explanations. The 2 first level entries were rational nutrition and food safety; the 6 second level entries were food and nutrients, balanced diet, good eating habits, nutritional practices, good hygiene habits and food borne diseases; the 60 third level entries needed to be studied in Level 1 were 24, Level 2 were 41, Level 3 were 55, and Level 4 were 59.@*Conclusion@#The nutrition health educational guidance outline for primary and secondary school students in Shanghai developed in this study focuses on key nutrition knowledge, rational dietary behaviors and nutrition practice skills, which can provide a reference and basis for the phased implementation of nutrition health education in primary and secondary schools.

Development of Index System for Assessing Parent s Ability on Child Injury Prevention by Delphi consultation / 中国学校卫生

Objective@#To construct and determine the weight of Index System for Assessing Parent s Ability on Child Injury Prevention, and to provide the basis for childhood injury intervention in family.@*Methods@#Twenty four experts majored in related fields were invited to participate in Delphi consultation. The final index system was constructed according to the consulting results and the weight of primary and secondary indicators were calculated.@*Results@#The final index system consisted of 5 subscales corresponding to 5 age groups: 0,1-2,3-5,6-11 and 12-17 years old. Each scale included 4 primary indicators and 11 secondary indicators. The weight of primary indicators obtained by analytic hierarchy process is 0.28 for "environment", 0.16 for "product", 0.31 for "behaviors and skills", and 0.25 for "psychology". The highest weight of secondary indicators for "environment", "product" and "behaviors and skills" was "water area", while the top secondary indicators for "psychology" included "parental style""emotional control" "family atmosphere", with all indicators weighted higher than 0.2.@*Conclusion@#The Index System for Assessing Parent s Ability on Child Injury Prevention by Delphi consultation is comprehensive in content, and with the focus on parental behaviors and skills on injury prevention.