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Generanks for differential shRNA effects from GENE-E class comparison analysis

Table S2. Genetic characterization of BL cell lines; Table S4. Genetic aberrations in aggressive B-NHL patients from the MMML consortium; Table S5. Annotation of TP53 mutation and MDM4 gain in cell lines from the Achilles project; Figure S1. RNAi screen identifies common and context-specific essential genes; Figure S2. Genes essential in the context of TP53 mutation; Figure S3. p53 reactivation causes cytotoxic effect; Figure S4. Molecular impact of MDM2 or MDM4 knock-down; Figure S5. Genetic profile in TP53wt and TP53mut aggressive B-NHL patients; Figure S6. Basal MDM4 mRNA in aggressive lymphomas stratified by TP53 mutation and 1q status.

Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-function screening in eight Burkitt lymphoma cell lines and integrated non-Burkitt lymphoma RNAi screens and genetic data. We identified 76 genes essential to Burkitt lymphoma, including genes associated with hematopoietic cell differentiation (FLI1, BCL11A) or B-cell development and activation (PAX5, CDKN1B, JAK2, CARD11) and found a number of context-specific dependencies including oncogene addiction in cell lines with TCF3/ID3 or MYD88 mutation. The strongest genotype–phenotype association was seen for TP53. MDM4, a negative regulator of TP53, was essential in TP53 wild-type (TP53wt) Burkitt lymphoma cell lines. MDM4 knockdown activated p53, induced cell-cycle arrest, and decreased tumor growth in a xenograft model in a p53-dependent manner. Small molecule inhibition of the MDM4–p53 interaction was effective only in TP53wt Burkitt lymphoma cell lines. Moreover, primary TP53wt Burkitt lymphoma samples frequently acquired gains of chromosome 1q, which includes the MDM4 locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and MDM4 was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles Project. Our findings highlight the critical role of p53 as a tumor suppressor in Burkitt lymphoma and identify MDM4 as a functional target of 1q gain in a wide range of cancers that is therapeutically targetable.Significance:Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.

Biallelic mutations in the RCBTB1 gene cause retinal dystrophy. Here, we characterized the effects of RCBTB1 gene deficiency in retinal pigment epithelial (RPE) cells derived from a patient with RCBTB1‐associated retinopathy and restored RCBTB1 expression in these cells using adeno‐associated viral (AAV) vectors. Induced pluripotent stem cells derived from a patient with compound heterozygous RCBTB1 mutations (c.170delG and c.707delA) and healthy control subjects were differentiated into RPE cells. RPE cells were treated with AAV vectors carrying a RCBTB1 transgene. Patient‐derived RPE cells showed reduced expression of RCBTB1. Expression of NFE2L2 showed a non‐significant reduction in patient RPE cells compared with controls, while expression of its target genes (RXRA, IDH1 and SLC25A25) was significantly reduced. Trans‐epithelial electrical resistance, surface microvillus densities and primary cilium lengths were reduced in patient‐derived RPE cells, compared with controls. Treatment of patient RPE with AAV vectors significantly increased RCBTB1, NFE2L2 and RXRA expression and cilium lengths. Our study provides the first report examining the phenotype of RPE cells derived from a patient with RCBTB1‐associated retinopathy. Furthermore, treatment of patient‐derived RPE with AAV‐RCBTB1 vectors corrected deficits in gene expression and RPE ultrastructure, supporting the use of gene replacement therapy for treating this inherited retinal disease.

Background: Mutations in the RCC1 and BTB domain-containing protein 1 (RCBTB1) gene have been implicated in a rare form of retinal dystrophy. Herein, we report the clinical features of a 45-year-ol...

A large π-conjugated perylenediimide bridged bis(β-cyclodextrin)-bonded stationary phase (PBCDP) was first prepared and characterized. The chiral HPLC performance was systematically evaluated using a series of chiral probes. The results showed that PBCDP could resolve 36 kinds of chiral compounds in reversed-phase and polar organic modes with high resolutions (Rs) 1.48-3.28 for profens, 1.25-2.85 for triazoles, 1.34-5.29 for flavanones, 1.66-4.58 for amino acids and 1.22-1.97 for β-blockers. Especially, PBCDP could completely resolve acidic non-steroidal chiral drugs (profens) and simultaneously resolve basic five triazole pesticides, which were difficult to separate by ordinary CDCSP. Compared with CDCSP (15 kinds), the new stationary phase has a wider resolution range (36 kinds). Obviously, the synergistic inclusion of the two cavities of bridged cyclodextrin, as well as the large π-π stacking, hydrogen bond, dipole-dipole and basic primary amine site (-NH-) provided by the perylenediimide bridging group contributed together to the improvement of the above chiral separations. PBCDP was a new type of versatile chiral separation material without port derivatization.

