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Background Although immune checkpoint inhibitor (ICI) is regarded as a breakthrough in cancer therapy, only a limited fraction of patients benefit from it. Cancer stemness can be the potential culprit in ICI resistance, but direct clinical evidence is lacking. Methods Publicly available scRNA-Seq datasets derived from ICI-treated patients were collected and analyzed to elucidate the association between cancer stemness and ICI response. A novel stemness signature (Stem.Sig) was developed and validated using large-scale pan-cancer data, including 34 scRNA-Seq datasets, The Cancer Genome Atlas (TCGA) pan-cancer cohort, and 10 ICI transcriptomic cohorts. The therapeutic value of Stem.Sig genes was further explored using 17 CRISPR datasets that screened potential immunotherapy targets. Results Cancer stemness, as evaluated by CytoTRACE, was found to be significantly associated with ICI resistance in melanoma and basal cell carcinoma (both P < 0.001). Significantly negative association was found between Stem.Sig and anti-tumor immunity, while positive correlations were detected between Stem.Sig and intra-tumoral heterogenicity (ITH) / total mutational burden (TMB). Based on this signature, machine learning model predicted ICI response with an AUC of 0.71 in both validation and testing set. Remarkably, compared with previous well-established signatures, Stem.Sig achieved better predictive performance across multiple cancers. Moreover, we generated a gene list ranked by the average effect of each gene to enhance tumor immune response after genetic knockout across different CRISPR datasets. Then we matched Stem.Sig to this gene list and found Stem.Sig significantly enriched 3% top-ranked genes from the list ( P = 0.03), including EMC3, BECN1, VPS35, PCBP2, VPS29, PSMF1, GCLC, KXD1, SPRR1B, PTMA, YBX1, CYP27B1, NACA, PPP1CA, TCEB2, PIGC, NR0B2, PEX13, SERF2, and ZBTB43, which were potential therapeutic targets. Conclusions We revealed a robust link between cancer stemness and immunotherapy resistance and developed a promising signature, Stem.Sig, which showed increased performance in comparison to other signatures regarding ICI response prediction. This signature could serve as a competitive tool for patient selection of immunotherapy. Meanwhile, our study potentially paves the way for overcoming immune resistance by targeting stemness-associated genes.

Ultracold polar molecules offer strong electric dipole moments and rich internal structure, which makes them ideal building blocks to explore exotic quantum matter 1 – 9 , implement quantum information schemes 10 – 12 and test the fundamental symmetries of nature 13 . Realizing their full potential requires cooling interacting molecular gases deeply into the quantum-degenerate regime. However, the intrinsically unstable collisions between molecules at short range have so far prevented direct cooling through elastic collisions to quantum degeneracy in three dimensions. Here we demonstrate evaporative cooling of a three-dimensional gas of fermionic sodium–potassium molecules to well below the Fermi temperature using microwave shielding. The molecules are protected from reaching short range with a repulsive barrier engineered by coupling rotational states with a blue-detuned circularly polarized microwave. The microwave dressing induces strong tunable dipolar interactions between the molecules, leading to high elastic collision rates that can exceed the inelastic ones by at least a factor of 460. This large elastic-to-inelastic collision ratio allows us to cool the molecular gas to 21 nanokelvin, corresponding to 0.36 times the Fermi temperature. Such cold and dense samples of polar molecules open the path to the exploration of many-body phenomena with strong dipolar interactions. A general and efficient approach to evaporatively cool ultracold polar molecules through elastic collisions to create a degenerate quantum gas in three dimensions is demonstrated using microwave shielding.

There is a debate in the literature about the relationship between green innovation, environmental management, environmental performance, and the value of a firm. Herein, the effects of green innovation and environmental management on environmental performance are analysed using a stochastic frontier model for energy-intensive listed companies from 2011 to 2017; the effects thereof on the value of a firm are assessed empirically. The results show that green innovation and environmental management have a positive effect on corporate environmental performance, and green innovation plays a complete mediating role between environmental management and environmental performance. The significant positive effect of green innovation on value of a firm confirms Porter’s hypothesis, but the positive effect of environmental management on value of a firm is not verified. Finally, recommendations that are aimed at improving corporate environmental performance are given.

