In response to the current global health emergency posed by the Zika virus (ZIKV) outbreak and its link to microcephaly and other neurological conditions, we performed a drug repurposing screen of ...∼6,000 compounds that included approved drugs, clinical trial drug candidates and pharmacologically active compounds; we identified compounds that either inhibit ZIKV infection or suppress infection-induced caspase-3 activity in different neural cells. A pan-caspase inhibitor, emricasan, inhibited ZIKV-induced increases in caspase-3 activity and protected human cortical neural progenitors in both monolayer and three-dimensional organoid cultures. Ten structurally unrelated inhibitors of cyclin-dependent kinases inhibited ZIKV replication. Niclosamide, a category B anthelmintic drug approved by the US Food and Drug Administration, also inhibited ZIKV replication. Finally, combination treatments using one compound from each category (neuroprotective and antiviral) further increased protection of human neural progenitors and astrocytes from ZIKV-induced cell death. Our results demonstrate the efficacy of this screening strategy and identify lead compounds for anti-ZIKV drug development.
Increased glycolysis is considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during therapeutic resistance development is under-studied. Here, through high-throughput ...stimulated Raman scattering imaging and single cell analysis, we find that cisplatin-resistant cells exhibit increased fatty acids (FA) uptake, accompanied by decreased glucose uptake and lipogenesis, indicating reprogramming from glucose to FA dependent anabolic and energy metabolism. A metabolic index incorporating glucose derived anabolism and FA uptake correlates linearly to the level of cisplatin resistance in ovarian cancer (OC) cell lines and primary cells. The increased FA uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing beta-oxidation. Consequently, blocking beta-oxidation by a small molecule inhibitor combined with cisplatin or carboplatin synergistically suppresses OC proliferation in vitro and growth of patient-derived xenografts in vivo. Collectively, these findings support a rapid detection method of cisplatin-resistance at single cell level and a strategy for treating cisplatin-resistant tumors.
Epigenetics is a discipline that studies heritable changes in gene expression that do not involve altering the DNA sequence. Over the past decade, researchers have shown that epigenetic regulation ...plays a momentous role in cell growth, differentiation, autoimmune diseases, and cancer. The main epigenetic mechanisms include the well-understood phenomenon of DNA methylation, histone modifications, and regulation by non-coding RNAs, a mode of regulation that has only been identified relatively recently and is an area of intensive ongoing investigation. It is generally known that the majority of human transcripts are not translated but a large number of them nonetheless serve vital functions. Non-coding RNAs are a cluster of RNAs that do not encode functional proteins and were originally considered to merely regulate gene expression at the post-transcriptional level. However, taken together, a wide variety of recent studies have suggested that miRNAs, piRNAs, endogenous siRNAs, and long non-coding RNAs are the most common regulatory RNAs, and, significantly, there is a growing body of evidence that regulatory non-coding RNAs play an important role in epigenetic control. Therefore, these non-coding RNAs (ncRNAs) highlight the prominent role of RNA in the regulation of gene expression. Herein, we summarize recent research developments with the purpose of coming to a better understanding of non-coding RNAs and their mechanisms of action in cells, thus gaining a preliminary understanding that non-coding RNAs feed back into an epigenetic regulatory network.
The transition of RNA polymerase II (Pol II) from initiation to productive elongation is a central, regulated step in metazoan gene expression. At many genes, Pol II pauses stably in early ...elongation, remaining engaged with the 25- to 60-nt-long nascent RNA for many minutes while awaiting signals for release into the gene body. However, 15%–20% of genes display highly unstable promoter Pol II, suggesting that paused polymerase might dissociate from template DNA at these promoters and release a short, non-productive mRNA. Here, we report that paused Pol II can be actively destabilized by the Integrator complex. Specifically, we present evidence that Integrator utilizes its RNA endonuclease activity to cleave nascent RNA and drive termination of paused Pol II. These findings uncover a previously unappreciated mechanism of metazoan gene repression, akin to bacterial transcription attenuation, wherein promoter-proximal Pol II is prevented from entering productive elongation through factor-regulated termination.
