Distinct transcription factor networks control neutrophil-driven inflammation.

Neutrophils display distinct gene expression patters depending on their developmental stage, activation state and tissue microenvironment. To determine the transcription factor networks that shape these responses in a mouse model, we integrated transcriptional and chromatin analyses of neutrophils during acute inflammation. We showed active chromatin remodeling at two transition stages: bone marrow-to-blood and blood-to-tissue. Analysis of differentially accessible regions revealed distinct sets of putative transcription factors associated with control of neutrophil inflammatory responses. Using ex vivo and in vivo approaches, we confirmed that RUNX1 and KLF6 modulate neutrophil maturation, whereas RELB, IRF5 and JUNB drive neutrophil effector responses and RFX2 and RELB promote survival. Interfering with neutrophil activation by targeting one of these factors, JUNB, reduced pathological inflammation in a mouse model of myocardial infarction. Therefore, our study represents a blueprint for transcriptional control of neutrophil responses in acute inflammation and opens possibilities for stage-specific therapeutic modulation of neutrophil function in disease.

EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer.

The transformation of lung adenocarcinoma to small cell lung cancer (SCLC) is a recognized resistance mechanism and a hindrance to therapies using epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). The paucity of pretranslational/posttranslational clinical samples limits the deeper understanding of resistance mechanisms and the exploration of effective therapeutic strategies. Here, we developed preclinical neuroendocrine (NE) transformation models. Next, we identified a transcriptional reprogramming mechanism that drives resistance to erlotinib in NE transformation cell lines and cell-derived xenograft mice. We observed the enhanced expression of genes involved in the EHMT2 and WNT/ß-catenin pathways. In addition, we demonstrated that EHMT2 increases methylation of the SFRP1 promoter region to reduce SFRP1 expression, followed by activation of the WNT/ß-catenin pathway and TKI-mediated NE transformation. Notably, the similar expression alterations of EHMT2 and SFRP1 were observed in transformed SCLC samples obtained from clinical patients. Importantly, suppression of EHMT2 with selective inhibitors restored the sensitivity of NE transformation cell lines to erlotinib and delayed resistance in cell-derived xenograft mice. We identify a transcriptional reprogramming process in NE transformation and provide a potential therapeutic target for overcoming resistance to erlotinib.

To Build by Destruction.

In this issue of Molecular Cell, Weith et al. (2018) demonstrate that p97, together with a SEP adaptor, can catalyze ordered subunit exchange to facilitate the biogenesis of protein phosphatase-1 (PP1) holoenzyme, establishing a novel ubiquitin-independent "segregase" function for this versatile ATPase.

Transcription factor SlWRKY50 enhances cold tolerance in tomato by activating the jasmonic acid signaling.

Tomato (Solanum lycopersicum) is a cold-sensitive crop but frequently experiences low-temperature stimuli. However, tomato responses to cold stress are still poorly understood. Our previous studies have shown that using wild tomato (Solanum habrochaites) as rootstock can significantly enhance the cold resistance of grafted seedlings, in which a high concentration of jasmonic acids (JAs) in scions exerts an important role, but the mechanism of JA accumulation remains unclear. Herein, we discovered that tomato SlWRKY50, a Group II WRKY transcription factor that is cold inducible, responds to cold stimuli and plays a key role in JA biosynthesis. SlWRKY50 directly bound to the promoter of tomato allene oxide synthase gene (SlAOS), and overexpressing SlWRKY50 improved tomato chilling resistance, which led to higher levels of Fv/Fm, antioxidative enzymes, SlAOS expression, and JA accumulation. SlWRKY50-silenced plants, however, exhibited an opposite trend. Moreover, diethyldithiocarbamate acid (a JA biosynthesis inhibitor) foliar treatment drastically reduced the cold tolerance of SlWRKY50-overexpression plants to wild-type levels. Importantly, SlMYC2, the key regulator of the JA signaling pathway, can control SlWRKY50 expression. Overall, our research indicates that SlWRKY50 promotes cold tolerance by controlling JA biosynthesis and that JA signaling mediates SlWRKY50 expression via transcriptional activation by SlMYC2. Thus, this contributes to the genetic knowledge necessary for developing cold-resistant tomato varieties.