Efficient on-chip manipulation of photon spin is of crucial importance in developing future integrated nanophotonics as is electron spin in spintronics. The unidirectionality induced by the interaction between spin and orbital angular momenta suffers low efficiency in classical macroscopic optics, while it can be highly enhanced on subwavelength scales with suitable architectures. Here we propose and demonstrate a spin-sorting achiral split-ring coupler to unidirectionally excite dielectric-loaded plasmonic modes in two independent waveguides. We found experimentally that the impinging light with different spin can be selectively directed into one of two branching plasmonic waveguides with a directionality contrast up to 15.1 dB. A circular-helicity-independent compact beam splitter is also realized demonstrating great potential in designing complex interconnect nanocircuits. The illustrated approach is believed to open new avenues for developing advanced optical functionalities with a flexible degree of freedom in manipulation of on-chip chirality within chiral optics.

In this paper, we developed an organic solvent-free, eco-friendly, simple and efficient one-pot approach for the preparation of amphiphilic conjugates (Ugi-OSAOcT) by grafting octylamine (OCA) to oxidized sodium alginate (OSA). The optimum reaction parameters that were obtained based on the degree of substitution (DS) of Ugi-OSAOcT were a reaction time of 12 h, a reaction temperature of 25 °C and a molar ratio of 1:2.4:3:3.3 (OSA:OCA:HAc:TOSMIC), respectively. The chemical structure and composition were characterized by Fourier transform infrared spectroscopy (FTIR), 1H nuclear magnetic resonance (1H NMR), X-ray diffraction (XRD), thermogravimetry analyser (TGA), gel permeation chromatography (GPC) and elemental analysis (EA). It was found that the Ugi-OSAOcT conjugates with a CMC value in the range of 0.30–0.085 mg/mL could self-assemble into stable and spherical micelles with a particle size of 135.7 ± 2.4–196.5 ± 3.8 nm and negative surface potentials of −32.8 ± 0.4–−38.2 ± 0.8 mV. Furthermore, ibuprofen (IBU), which served as a model poorly water-soluble drug, was successfully incorporated into the Ugi-OSAOcT micelles by dialysis method. The drug loading capacity (%DL) and encapsulation efficiency (%EE) of the IBU-loaded Ugi-OSAOcT micelles (IBU/Ugi-OSAOcT = 3:10) reached as much as 10.9 ± 0.4–14.6 ± 0.3% and 40.8 ± 1.6–57.2 ± 1.3%, respectively. The in vitro release study demonstrated that the IBU-loaded micelles had a sustained and pH-responsive drug release behavior. In addition, the DS of the hydrophobic segment on an OSA backbone was demonstrated to have an important effect on IBU loading and drug release behavior. Finally, the in vitro cytotoxicity assay demonstrated that the Ugi-OSAOcT conjugates exhibited no significant cytotoxicity against RAW 264.7 cells up to 1000 µg/mL. Therefore, the amphiphilic Ugi-OSAOcT conjugates synthesized by the green method exhibited great potential to load hydrophobic drugs, acting as a promising nanocarrier capable of responding to pH for sustained release of hydrophobic drugs.

Retinitis pigmentosa 11 (RP11) is caused by dominant mutations in PRPF31, however a significant proportion of mutation carriers do not develop retinopathy. Here, we investigated the relationship between CNOT3 polymorphism, MSR1 repeat copy number and disease penetrance in RP11 patients and non-penetrant carriers (NPCs). We further characterized PRPF31 and CNOT3 expression in fibroblasts from eight RP11 patients and one NPC from a family carrying the c.1205C&gt, T variant. Retinal organoids (ROs) and retinal pigment epithelium (RPE) were differentiated from induced pluripotent stem cells derived from RP11 patients, an NPC and a control subject. All RP11 patients were homozygous for the 3-copy MSR1 repeat in the PRPF31 promoter, while 3/5 NPCs carried a 4-copy MSR1 repeat. The CNOT3 rs4806718 genotype did not correlate with disease penetrance. PRFP31 expression declined with age in adult cadaveric retina. PRPF31 and CNOT3 expression was reduced in RP11 fibroblasts, RO and RPE compared with controls. Both RP11 and NPC RPE displayed shortened primary cilia compared with controls, however a subpopulation of cells with normal cilia lengths was present in NPC RPE monolayers. Our results indicate that RP11 non-penetrance is associated with the inheritance of a 4-copy MSR1 repeat, but not with CNOT3 polymorphisms.

