Long noncoding RNAs (lncRNAs) are increasingly appreciated as regulators of cell-specific gene expression. Here, an enhancer-like lncRNA termed NeST (nettoie Salmonella pas Theiler’s cleanup ...Salmonella not Theiler’s) is shown to be causal for all phenotypes conferred by murine viral susceptibility locus Tmevp3. This locus was defined by crosses between SJL/J and B10.S mice and contains several candidate genes, including NeST. The SJL/J-derived locus confers higher lncRNA expression, increased interferon-γ (IFN-γ) abundance in activated CD8+ T cells, increased Theiler’s virus persistence, and decreased Salmonella enterica pathogenesis. Transgenic expression of NeST lncRNA alone was sufficient to confer all phenotypes of the SJL/J locus. NeST RNA was found to bind WDR5, a component of the histone H3 lysine 4 methyltransferase complex, and to alter histone 3 methylation at the IFN-γ locus. Thus, this lncRNA regulates epigenetic marking of IFN-γ-encoding chromatin, expression of IFN-γ, and susceptibility to a viral and a bacterial pathogen.
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► Dissection of viral susceptibility locus reveals the role of a long noncoding RNA, NeST ► NeST RNA expression is required for inducible IFN-γ synthesis in CD8+ T cells ► NeST RNA increases Theiler’s virus persistence and reduces Salmonella lethality ► NeST binds to histone modification complex, changing epigenetic marks at the Ifng locus
NeST, a long noncoding RNA whose expression and sequence are polymorphic in murine and human populations, epigenetically controls the expression of interferon-γ and confers differential pathogen susceptibility in the mouse.
The design of efficient gene delivery vectors is a challenging task in gene therapy. Recent progress in living/controlled radical polymerizations (LRPs), in particular atom transfer radical ...polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization providing a means for the design and synthesis of new polymeric gene vectors with well-defined compositions, architectures and functionalities is reviewed here. Polymeric gene vectors with different architectures, including homopolymers, block copolymers, graft copolymers, and star-shaped polymers, are conveniently prepared
via ATRP and RAFT polymerization. The corresponding synthesis strategies are described in detail. The recent research activities indicate that ATRP and RAFT polymerization have become essential tools for the design and synthesis of advanced, noble and novel gene carriers.
One of the outstanding challenges to information processing is the eloquent suppression of energy consumption in the execution of logic operations. The Landauer principle sets an energy constraint in ...deletion of a classical bit of information. Although some attempts have been made to experimentally approach the fundamental limit restricted by this principle, exploring the Landauer principle in a purely quantum mechanical fashion is still an open question. Employing a trapped ultracold ion, we experimentally demonstrate a quantum version of the Landauer principle, i.e., an equality associated with the energy cost of information erasure in conjunction with the entropy change of the associated quantized environment. Our experimental investigation substantiates an intimate link between information thermodynamics and quantum candidate systems for information processing.
We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer ...Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application.
We assessed a retrospective cohort of women from the Tübingen University Women’s Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features.
Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB 89 (19.7%), stage II 26 (5.8%), and stage III/IV 61 (13.5%). ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression-free (P=0.001) and disease-specific (P=0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, κ 0.88.
We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials.
Differential interference contrast (DIC) microscopy allows high-contrast, low-phototoxicity, and label-free imaging of transparent biological objects, and has been applied in the field of cellular ...morphology, cell segmentation, particle tracking, optical measurement and others. Commercial DIC microscopy based on Nomarski or Wollaston prism resorts to the interference of two polarized waves with a lateral differential offset (shear) and axial phase shift (bias). However, the shear generated by these prisms is limited to the rectilinear direction, unfortunately resulting in anisotropic contrast imaging. Here we propose an ultracompact metasurface-assisted isotropic DIC (i-DIC) microscopy based on a grand original pattern of radial shear interferometry, that converts the rectilinear shear into rotationally symmetric along radial direction, enabling single-shot isotropic imaging capabilities. The i-DIC presents a complementary fusion of typical meta-optics, traditional microscopes and integrated optical system, and showcases the promising and synergetic advancements in edge detection, particle motion tracking, and label-free cellular imaging.
Light strongly interacts with structures that are of a similar scale to its wavelength, typically nanoscale features for light in the visible spectrum. However, the optical response of these ...nanostructures is usually fixed during the fabrication. Phase change materials offer a way to tune the properties of these structures in nanoseconds. Until now, phase change active photonics has used materials that strongly absorb visible light, which limits their application in the visible spectrum. In contrast, Sb2S3 is an underexplored phase change material with a bandgap that can be tuned in the visible spectrum from 2.0 to 1.7 eV. This tuneable bandgap is deliberately coupled to an optical resonator such that it responds dramatically in the visible spectrum to Sb2S3 reversible structural phase transitions. It is shown that this optical response can be triggered both optically and electrically. High‐speed reprogrammable Sb2S3 based photonic devices, such as those reported here, are likely to have wide applications in future intelligent photonic systems, holographic displays, and microspectrometers.
Sb2S3 is a phase change material that is transparent to visible light. It exhibits a unity change in refractive index in the visible and near infrared range and can be switched in tens of nanoseconds. These properties are useful for high speed tuning and reprogramming of visible photonics devices.
Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the ...molecular categories identified in The Cancer Genome Atlas is proposed.
Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared.
Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves.
Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.