Vasorin promotes endothelial differentiation of glioma stem cells via stimulating the transcription of VEGFR2.

Gliomas are highly vascularized malignancies, but current anti-angiogenic treatments have not demonstrated practical improvements in patient survival. Studies have suggested that glioma-derived endothelial cell (GdEC) formed by glioma stem cell (GSC) differentiation may contribute to the failure of this treatment. However, the molecular mechanisms involved in GSC endothelial differentiation remain poorly understood. We previously reported that vasorin (VASN) is highly expressed in glioma and promotes angiogenesis. Here, we show that VASN expression positively correlates with GdEC signatures in glioma patients. VASN promotes the endothelial differentiation capacity of GSC in vitro and participates in the formation of GSC-derived vessels in vivo. Mechanistically, vascular endothelial growth factor receptor 2 (VEGFR2) is a critical factor that mediates the regulation of VASN on GSC endothelial differentiation. Separation of cell chromatin fractionation and chromatin immunoprecipitation-sequencing analysis show that VASN interacts with Notch1 and co-translocates into the cell nuclei, where VASN binds to the VEGFR2 gene promoter to stimulate its transcription during the progression of GSC differentiation into GdEC. Together, these findings elucidate the role and mechanisms of VASN in promoting the endothelial differentiation of GSC and suggest VASN as a potential target for anti-angiogenic therapy based on intervention in GdEC formation in gliomas.

Correction: Bacterial recognition by PGRP-SA and downstream signalling by Toll/DIF sustain commensal gut bacteria in Drosophila.

[This corrects the article DOI: 10.1371/journal.pgen.1009992.].

Bacterial recognition by PGRP-SA and downstream signalling by Toll/DIF sustain commensal gut bacteria in Drosophila.

The gut sets the immune and metabolic parameters for the survival of commensal bacteria. We report that in Drosophila, deficiency in bacterial recognition upstream of Toll/NF-κB signalling resulted in reduced density and diversity of gut bacteria. Translational regulation factor 4E-BP, a transcriptional target of Toll/NF-κB, mediated this host-bacteriome interaction. In healthy flies, Toll activated 4E-BP, which enabled fat catabolism, which resulted in sustaining of the bacteriome. The presence of gut bacteria kept Toll signalling activity thus ensuring the feedback loop of their own preservation. When Toll activity was absent, TOR-mediated suppression of 4E-BP made fat resources inaccessible and this correlated with loss of intestinal bacterial density. This could be overcome by genetic or pharmacological inhibition of TOR, which restored bacterial density. Our results give insights into how an animal integrates immune sensing and metabolism to maintain indigenous bacteria in a healthy gut.

KDM1A, a potent and selective target, for the treatment of DNMT3A-deficient non-small cell lung cancer.

BACKGROUND: DNMT3A is a crucial epigenetic regulation enzyme. However, due to its heterogeneous nature and frequent mutation in various cancers, the role of DNMT3A remains controversial. Here, we determine the role of DNMT3A in non-small cell lung cancer (NSCLC) to identify potential treatment strategies. METHODS: To investigate the role of loss-of-function mutations of DNMT3A in NSCLC, CRISPR/Cas9 was used to induce DNMT3A-inactivating mutations. Epigenetic inhibitor library was screened to find the synthetic lethal partner of DNMT3A. Both pharmacological inhibitors and gene manipulation were used to evaluate the synthetic lethal efficacy of DNMT3A/KDM1A in vitro and in vivo. Lastly, MS-PCR, ChIP-qPCR, dual luciferase reporter gene assay and clinical sample analysis were applied to elucidate the regulation mechanism of synthetic lethal interaction. RESULTS: We identified DNMT3A is a tumour suppressor gene in NSCLC and KDM1A as a synthetic lethal partner of DNMT3A deletion. Both chemical KDM1A inhibitors and gene manipulation can selectively reduce the viability of DNMT3A-KO cells through inducing cell apoptosis in vitro and in vivo. We clarified that the synthetic lethality is not only limited to the death mode, but also involved into tumour metastasis. Mechanistically, DNMT3A deficiency induces KDM1A upregulation through reducing the methylation status of the KDM1A promoter and analysis of clinical samples indicated that DNMT3A expression was negatively correlated with KDM1A level. CONCLUSION: Our results provide new insight into the role of DNMT3A in NSCLC and elucidate the mechanism of synthetic lethal interaction between KDM1A and DNMT3A, which might represent a promising approach for treating patients with DNMT3A-deficient tumours.