Oncogenic MYC activation promotes proliferation in Burkitt lymphoma, but also induces cell-cycle arrest and apoptosis mediated by p53, a tumor suppressor that is mutated in 40% of Burkitt lymphoma cases. To identify molecular dependencies in Burkitt lymphoma, we performed RNAi-based, loss-of-function screening in eight Burkitt lymphoma cell lines and integrated non-Burkitt lymphoma RNAi screens and genetic data. We identified 76 genes essential to Burkitt lymphoma, including genes associated with hematopoietic cell differentiation (FLI1, BCL11A) or B-cell development and activation (PAX5, CDKN1B, JAK2, CARD11) and found a number of context-specific dependencies including oncogene addiction in cell lines with TCF3/ID3 or MYD88 mutation. The strongest genotype–phenotype association was seen for TP53. MDM4, a negative regulator of TP53, was essential in TP53 wild-type (TP53wt) Burkitt lymphoma cell lines. MDM4 knockdown activated p53, induced cell-cycle arrest, and decreased tumor growth in a xenograft model in a p53-dependent manner. Small molecule inhibition of the MDM4–p53 interaction was effective only in TP53wt Burkitt lymphoma cell lines. Moreover, primary TP53wt Burkitt lymphoma samples frequently acquired gains of chromosome 1q, which includes the MDM4 locus, and showed elevated MDM4 mRNA levels. 1q gain was associated with TP53wt across 789 cancer cell lines and MDM4 was essential in the TP53wt-context in 216 cell lines representing 19 cancer entities from the Achilles Project. Our findings highlight the critical role of p53 as a tumor suppressor in Burkitt lymphoma and identify MDM4 as a functional target of 1q gain in a wide range of cancers that is therapeutically targetable. Significance: Targeting MDM4 to alleviate degradation of p53 can be exploited therapeutically across Burkitt lymphoma and other cancers with wild-type p53 harboring 1q gain, the most frequent copy number alteration in cancer.

Acoustic-graphene-plasmons (AGPs) are highly confined electromagnetic modes, which carry extreme momentum and low loss in the Mid-infrared (MIR) to Terahertz (THz) spectra. They are therefore enablers of extremely strong light-matter interactions at these long wavelengths. However, owing to their large momentum they are also challenging to excite and detect. Here, we demonstrate a new way to excite AGPs that are confined to nanometric-scale cavities directly from the far-field, via localized graphene-plasmon-magnetic-resonators (GPMRs). This approach enables the efficient excitation of single AGP cavities, which are able to confine MIR light to record-breaking ultra-small mode-volumes, which are over a billion times smaller than their free-space volume.

Acoustic-graphene-plasmons (AGPs) are highly confined electromagnetic modes, which carry extreme momentum and low loss in the Mid-infrared (MIR) to Terahertz (THz) spectra. In this work [1], we demonstrate a new way to excite AGPs from the far-field, which are confined to nanometric-scale cavities, via localized graphene-plasmon-magnetic-resonators (GPMRs). This approach enables the efficient excitation of single AGP cavities, which are able to confine MIR light to record-breaking ultra-small mode-volumes that are ∼5·1010 times smaller than their free-space volume.

Background Mutations in CLN3 cause Batten disease, however non‐syndromic CLN3 disease, characterized by retinal‐specific degeneration, has been also described. Here, we characterized an induced pluripotent stem cell (iPSC)‐derived disease model derived from a patient with non‐syndromic CLN3‐associated retinopathy. Methods Patient‐iPSC, carrying the 1 kb‐deletion and c.175G>A variants in CLN3, coisogenic iPSC, in which the c.175G>A variant was corrected, and control iPSC were differentiated into neural retinal organoids (NRO) and cardiomyocytes. CLN3 transcripts were analyzed by Sanger sequencing. Gene expression was characterized by qPCR and western blotting. NRO were characterized by immunostaining and electron microscopy. Results Novel CLN3 transcripts were detected in adult human retina and control‐NRO. The major transcript detected in patient‐NRO displayed skipping of exons 2 and 4–9. Accumulation of subunit‐C of mitochondrial ATPase (SCMAS) protein was demonstrated in patient‐derived cells. Photoreceptor progenitor cells in patient‐NRO displayed accumulation of peroxisomes and vacuolization of inner segments. Correction of the c.175G>A variant restored CLN3 mRNA and protein expression and prevented SCMAS and inner segment vacuolization. Conclusion Our results demonstrate the expression of novel CLN3 transcripts in human retinal tissues. The c.175G>A variant alters splicing of the CLN3 pre‐mRNA, leading to features consistent with CLN3 deficiency, which were prevented by gene correction., In this paper, we examined the phenotype of retinal organoids derived from a patient with non‐syndromic CLN3 disease. We showed that accumulation of subunit C of mitochondrial ATPase occurs in patient retinal cells and cardiomyocytes, and could be prevented by gene correction. Additionally, we demonstrated that novel CLN3 transcripts are expressed in the human retina.

