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Hederacoside C (HSC) has attracted much attention as a novel modulator of inflammation, but its anti-inflammatory mechanism remains elusive. In the present study, we investigated how HSC attenuated intestinal inflammation in vivo and in vitro. HSC injection significantly alleviated TNBS-induced colitis by inhibiting pro-inflammatory cytokine production and colonic epithelial cell apoptosis, and partially restored colonic epithelial cell proliferation. The therapeutic effect of HSC injection was comparable to that of oral administration of mesalazine (200 mg·kg

Neddylation is a sequential enzyme-based process which regulates the function of E3 Cullin-RING ligase (CRL) and thus degradation of substrate proteins. Here we show that CD8+ T cells are a direct target for therapeutically relevant anti-lymphoma activity of pevonedistat, a Nedd8-activating enzyme (NAE) inhibitor. Pevonedistat-treated patient-derived CD8+ T cells upregulated TNFα and IFNγ and exhibited enhanced cytotoxicity. Pevonedistat induced CD8+ T-cell inflamed microenvironment and delayed tumor progression in A20 syngeneic lymphoma model. This anti-tumor effect lessened when CD8+ T cells lost the ability to engage tumors through MHC class I interactions, achieved either through CD8+ T-cell depletion or genetic knockout of B2M. Meanwhile, loss of UBE2M in tumor did not alter efficacy of pevonedistat. Concurrent blockade of NAE and PD-1 led to enhanced tumor immune infiltration, T-cell activation and chemokine expression and synergistically restricted tumor growth. shRNA-mediated knockdown of HIF-1α, a CRL substrate, abrogated the in vitro effects of pevonedistat, suggesting that NAE inhibition modulates T-cell function in HIF-1α-dependent manner. scRNA-Seq-based clinical analyses in lymphoma patients receiving pevonedistat therapy demonstrated upregulation of interferon response signatures in immune cells. Thus, targeting NAE enhances the inflammatory T-cell state, providing rationale for checkpoint blockade-based combination therapy.

Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.

KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available KRAS-G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of KRAS-G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing KRAS-G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a “quasi-triad plane” that stacks over the two external G-tetrads. The binding involves both π-stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the KRAS mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with KRAS-G4 and is beneficial for the design of specific KRAS-G4-interactive drugs.

Nephropathy is a chronic complication of diabetes which lacks an effective treatment. “Baitouweng,” a traditional Chinese medicinal herb, is the root of Anemone chinensis Bunge, Ranunculaceae, and is used for its antidiabetes properties. However, the mechanism by which it exerts its effects has not been fully elucidated. Anemoside B4 is the most abundant triterpenoid saponin in this plant with anti-inflammatory and anti-apoptosis activities. This study aimed to investigate the therapeutic effect of anemoside B4 on diabetic nephropathy and elucidate the underlying mechanism. Our data showed that anemoside B4 did not affect the proliferation of mesangial cells, but it could significantly inhibit the proliferation induced by high glucose. Mechanistically, anemoside B4 decreased the content of reactive oxygen species and improved glutathione and catalase activity. Also, the activation of the MAPK and NF-κB signaling pathway was inhibited. Therefore, anemoside B4 has a protective activity against diabetic nephropathy with the characteristics of having high safety, low toxicity, and high solubility.

Empirical-likelihood-based inference for parameters defined by the general estimating equations of Qin and Lawless (1994) remains an active research topic. When the response is missing at random (MAR) and the dimension of covariate is not low, the authors propose a two-stage estimation procedure by using the dimension-reduced kernel estimators in conjunction with an unbiased estimating function based on augmented inverse probability weighting and multiple imputation (AIPW-MI) methods. The authors show that the resulting estimator achieves consistency and asymptotic normality. In addition, the corresponding empirical likelihood ratio statistics asymptotically follow central chi-square distributions when evaluated at the true parameter. The finite-sample performance of the proposed estimator is studied through simulation, and an application to HIV-CD4 data set is also presented.

Young women’s breast cancer (YWBC) has poor prognosis and known interactions with parity. Women diagnosed within 5–10 years of childbirth, defined as postpartum breast cancer (PPBC), have poorer prognosis compared to age, stage, and biologic subtype-matched nulliparous patients. Genomic differences that explain this poor prognosis remain unknown. In this study, using RNA expression data from clinically matched estrogen receptor positive (ER+) cases (n = 16), we observe that ER+ YWBC can be differentiated based on a postpartum or nulliparous diagnosis. The gene expression signatures of PPBC are consistent with increased cell cycle, T-cell activation and reduced estrogen receptor and TP53 signaling. When applied to a large YWBC cohort, these signatures for ER+ PPBC associate with significantly reduced 15-year survival rates in high compared to low expressing cases. Cumulatively these results provide evidence that PPBC is a unique entity within YWBC with poor prognostic phenotypes., The molecular differences between postpartum (PPBC) and nulliparous (NPBC) young women breast cancer (YWBC) patients remain unknown. Here the authors perform RNA sequencing and multiplex immunohistochemistry on an FFPE breast cancer cohort and suggest that PPBC is a unique entity within YWBC with poor prognosis.