Direct Observation of Z-Scheme Route in Cu31 S16 /Znx Cd1-x S Heteronanoplates for Highly Efficient Photocatalytic Hydrogen Evolution.

Although photocatalytic hydrogen production from water holds great potential as a renewable and sustainable energy alternative, the practical application of the technology demands cost-effective, simple photocatalytic systems with high efficiency in hydrogen evolution reaction (HER). Herein, the synthesis and characterization of Cu31 S16 /Znx Cd1-x S heterostructured nanoplates (Cu31 S16 /ZnCdS HNPs) as a high photocatalytic system are reported. The cost-effective, hierarchical structures are easily prepared using the Cu31 S16 NPs as the seed by the epitaxial growth of the ZnCdS nanocrystals (NCs). The Cu31 S16 /ZnCdS without the noble metal cocatalyst exhibits a high HER rate of 61.7 mmol g-1  h-1 , which is 8,014 and 17 times higher than that of Cu31 S16 and ZnCdS, respectively, under visible light irradiation. The apparent quantum yield (AQY) of Cu31 S16 /ZnCdS reaches 67.9% at 400 nm with the highest value so far in the reported ZnCdS-based photocatalysts. The excellent activity and stability of the Cu31 S16 /ZnCdS are attributed to the formation of a strong internal electric field (IEF) and the Z-scheme pathway. The comprehensive experiments and theoretical calculations provide the direct evidences of the Z-scheme route. This work may offer a way for the design and development of efficient photocatalysts to achieve solar-to-chemical energy conversion at a practically useful level.

Multiple strategies, including 6mA methylation, affecting plant alternative splicing in allopolyploid peanut.

Alternative splicing (AS), an important post-transcriptional regulation mechanism in eukaryotes, can significantly increase transcript diversity and contribute to gene expression regulation and many other complicated developmental processes. While plant gene AS events are well described, few studies have investigated the comprehensive regulation machinery of plant AS. Here, we use multi-omics to analyse peanut AS events. Using long-read isoform sequencing, 146 464 full-length non-chimeric transcripts were obtained, resulting in annotation corrections for 1782 genes and the identification of 4653 new loci. Using Iso-Seq RNA sequences, 271 776 unique splice junctions were identified, 82.49% of which were supported by transcriptome data. We characterized 50 977 polyadenylation sites for 23 262 genes, 12 369 of which had alternative polyadenylation sites. AS allows differential regulation of the same gene by miRNAs at the isoform level coupled with polyadenylation. In addition, we identified many long non-coding RNAs and fusion transcripts. There is a suppressed effect of 6mA on AS and gene expression. By analysis of chromatin structures, the genes located in the boundaries of topologically associated domains, proximal chromosomal telomere regions, inter- or intra-chromosomal loops were found to have more unique splice isoforms, higher expression, lower 6mA and more transposable elements (TEs) in their gene bodies than the other genes, indicating that chromatin interaction, 6mA and TEs play important roles in AS and gene expression. These results greatly refine the peanut genome annotation and contribute to the study of gene expression and regulation in peanuts. This work also showed AS is associated with multiple strategies for gene regulation.

Adaptive milliseconds tracking and zooming optics based on a high-speed gaze controller and liquid lenses.