Many approaches to identify therapeutically relevant neoantigens couple tumor sequencing with bioinformatic algorithms and inferred rules of tumor epitope immunogenicity. However, there are no reference data to compare these approaches, and the parameters governing tumor epitope immunogenicity remain unclear. Here, we assembled a global consortium wherein each participant predicted immunogenic epitopes from shared tumor sequencing data. 608 epitopes were subsequently assessed for T cell binding in patient-matched samples. By integrating peptide features associated with presentation and recognition, we developed a model of tumor epitope immunogenicity that filtered out 98% of non-immunogenic peptides with a precision above 0.70. Pipelines prioritizing model features had superior performance, and pipeline alterations leveraging them improved prediction performance. These findings were validated in an independent cohort of 310 epitopes prioritized from tumor sequencing data and assessed for T cell binding. This data resource enables identification of parameters underlying effective anti-tumor immunity and is available to the research community.

The potential association between coal-burning arsenic exposure and type 2 diabetes (T2D) was examined through a case control study, conducted in coal-burning arsenic poisoning areas in the Guizhou Province. This study included patients diagnosed with type 2 diabetes. Control subjects without type 2 diabetes were recruited randomly after gender and age 1:1 matching. All subjects completed questionnaire surveys and underwent physical examination and whole blood arsenic level testing. The whole blood arsenic level was associated with a significant increase in the risk of type 2 diabetes (75th versus 25th, adjusted OR = 1.76, 95% CI: 1.03-3.01). However, a nonlinear relationship was observed between the blood arsenic level and type 2 diabetes. The risk of type 2 diabetes increased with blood arsenic levels above 3.69 μg/L (Log As ≥0.57). The subgroup analysis revealed that blood arsenic levels were associated with significantly increased risk of type 2 diabetes in people who ever smoked (P .05), particularly those who smoked ≥15 years (adjusted OR = 3.15, 95% CI: 1.9-7.28). Therefore, prolonged arsenic exposure, even at a low level, is associated with a higher prevalence of type 2 diabetes in a nonlinear pattern. Blood arsenic levels less than 3.69 μg/L may be considered safe with respect to the risk of T2D. However, smoking, particularly smoking ≥15 years, may be associated with the development of diabetes in patients with arsenic exposure.

Acoustic-graphene-plasmons (AGPs) are highly confined electromagnetic modes, which carry extreme momentum and low loss in the Mid-infrared (MIR) to Terahertz (THz) spectra. In this work [1], we demonstrate a new way to excite AGPs from the far-field, which are confined to nanometric-scale cavities, via localized graphene-plasmon-magnetic-resonators (GPMRs). This approach enables the efficient excitation of single AGP cavities, which are able to confine MIR light to record-breaking ultra-small mode-volumes that are ~5·1010 times smaller than their free-space volume.

In order to adapt to the current trend of higher education popularization and the need of mathematics teaching in the Internet Age, this paper combines the mobile terminal of Internet technology with the traditional higher mathematics classroom teaching and explores the hybrid teaching mode based on the support of Internet class. The purpose is to fully give play to the teacher’s guiding role in guiding, inspiring, and monitoring the teaching process and mobilize the students’ enthusiasm and creativity in the learning process.

The flipped classroom is a new type of teaching organization emerging in recent years, and it’s also an effective way to realize blended learning. The combination of these can realize the innovation and development of teaching methods. This article proposes the blended teaching models based on the flipped classroom concept, including traditional classroom teaching, partial flipped classroom and complete flipped classroom. Based on the model, the teaching design and practice of the course “measurement and evaluation of mathematics education” for graduate students majoring in subject teaching (math) were carried out, and suggestions are made for the effective application of the mode to solve the problem of teaching, improving teaching quality, promoting teaching reform.