BET bromodomain inhibitors block prostate cancer cell growth at least in part through c-Myc and androgen receptor (AR) suppression. However, little is known about other transcriptional regulators whose suppression contributes to BET bromodomain inhibitor anti-tumor activity. Moreover, the anti-tumor activity of BET bromodomain inhibition in AR-independent castration-resistant prostate cancers (CRPC), whose frequency is increasing, is also unknown. Herein, we demonstrate that BET bromodomain inhibition blocks growth of a diverse set of CRPC cell models, including those that are AR-independent or in which c-Myc is not suppressed. To identify transcriptional regulators whose suppression accounts for these effects, we treated multiple CRPC cell lines with the BET bromodomain inhibitor JQ1 and then performed RNA-sequencing followed by Master Regulator computational analysis. This approach identified several previously unappreciated transcriptional regulators that are highly expressed in CRPC and whose suppression, via both transcriptional or post-translational mechanisms, contributes to the anti-tumor activity of BET bromodomain inhibitors.

Titania nanowires (TiO2-NW) with tunable aspect ratios and morphologies were directly synthesized using a simple alcohol-thermal technique. Specifically, ethanol and acetic acid were used as solvents and lithium ion was used as the capping agent to promote the conversion of titanium butoxide into TiO2-NW. The morphologies and crystal phases of TiO2-NW were determined by the molar ratio of solvents and the content (mol%) of lithium ion. The band gap of TiO2-NW with pure anatase phase is slightly bigger than that of TiO2-NW with a mixture of anatase and rutile phases. All TiO2-NW could achieve effective decolorization of methyl blue (the decolorization rate is over 95%) after 35-min ultraviolet (UV) irradiation.

Alternative polyadenylation (APA) has emerged as a prevalent feature associated with cancer development and progression. The advantage of APA to tumor progression is to induce oncogenes through 3'-UTR shortening, and to inactivate tumor suppressor genes via the re-routing of microRNA competition. We previously identified the Mammalian Cleavage Factor I-25 (CFIm25) (encoded by Nudt21 gene) as a master APA regulator whose expression levels directly impact the tumorigenicity of glioblastoma (GBM) in vitro and in vivo. Despite its importance, the role of Nudt21 in GBM development is not known and the genes subject to Nudt21 APA regulation that contribute to GBM progression have not been identified. Here, we find that Nudt21 is reduced in low grade glioma (LGG) and all four subtypes of high grade glioma (GBM). Reduced expression of Nudt21 associates with worse survival in TCGA LGG cohorts and two TCGA GBM cohorts. Moreover, although CFIm25 was initially identified as biochemically associated with both CFIm59 and CFIm68, we observed three CFIm distinct subcomplexes exist and CFIm59 protein level is dependent on Nudt21 expression in GBM cells, but CFIm68 is not, and that only CFIm59 predicts prognosis of GBM patients similar to Nudt21. Through the use of Poly(A)-Click-Seq to characterize APA, we define the mRNAs subject to 3'-UTR shortening upon Nudt21 depletion in GBM cells and observed enrichment in genes important in the Ras signaling pathway, including Pak1. Remarkably, we find that Pak1 expression is regulated by Nudt21 through its 3'-UTR APA, and the combination of Pak1 and Nudt21 expression generates an even stronger prognostic indicator of GBM survival versus either value used alone. Collectively, our data uncover Nudt21 and its downstream target Pak1 as a potential "combination biomarker" for predicting prognosis of GBM patients.

Measurement device-independent quantum key distribution (MDI-QKD) protocols are immune to all possible attacks on the photon detectors during quantum communication, but their key generation rates are low compared with those of other QKD schemes. Increasing each individual photons channel capacity is an efficient way to increase the key generation rate, and high-dimensional (HD) encoding is a powerful tool for increasing the channel capacity of photons. In this paper, we propose an HD MDI-QKD protocol with qudits hyper-encoded in spatial mode and polarization degrees of freedom (DOFs). In the proposed protocol, keys can be generated using the spatial mode and polarization DOFs simultaneously. The proposed protocol is unconditionally secure, even for weak coherent pulses with decoy states. The proposed MDI-QKD protocol may be useful for future quantum secure communication applications.

We present a highly scalable assay for whole-genome methylation profiling of single cells. We use our approach, single-cell combinatorial indexing for methylation analysis (sci-MET), to produce 3,282 single-cell bisulfite sequencing libraries and achieve read alignment rates of 68 ± 8%. We apply sci-MET to discriminate the cellular identity of a mixture of three human cell lines and to identify excitatory and inhibitory neuronal populations from mouse cortical tissue.

Ramie is an important fiber and forage crop in China. Breeding of late- or non-flowering varieties with higher vegetative yields is an important goal because this high yield is required for ramie production for both fiber and feed use. However, the genetic basis for the flowering time trait is poorly understood, and this has severely hindered the improvement of this trait in ramie breeding. In our previous study, a genetic linkage map has been constructed based on an F2 agamous line (FAL) population derived from two parents, Qingyezhuma and Zhongzhu 1. In this study, four traits, i.e., days from sprouting to the appearance of male flower buds (DSAMB), days from sprouting to male flowering (DSMF), days from sprouting to the appearance of female flower buds, and days from sprouting to female flowering (DSFF), were investigated in this FAL population. Significant difference between two parents and large variation in FALs was observed for these four traits. The analysis of quantitative trait locus (QTL) for these four flowering time traits was performed in ramie for the first time. Finally, a total of 7, 5, 10, and 7 QTLs for DSAMB, DSMF, DSAFB, and DSFF, respectively, were identified in the FAL population in 2 years. Of these 29 QTLs, 15 were detected in both years, and 16 QTLs exhibited overdominance. Moreover, 11 QTL clusters were identified. The identification of these QTLs will be helpful for molecular designing of the flowering time traits in ramie breeding programs by marker-assisted selection.