Intracranial aneurysms, a rare complication of radiation therapy, have been reported mainly in case reports or case series. We performed a multicenter, retrospective cohort study to investigate the ...characteristics of radiation-induced intracranial aneurysms.
Data on 2641 patients with intracranial aneurysms were retrospectively collected from 3 hospitals between January 2005 and June 2014. An additional 1519 patients were recruited from a single center between July 2014 and March 2020. Aneurysms in patients with a history of radiation therapy for at least 6 months were defined as radiation-related aneurysms. Patients' demographic profiles, clinical characteristics, and aneurysm parameters detected on CTA were compared between radiation-related and control groups.
Of the 4160 patients, the average age was 57.9 (SD, 13.5) years, 2406 (57.8%) were women, 477 (11.5%) had multiple aneurysms, 3009 (72.3%) had SAH, and 34 (0.8%) had radiation-related aneurysms. The male-to-female ratio in the radiation-related group was significantly higher than that in the control group (2.4:1 versus 0.72:1,
= .001). The mean age of the radiation-related group was significantly younger than in the control group (51.4 SD, 15.0 years versus 58.2 SD, 13.5 years,
= .003). More patients in the radiation-related group presented with SAH than in the control group (without age and sex matching, 88.2% versus 72.2%,
= .037; with age and sex matching, 88.2% versus 58.8%,
= .006). Of the 4813 intracranial aneurysms, only 43 (0.9%) aneurysms were categorized as in the radiation-related group, whereas 4770 (99.1%) aneurysms constituted the control group. Compared with the control group, there was a significantly higher proportion of sidewall aneurysms (46.5% versus 32.3%,
= .048) and a predilection for aneurysms involving the ICA and posterior circulation arteries (72.1% versus 52.2%,
= .046) in the radiation-related group.
Compared with the control group, radiation-related aneurysms are more prone to occur in men and young patients, with a higher percentage of sidewall aneurysms located in the ICA and posterior circulation arteries. Furthermore, SAH is highly prevalent in patients with radiation-induced aneurysms, indicating that dedicated screening for aneurysms after radiation therapy is necessary, but further studies are needed to determine when and how to screen.
Lanthanide‐doped nanophosphors are promising in anti‐counterfeiting and security printing applications. These nanophosphors can be incorporated as transparent inks that fluoresce by upconverting ...near‐infrared illumination into visible light to allow easy verification of documents. However, these inks typically exhibit a single luminescent color, low emission efficiency, and low print resolutions. Tunable resonator‐upconverted emission (TRUE) is achieved by placing upconversion nanoparticles (UCNPs) within plasmonic nanoresonators. A range of TRUE colors are obtained from a single‐UCNP species self‐assembled within size‐tuned gap‐plasmon resonances in Al nanodisk arrays. The luminescence intensities are enhanced by two orders of magnitude through emission and absorption enhancements. The enhanced emissive and plasmonic colors are simultaneously employed to generate TRUE color prints that exhibit one appearance under ambient white light, and a multicolored luminescence appearance that is revealed under near‐infrared excitation. The printed color and luminescent images are of ultrahigh resolutions (≈50 000 dpi), and enable multiple colors from a single excitation source for increased level of security.
Tunable resonator‐upconverted emission is demonstrated with embedding monolayer NaGdF4:Yb,Er nanocrystals within gap‐plasmon resonators. Plasmonic enhanced absorption and radiative decay underpin the greatly enhanced luminescence. Multiple luminescent and plasmonic colors are simultaneously utilized to incorporate different covert luminescent information underneath an ultrahigh resolution plasmonic color print.
The genetic basis of many brain and spinal arteriovenous malformations is unclear. Hong et al. reveal a causative role for somatic tumour-related mutations in KRAS/BRAF in the majority of patients ...tested. This homogeneity supports therapeutic targeting of the RAS/RAF/MAPK pathway without the need for tissue genetic diagnosis.
Abstract
Brain and spinal arteriovenous malformations are congenital lesions causing intracranial haemorrhage or permanent disability especially in young people. We investigated whether the vast majority or all brain and spinal arteriovenous malformations are associated with detectable tumour-related somatic mutations. In a cohort of 31 patients (21 with brain and 10 with spinal arteriovenous malformations), tissue and paired blood samples were analysed with ultradeep next generation sequencing of a panel of 422 common tumour genes to identify the somatic mutations. We used droplet digital polymerase chain reaction to confirm the panel sequenced mutations and identify the additional low variant frequency mutations. The association of mutation variant frequencies and clinical features were analysed. The average sequencing depth was 1077 ± 298×. High prevalence (87.1%) of KRAS/BRAF somatic mutations was found in brain and spinal arteriovenous malformations with no other replicated tumour-related mutations. The prevalence of KRAS/BRAF mutation was 81.0% (17 of 21) in brain and 100% (10 of 10) in spinal arteriovenous malformations. We detected activating BRAF mutations and two novel mutations in KRAS (p.G12A and p.S65_A66insDS) in CNS arteriovenous malformations for the first time. The mutation variant frequencies were negatively correlated with nidus volumes of brain (P = 0.038) and spinal (P = 0.028) arteriovenous malformations but not ages. Our findings support a causative role of somatic tumour-related mutations of KRAS/BRAF in the overwhelming majority of brain and spinal arteriovenous malformations. This pathway homogeneity and high prevalence implies the development of targeted therapies with RAS/RAF pathway inhibitors without the necessity of tissue genetic diagnosis.
10.1093/brain/awy307_video1
awy307media1
5978667388001
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