We propose and experimentally demonstrate a polarization-selective waveguide hologram at optical wavelengths, based on an all-dielectric metamaterial multilayer system. We show that two spatially separated or overlapped holographic images can be produced with two orthogonally polarized beams, incorporated into a binary computer generated hologram (CGH). These two images can be combined into a single 3D stereoscopic image observable using linearly or circularly polarized glasses. The two polarized beams can also be utilized to construct radially and azimuthally polarized "vortex" beams. The fundamental and first higher-order TM and TE modes of an optical waveguide are used to guide the two polarization states with distinct propagation constants. The two guided waves act as spatially distinct reference waves such that the integrated, on-chip hologram can distinguish the two and provide two independent images corresponding to the two polarizations. Polarization selective waveguide holograms can be used in a diverse set of applications, from chip-scale displays and augmented reality (AR) to optical trapping.

Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy1,2,3. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations2. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes1,3. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1)1,3,4. Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat., This work was supported by an Alex's Lemonade Stand Young Investigator Award (S.C.M.), The CIHR Banting Fellowship (S.C.M.), The Cancer Prevention Research Institute of Texas (S.C.M., RR170023), Sibylle Assmus Award for Neurooncology (K.W.P.), the DKFZ-MOST (Ministry of Science, Technology & Space, Israel) program in cancer research (H.W.), James S. McDonnell Foundation (J.N.R.) and NIH grants: CA154130 (J.N.R.), R01 CA169117 (J.N.R.), R01 CA171652 (J.N.R.), R01 NS087913 (J.N.R.) and R01 NS089272 (J.N.R.). R.C.G. is supported by NIH grants T32GM00725 and F30CA217065. M.D.T. is supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Pediatric Brain Tumour Foundation, Grand Challenge Award from CureSearch for Children’s Cancer, the National Institutes of Health (R01CA148699, R01CA159859), The Terry Fox Research Institute and Brainchild. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113).

This paper characterizes the Single Event Effect (SEE) sensitivities of the Serializer/Deserializer (SerDes) module on the advanced 28 nm Xilinx Kintex-7 Field Programmable Gate Array (FPGA). A systematical SEE measurement method is proposed and implemented to evaluate the SEE sensitivity of the SerDes circuits. In our experiments, an extremely low Single Event Upset (SEU) Linear Energy Transfer (LET) threshold of the SerDes circuits was investigated, and both the recoverable and unrecoverable Single Event Functional Interrupts (SEFIs) were clearly distinguished and classified. In the experiments, it was found that the SEUs and recoverable SEFIs of the TX and RX in the same channel were closely related due to their shared clock and control circuits. Based on this detailed survey, a further discussion of the mechanisms of the SEU, recoverable SEFI, and unrecoverable SEFI is also provided. The SEE sensitivity of the high-speed SerDes circuits presented in this paper will promote the effective utilization of error mitigation strategies in order to control the risks of applications in radiation environments.

Task allocation of unmanned surface vehicles (USVs) with low task cost is an important research area which assigns USVs from starting points to different target points to complete tasks. Most of the research lines of task allocation are using heuristic algorithms to obtain suboptimal solutions to reduce both the max task cost and total task cost. In practice, reducing the maximum is more important to task time, which is from the departure of USVs to the last USV arriving at the designated position. In this paper, an exact algorithm is proposed to minimize the max task time and reduce the total task time based on the Hungarian algorithm. In this algorithm, task time is composed of the travel time along the planned path and the turning time at initial and target points. The fast marching square method (FMS) is used to plan the travel path with obstacle avoidance. The effectiveness and practicability of the proposed algorithm are verified by comparing it with the Hungarian algorithm (HA), the auction algorithm (AA), the genetic algorithm (GA) and the ant colony optimization algorithm (ACO). The results of path planning and task allocation are displayed in the simulation.

Variants in RCBTB1 have been implicated in inherited retinal disease (IRD). Here, we generated induced pluripotent stem cells (iPSCs) from a 45-year-old female IRD patient harbouring compound heterozygous mutations in the RCBTB1 gene. Episomal plasmids containing OCT4, SOX2, KLF4, MYCL, LIN28, shRNA for TP53 and mir302/367 microRNA were employed to conduct the reprogramming of primary dermal fibroblasts. These iPSC lines provide a useful model for further investigations on the pathophysiological role of mutations in the RCBTB1 gene in IRD.