Background Long noncoding RNAs (lncRNAs) play nonnegligible roles in the epigenetic regulation of cancer cells. This study aimed to identify a specific lncRNA that promotes the colorectal cancer (CRC) progression and could be a potential therapeutic target. Methods We screened highly expressed lncRNAs in human CRC samples compared with their matched adjacent normal tissues. The proteins that interact with LINRIS (Long Intergenic Noncoding RNA for IGF2BP2 Stability) were confirmed by RNA pull-down and RNA immunoprecipitation (RIP) assays. The proliferation and metabolic alteration of CRC cells with LINRIS inhibited were tested in vitro and in vivo . Results LINRIS was upregulated in CRC tissues from patients with poor overall survival (OS), and LINRIS inhibition led to the impaired CRC cell line growth. Moreover, knockdown of LINRIS resulted in a decreased level of insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a newly found N 6 -methyladenosine (m 6 A) ‘reader’. LINRIS blocked K139 ubiquitination of IGF2BP2, maintaining its stability. This process prevented the degradation of IGF2BP2 through the autophagy-lysosome pathway (ALP). Therefore, knockdown of LINRIS attenuated the downstream effects of IGF2BP2, especially MYC-mediated glycolysis in CRC cells. In addition, the transcription of LINRIS could be inhibited by GATA3 in CRC cells. In vivo experiments showed that the inhibition of LINRIS suppressed the proliferation of tumors in orthotopic models and in patient-derived xenograft (PDX) models. Conclusion LINRIS is an independent prognostic biomarker for CRC. The LINRIS -IGF2BP2-MYC axis promotes the progression of CRC and is a promising therapeutic target.

The interplay of quantum statistics and interactions in atomic Bose–Fermi mixtures leads to a phase diagram markedly different from pure fermionic or bosonic systems. However, investigating this phase diagram remains challenging when bosons condense due to the resulting fast interspecies loss. Here we report observations consistent with a phase transition from a polaronic to a molecular phase in a density-matched degenerate Bose–Fermi mixture. The condensate fraction, representing the order parameter of the transition, is depleted by interactions, and the build-up of strong correlations results in the emergence of a molecular Fermi gas. The features of the underlying quantum phase transition represent a new phenomenon complementary to the paradigmatic Bose–Einstein condensate/Bardeen–Cooper–Schrieffer crossover observed in Fermi systems. By driving the system through the transition, we produce a sample of sodium–potassium molecules exhibiting a large molecule-frame dipole moment in the quantum-degenerate regime.Tuning interspecies interactions in atomic Bose–Fermi mixtures is shown to drive the system through a quantum phase transition. This enables the generation of heteronuclear molecules in the quantum-degenerate regime.

In the twentieth century, China underwent huge social transformations, probably with equally great changes in education. Under the influence of the influx of Western learning in this period, traditional education models were challenged, and new schools, together with new educational concepts, started to come into being. Inside this process, the roles and images of intellectuals changed a lot as keen observers and active participants in social change. The paper compares two representative figures, Mr. Zhu from White Deer Plain and Ni Huanzhi from Ni Huanzhi , in efforts to comprehend the intellectuals in their various roles within the context of contemporary Chinese educational reforms. Mr. Zhu was a protector and promoter of traditional culture and thoughts, while Ni Huanzhi was an advocate for new cultures and ideas. Their divergent paths, and different roles in society, have been carved out by different life experiences. This paper also explores differences in positions in educational reforms, contributions toward educational progress, and strategies in the face of social changes. The significance of these preceding analyses is to assess their historical value with a view to drawing reflective lessons and insights that would enlighten contemporary educators.