The high-speed gaze and high resolution are critical factors for actual monitoring systems. However, the conventional method cannot track and zoom as fast as expected due to the larger inertia and it results in a low resolution due to the digital zoom. In this paper, we proposed a high-speed tracking and zooming optics that is coaxial designed and with an active tracking unit and an optical zooming unit to overcome the above issues. The tracking unit always tracks the object in the center of view by a pan-tilt mirror controller and a visual feedback tracking algorithm within 4 milliseconds response order. The zooming unit can continuously change the magnification from 1X to 2X by three liquid lenses within milliseconds. Besides, the zooming unit provides a compensation algorithm to achieve accurate zoom and focus.

ALKBH5 regulates paclitaxel resistance in NSCLC via inhibiting CEMIP-mediated EMT.

N6-methyladenosine (m6A) is the most prevalent mRNA modification, and it is verified to be closely correlated with cancer occurrence and progression. The m6A demethylase ALKBH5 (alkB homolog 5) is dysregulated in various cancers. However, the role and underlying mechanism of ALKBH5 in the pathogenesis and especially the chemo-resistance of non-small cell lung cancer (NSCLC) is poorly elucidated. The current study shows that ALKBH5 expression is reduced in paclitaxel (PTX) resistant NSCLC cells and down-regulation of ALKBH5 usually implies poor prognosis of NSCLC patients. Over-expression of ALKBH5 in PTX-resistant cells can suppress cell proliferation and enhance chemo-sensitivity, while knockdown of ALKBH5 exerts the opposite effect, which further supports the tumor suppressive role of ALKBH5. Over-expression of ALKBH5 can also reverse the epithelial-mesenchymal transition (EMT) process in PTX-resistant cancer cells. Mechanistically, data from RNA-seq, real-time PCR and western blotting indicate that CEMIP (cell migration inducing hyaluronidase 1), also known as KIAA1199, may be the downstream target of ALKBH5. Furthermore, ALKBH5 negatively regulates the CEMIP level by reducing the stability of CEMIP mRNA. Collectively, the current data demonstrate that the ALKBH5/CEMIP axis modulates the EMT process in NSCLC, which in turn regulates the chemo-sensitivity of cancer cells to PTX.

Endometrial stem cells alleviate cisplatin-induced ferroptosis of granulosa cells by regulating Nrf2 expression.

BACKGROUND: Premature ovarian failure (POF) caused by cisplatin is a severe and intractable sequela for young women with cancer who received chemotherapy. Cisplatin causes the dysfunction of granulosa cells and mainly leads to but is not limited to its apoptosis and autophagy. Ferroptosis has been also reported to participate, while little is known about it. Our previous experiment has demonstrated that endometrial stem cells (EnSCs) can repair cisplatin-injured granulosa cells. However, it is still unclear whether EnSCs can play a repair role by acting on ferroptosis. METHODS: Western blotting and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) were applied to detect the expression levels of ferroptosis-related genes. CCK-8 and 5-Ethynyl-2'-deoxyuridine (EdU) assays were used to evaluate cell viability. Transmission electron microscopy (TEM) was performed to detect ferroptosis in morphology. And the extent of ferroptosis was assessed by ROS, GPx, GSSG and MDA indicators. In vivo, ovarian morphology was presented by HE staining and the protein expression in ovarian tissue was detected by immunohistochemistry. RESULTS: Our results showed that ferroptosis could occur in cisplatin-injured granulosa cells. Ferroptosis inhibitor ferrostatin-1 (Fer-1) and EnSCs partly restored cell viability and mitigated the damage of cisplatin to granulosa cells by inhibiting ferroptosis. Moreover, the repair potential of EnSCs can be markedly blocked by ML385. CONCLUSION: Our study demonstrated that cisplatin could induce ferroptosis in granulosa cells, while EnSCs could inhibit ferroptosis and thus exert repair effects on the cisplatin-induced injury model both in vivo and in vitro. Meanwhile, Nrf2 was validated to participate in this regulatory process and played an essential role.

Pelvic floor muscle strength and influencing factors based on vaginal manometry among healthy women at different life stages: A multicentre cross-sectional study.