Display omitted
•Integrator inhibits transcription elongation at ∼15% of mRNA genes and enhancers•Integrator targets promoter-proximally paused Pol II for termination•The RNA endonuclease of Integrator subunit 11 is critical for gene repression•Integrator depletion increases productive elongation and histone H3 K4 methylation
Here, Elrod et al. demonstrate that the Integrator complex associates with paused RNA polymerase II at promoters and enhancers to terminate RNA synthesis. This attenuation mechanism potently represses expression of both stress- and growth-responsive genes in Drosophila and mammalian cells.
A strategy to expand anti‐Stokes shifting from the far‐red to deep‐blue region in metal‐free triplet–triplet annihilation upconversion (TTA‐UC) is presented. The method is demonstrated by in vivo ...titration of the photorelease of an anticancer prodrug. This new TTA system has robust brightness and the longest anti‐Stokes shift of any reported TTA system. TTA core–shell‐structured prodrug delivery capsules that benefit from these properties were developed; they can operate with low‐power density far‐red light‐emitting diode light. These capsules contain mesoporous silica nanoparticles preloaded with TTA molecules as the core, and amphiphilic polymers encapsulating anticancer prodrug molecules as the shell. When stimulated by far‐red light, the intense TTA upconversion blue emission in the system activates the anticancer prodrug molecules and shows effective tumor growth inhibition in vivo. This work paves the way to new organic TTA upconversion techniques that are applicable to in vivo photocontrollable drug release and other biophotonic applications.
Seeing red: Triplet–triplet annihilation upconversion (TTA‐UC) has robust brightness and the record longest anti‐Stokes shift from far‐red to deep‐blue light. TTA core–shell‐structured nanocapsules photorelease coumarin–chlorambucil (Cou‐C) prodrug upon irradiation with low‐power density far‐red light‐emitting diode (LED) light, to achieve potent tumor growth inhibition in vivo.
Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRR) with a crucial function in innate immune responses. Activation of TLR4 signaling at the plasma membrane by ...lipopolysaccharide (LPS) stimulates proinflammatory signaling pathways dependent on the E3 ubiquitin ligase TRAF6. Here we show the LPS-induced long non-coding RNA (lncRNA) Mirt2 functions as a checkpoint to prevent aberrant activation of inflammation, and is a potential regulator of macrophage polarization. Mirt2 associates with, and attenuates Lys63 (K63)-linked ubiquitination of, TRAF6, thus inhibiting activation of NF-κB and MAPK pathways and limiting production of proinflammatory cytokines. Adenovirus mediated gene transfer of Mirt2 protects mice from endotoxemia induced fatality and multi-organ dysfunction. These findings identify lncRNA Mirt2 as a negative feedback regulator of excessive inflammation.
Objective
There is no useful tool to clinically predict the occurrence of osteoradionecrosis (ORN) of the mandible quantitatively. The aim was to investigate the risk factors, including different ...modalities of radiotherapy, for developing mandibular ORN in patients undergoing marginal mandibulectomy and postoperative radiotherapy.
Methods
Between January 2006 and December 2012, 167 subjects who underwent marginal mandibulectomy and postoperative radiotherapy with different modalities were enrolled. The association of ORN with mandibular bone measurements and patient variables was analyzed, and a nomogram was established.
Results
Fifteen (8.98%) of the 167 patients developed ORN during the follow‐up period, and ORN was significantly associated with diabetes mellitus (DM), body mass index (BMI), remaining bone height, remaining bone height to original bone height ratio, resected bone height to original bone height ratio, and mandibular dose (P: < 0.001, 0.004, 0.042, 0.018, 0.010, 0.020, respectively). Interestingly, the risk of ORN had no significant difference between conformal and intensity modulation radiation therapy (P = 0.407). Multivariate analysis revealed that DM and resected bone height to original bone height ratio ≥ 50% were independent risk factors for postoperative ORN. A nomogram consisting of BMI, DM, resected bone height to original bone height ratio, mandibulotomy, and mandibular dose for predicting the ORN‐free probability was established; and the c‐index of the nomogram for ORN status was 0.803.
Conclusion
A nomogram based on the risk factors was plotted to strengthen the prediction of ORN quantitatively. Surgeons should be more discrete regarding the treatment plan for patients with higher probability of ORN.