Scattering resonances are an essential tool for controlling the interactions of ultracold atoms and molecules. However, conventional Feshbach scattering resonances 1 , which have been extensively studied in various platforms 1 – 7 , are not expected to exist in most ultracold polar molecules because of the fast loss that occurs when two molecules approach at a close distance 8 – 10 . Here we demonstrate a new type of scattering resonance that is universal for a wide range of polar molecules. The so-called field-linked resonances 11 – 14 occur in the scattering of microwave-dressed molecules because of stable macroscopic tetramer states in the intermolecular potential. We identify two resonances between ultracold ground-state sodium–potassium molecules and use the microwave frequencies and polarizations to tune the inelastic collision rate by three orders of magnitude, from the unitary limit to well below the universal regime. The field-linked resonance provides a tuning knob to independently control the elastic contact interaction and the dipole–dipole interaction, which we observe as a modification in the thermalization rate. Our result provides a general strategy for resonant scattering between ultracold polar molecules, which paves the way for realizing dipolar superfluids 15 and molecular supersolids 16 , as well as assembling ultracold polyatomic molecules. A type of universal scattering resonance between ultracold microwave-dressed polar molecules associated with field-linked tetramer bound states in the long-range potential well is observed, providing a general strategy for resonant scattering between ultracold polar molecules.

Inducing cancer differentiation is a promising approach to treat cancer. Here, we identified chlorogenic acid (CA), a potential differentiation inducer, for cancer therapy, and elucidated the molecular mechanisms underlying its differentiation-inducing effects on cancer cells. Cancer cell differentiation was investigated by measuring malignant behavior, including growth rate, invasion/migration, morphological change, maturation, and ATP production. Gene expression was analyzed by microarray analysis, qRT-PCR, and protein measurement, and molecular biology techniques were employed for mechanistic studies. LC/MS analysis was the method of choice for chemical detection. Finally, the anticancer effect of CA was evaluated both and Results: Cancer cells treated with CA showed reduced proliferation rate, migration/invasion ability, and mitochondrial ATP production. Treating cancer cells with CA resulted in elevated SUMO1 expression through acting on its 3'UTR and stabilizing the mRNA. The increased SUMO1 caused c-Myc sumoylation, miR-17 family downregulation, and p21 upregulation leading to G /G arrest and maturation phenotype. CA altered the expression of differentiation-related genes in cancer cells but not in normal cells. It inhibited hepatoma and lung cancer growth in tumor-bearing mice and prevented new tumor development in naïve mice. In glioma cells, CA increased expression of specific differentiation biomarkers Tuj1 and GFAP inducing differentiation and reducing sphere formation. The therapeutic efficacy of CA in glioma cells was comparable to that of temozolomide. CA was detectable both in the blood and brain when administered intraperitoneally in animals. Most importantly, CA was safe even at very high doses. CA might be a safe and effective differentiation-inducer for cancer therapy. \"Educating\" cancer cells to differentiate, rather than killing them, could be a novel therapeutic strategy for cancer.

Penicillium oxalicum k10 isolated from soil revealed the hydrolyzing ability of shrimp chitin and antifungal activity against Sclerotinia sclerotiorum. The k10 chitinase was produced from a powder chitin-containing medium and purified by ammonium sulfate precipitation and column chromatography. The purified chitinase showed maximal activity toward colloidal chitin at pH 5 and 40 °C. The enzymatic activity was enhanced by potassium and zinc, and it was inhibited by silver, iron, and copper. The chitinase could convert colloidal chitin to N-acetylglucosamine (GlcNAc), (GlcNAc)2, and (GlcNAc)3, showing that this enzyme had endocleavage and exocleavage activities. In addition, the chitinase prevented the mycelial growth of the phytopathogenic fungi S. sclerotiorum and Mucor circinelloides. These results indicate that k10 is a potential candidate for producing chitinase that could be useful for generating chitooligosaccharides from chitinous waste and functions as a fungicide.