OBJECTIVE: To assess pelvic floor muscle (PFM) strength and influencing factors among healthy women at different life stages. DESIGN: Multicentre cross-sectional study. SETTING: Fourteen hospitals in China. POPULATION: A total of 5040 healthy women allocated to the following groups (with 1680 women per group): premenopausal nulliparous, premenopausal parous and postmenopausal. METHODS: The PFM strength was evaluated by vaginal manometry. Multivariate logistic regression was used to determine the influencing factors for low PFM strength. MAIN OUTCOME MEASURES: Maximum voluntary contraction pressure (MVCP). RESULTS: The median MVCP values were 36, 35 and 35 cmH2O in premenopausal nulliparous (aged 19-51 years), premenopausal parous (aged 22-61 years), and postmenopausal (aged 40-86 years) women, respectively. In the premenopausal nulliparous group, physical work (odds ratio, OR 2.05) was the risk factor for low PFM strength, which may be related to the chronic increased abdominal pressure caused by physical work. In the premenopausal parous group, the number of vaginal deliveries (OR 1.28) and diabetes (OR 2.70) were risk factors for low PFM strength, whereas sexual intercourse (<2 times per week vs. none, OR 0.55; ≥2 times per week vs. none, OR 0.56) and PFM exercise (OR 0.50) may have protective effects. In the postmenopausal group, the number of vaginal deliveries (OR 1.32) and family history of pelvic organ prolapse (POP) (OR 1.83) were risk factors for low PFM strength. CONCLUSIONS: Physical work, vaginal delivery, diabetes and a family history of POP are all risk factors for low PFM strength, whereas PFM exercises and sexual life can have a protective effect. The importance of these factors varies at different stages of a woman's life.

Characterization of the prognostic, diagnostic, and immunological roles of DSCC1 and its genomic alteration and instability in human cancers.

DNA replication and sister chromatid cohesion 1 (DSCC1) exerts various functions including sister chromatid cohesion. DSCC1 overexpression plays an important role in cancer development, such as in colorectal, breast, and hepatocellular cancers. The specific role of DSCC1 in tumor progression remains largely unknown, necessitating a pan-cancer investigation to understand the potential function of DSCC1 in various cancers. In this study, we obtained data on physiological conditions, transcriptional expression, survival prognosis, genomic alteration, genomic instability, enriched pathways, immune infiltration, and immunotherapy from The Cancer Genome Atlas, The Genotype-Tissue Expression, cBioPortal, and other publicly available databases to systematically characterize the oncogenic and immunological roles of DSCC1 in 33 different cancers. We found that DSCC1 expression was upregulated at both mRNA and protein levels in various cancers. Additionally, DSCC1 expression was associated with higher tumor stage and grade in specific cancers. DSCC1 was a potential pan-cancer prognostic biomarker for its close association with patient prognosis and a diagnostic biomarker for its high predictive value in distinguishing tumor tissues from normal tissues. DSCC1 was universally amplified across different cancers and tightly associated with genomic instability. Moreover, DSCC1 had a close relationship with tumor immune cell infiltration; thus, it could be used as a potential biomarker for predicting the response and survival of patients with cancer who receive immune checkpoint blockade treatment. To sum up, our study revealed that DSCC1 is a promising target for tumor therapy.

2,2- dimethylbenzopyran derivatives containing pyridone structural fragments as selective dual-targeting inhibitors of HIF-1α and EZH2 for the treatment of lung cancer.

We formerly reported that EZH2 inhibitors sensitized HIF-1 inhibitor-resistant cells and inhibited HIF-1α to promote SUZ12 transcription, leading to enhanced EZH2 enzyme activity and elevated H3K27me3 levels, and conversely, inhibition of EZH2 promoted HIF-1α transcription. HIF-1α and EZH2 interacted to form a negative feedback loop that reinforced each other's activity. In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03, a HIF-1α inhibitor previously reported by our group, and Tazemetostat, an EZH2 inhibitor approved by FDA, as lead compounds. Among these compounds, D-01 had significant inhibitory activities on HIF-1α and EZH2. In vitro experiments showed that D-01 significantly inhibited the migration of A549 cells, clone, invasion and angiogenesis. Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds.