Level of Evidence
3b Laryngoscope, 130:101–107, 2020
Phosphatidylinositol 3-kinase (PI3K)/AKT pathway regulates cell growth, proliferation, survival, mobility and invasion. Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase ...(ERK) pathway is also an important mitogenic signaling pathway involved in various cellular progresses. AKT, also named protein kinase B (PKB), is a primary mediator of the PI3K signaling pathway; and ERK at the end of MAPK signaling is the unique substrate and downstream effector of mitogen-activated protein/extracellular signal-regulated kinase (MEK). The AKT and ERK signaling are both aberrantly activated in a wide range of human cancers and have long been targeted for cancer therapy, but the clinical benefits of these targeted therapies have been limited due to complex cross-talk. Novel strategies, such as AKT/ERK dual inhibitors, may be needed.
•Aberrant activation and oncogenesis of PI3K/AKT and MAPK/ERK pathways in cancer.•Cross-talk between the PI3K/AKT and MAPK/ERK pathways drives drug resistance.•Dual inhibitors of AKT and ERK yield clinical benefits in targeted cancer therapy.
•Using CNN to detect rice phenology by a mono-temporal imagery of UAV was investigated.•Shape-model-fitting method underperformed with short length of time-series data.•Integrating regional mean ...thermal time into CNN improve the detection accuracy.•The estimated harvest dates was in close agreement with the observation.•The proposed approach provides near real-time estimation of the principal phenological stages of rice.
Near real-time crop phenology detection is essential for crop management, estimation of harvest time and yield estimation. Previous approaches to crop phenology detection have relied on time-series (multi-temporal) vegetation index (VI) data, and have included threshold-based, phenometrics-based and shape-model-fitting-based (SMF) methods. However, the performance of these methods depends on the duration and temporal resolution of the time-series data. In this study, we propose a new approach which identifies the principal growth stages of rice (Oryza sativa L.) directly from RGB images. Only a mono-temporal unmanned aerial vehicle (UAV) imagery was required for a large-area phenology detection via the well-trained network. An efficient convolutional neural network (CNN) architecture was designed to estimate rice phenology. The CNN incorporated spatial pyramid pooling (SPP), transfer learning and an auxiliary branch with external data. A total of 82 plots across a 160-hectare rice cultivation area of Southern China were selected to evaluate the proposed network. CNN predictions were ground truthed using rice phenology measurements taken from each plot throughout the growing season. Aerial data were collected using a fixed-wing UAV equipped with multispectral and RGB cameras. The performance of traditional SMF methods deteriorated when time-series VI data were of short duration. In contrast, the phenological stage estimated by the proposed network showed good agreement with ground observations, with a top-1 accuracy rate of 83.9% and mean absolute error (MAE) of 0.18. The spatial distribution of harvest dates for 627 plots in the study area were computed from the phenological stage estimates. The estimates matched well with the observed harvest dates. The results demonstrated the excellent performance of the proposed deep learning approach in near real-time phenology detection and harvest time estimation.
The extraordinary electronic, optical, and mechanical characteristics of 2D materials make them promising candidates for optoelectronics, specifically in infrared (IR) detectors owing to their ...flexible composition and tunable optoelectronic properties. This review presents the recent progress in IR detectors composed of 2D materials and their hybrid structures, including graphene, black phosphorous, transition metal dichalcogenides, halide perovskite as well as other new layered materials and their heterostructures. The focus is on the short‐wave, mid‐wave, and long‐wave infrared regimes, which pose a grand challenge for rational materials and device designs. The dependence of the device performance on the optical and electronic properties of 2D materials is extensively discussed, aiming to present the general strategies for designing optoelectronic devices with optimal performance. Furthermore, the recent results on 2D material‐based heterostructures are presented with an emphasis on the relationship between band alignment, charge transfer, and IR photodetection. Finally, a summary is given as well as the discussion of existing challenges and future directions.
2D materials are among the most rapidly emerging building blocks for high‐performance infrared photodetection. This review elucidates the advantages and the crucial role of 2D materials in achieving high performance and enhanced stability in infrared photodetection, especially in short‐wave, mid‐wave, and long‐wave infrared regimes.
PDF