Dissociated amplitude and phase effects of alpha oscillation in a nested structure of rhythm- and sequence-based temporal expectation.

The human brain can utilize various information to form temporal expectations and optimize perceptual performance. Here we show dissociated amplitude and phase effects of prestimulus alpha oscillation in a nested structure of rhythm- and sequence-based expectation. A visual stream of rhythmic stimuli was presented in a fixed sequence such that their temporal positions could be predicted by either the low-frequency rhythm, the sequence, or the combination. The behavioral modeling indicated that rhythmic and sequence information additively led to increased accumulation speed of sensory evidence and alleviated threshold for the perceptual discrimination of the expected stimulus. The electroencephalographical results showed that the alpha amplitude was modulated mainly by rhythmic information, with the amplitude fluctuating with the phase of the low-frequency rhythm (i.e. phase-amplitude coupling). The alpha phase, however, was affected by both rhythmic and sequence information. Importantly, rhythm-based expectation improved the perceptual performance by decreasing the alpha amplitude, whereas sequence-based expectation did not further decrease the amplitude on top of rhythm-based expectation. Moreover, rhythm-based and sequence-based expectations collaboratively improved the perceptual performance by biasing the alpha oscillation toward the optimal phase. Our findings suggested flexible coordination of multiscale brain oscillations in dealing with a complex environment.

Representing linguistic communicative functions in the premotor cortex.

Linguistic communication is often regarded as an action that serves a function to convey the speaker's goal to the addressee. Here, with an functional magnetic resonance imaging (fMRI) study and a lesion study, we demonstrated that communicative functions are represented in the human premotor cortex. Participants read scripts involving 2 interlocutors. Each script contained a critical sentence said by the speaker with a communicative function of either making a Promise, a Request, or a Reply to the addressee's query. With various preceding contexts, the critical sentences were supposed to induce neural activities associated with communicative functions rather than specific actions literally described by these sentences. The fMRI results showed that the premotor cortex contained more information, as revealed by multivariate analyses, on communicative functions and relevant interlocutors' attitudes than the perisylvian language regions. The lesion study results showed that, relative to healthy controls, the understanding of communicative functions was impaired in patients with lesions in the premotor cortex, whereas no reliable difference was observed between the healthy controls and patients with lesions in other brain regions. These findings convergently suggest the crucial role of the premotor cortex in representing the functions of linguistic communications, supporting that linguistic communication can be seen as an action.

Dynamic projection mapping for non-planar objects with a variable focus lens and visual feedback.

Dynamic projection mapping for moving objects has attracted much attention in recent years. However, conventional approaches have faced some issues, such as the target objects being limited to the moving speed of the objects, the limitation of the narrow depth-of-field optics, and the planar shape objects. This work proposed an adaptive three-dimensional projection prototype, and it could project an always in-focus image on a non-planar object based on liquid lens optics. The location of the non-planar object could be detected, and the mapped projection contents calculated; as a result, a stable "printed" projection mapping should be viewed on a moving object.

Measurement method of virtual image distance for a head-mounted display based on a variable-focus liquid lens.

The distance from the virtual image to the human eye is an important factor in measuring the comfort of a head-mounted display (HMD). However, accurately measuring their distance is challenging due to the dynamic changes in virtual presence and distance. In this paper, we proposed a virtual image distance measurement prototype based on a variable-focus liquid lens and derived a virtual image distance calculation model. We built a variable-focus liquid lens experimental platform to verify the method's correctness. In addition, we proposed an improved optimization algorithm that can efficiently and accurately search for the optimal focal length corresponding to the maximum sharpness moment of the virtual image within the focal length value space. Verified in an experimental scene of 0.5 m to 3.5 m, we observed that the error between the object image distance and the virtual image distance at the same focal length is about 5 cm. The proposed virtual image distance measurement method can accurately measure the distance value of the virtual image in the HMD. This method can be widely used in virtual and augmented reality, especially in the task of constructing realistic scenes.