LINC00115 promotes chemoresistant breast cancer stem-like cell stemness and metastasis through SETDB1/PLK3/HIF1α signaling.

BACKGROUND: Cancer stem-like cell is a key barrier for therapeutic resistance and metastasis in various cancers, including breast cancer, yet the underlying mechanisms are still elusive. Through a genome-wide lncRNA expression profiling, we identified that LINC00115 is robustly upregulated in chemoresistant breast cancer stem-like cells (BCSCs). METHODS: LncRNA microarray assay was performed to document abundance changes of lncRNAs in paclitaxel (PTX)-resistant MDA-MB-231 BCSC (ALDH+) and non-BCSC (ALDH-). RNA pull-down and RNA immunoprecipitation (RIP) assays were performed to determine the binding proteins of LINC00115. The clinical significance of the LINC00115 pathway was examined in TNBC metastatic lymph node tissues. The biological function of LINC00115 was investigated through gain- and loss-of-function studies. The molecular mechanism was explored through RNA sequencing, mass spectrometry, and the CRISPR/Cas9-knockout system. The therapeutic potential of LINC00115 was examined through xenograft animal models. RESULTS: LINC00115 functions as a scaffold lncRNA to link SETDB1 and PLK3, leading to enhanced SETDB1 methylation of PLK3 at both K106 and K200 in drug-resistant BCSC. PLK3 methylation decreases PLK3 phosphorylation of HIF1α and thereby increases HIF1α stability. HIF1α, in turn, upregulates ALKBH5 to reduce m6A modification of LINC00115, resulting in attenuated degradation of YTHDF2-dependent m6A-modified RNA and enhanced LINC00115 stability. Thus, this positive feedback loop provokes BCSC phenotypes and enhances chemoresistance and metastasis in triple-negative breast cancer. SETDB1 inhibitor TTD-IN with LINC00115 ASO sensitizes PTX-resistant cell response to chemotherapy in a xenograft animal model. Correlative expression of LINC00115, methylation PLK3, SETDB1, and HIF1α are prognostic for clinical triple-negative breast cancers. CONCLUSIONS: Our findings uncover LINC00115 as a critical regulator of BCSC and highlight targeting LINC00115 and SETDB1 as a potential therapeutic strategy for chemotherapeutic resistant breast cancer.

Full Spatial Characterization of Entangled Structured Photons.

Vector modes are fully polarized modes of light with spatially varying polarization distributions, and they have found widespread use in numerous applications such as microscopy, metrology, optical trapping, nanophotonics, and communications. The entanglement of such modes has attracted significant interest, and it has been shown to have tremendous potential in expanding existing applications and enabling new ones. However, due to the complex spatially varying polarization structure of entangled vector modes (EVMs), a complete entanglement characterization of these modes remains challenging and time consuming. Here, we have used a time-tagging event camera to demonstrate the ability to completely characterize the entanglement of EVMs. Leveraging the camera's capacity to provide independent measurements for each pixel, we simultaneously characterize the entanglement of approximately 2.6×10^{6} modes between a bipartite EVM through measuring only 16 observables in polarization. We reveal that EVMs can naturally generate various polarization-entangled Bell states. This achievement is an important milestone in high-dimensional entanglement characterization of structured light, and it could significantly impact the implementation of related quantum technologies. The potential applications of this technique are extensive, and it could pave the way for advancements in quantum communication, quantum imaging, and other areas where structured entangled photons play a crucial role.

Germline Neurofibromin 1 mutation enhances the anti-tumour immune response and decreases juvenile myelomonocytic leukaemia tumourigenicity.

Juvenile myelomonocytic leukaemia (JMML) is an aggressive paediatric leukaemia characterized by mutations in five canonical RAS pathway genes, including the NF1 gene. JMML is driven by germline NF1 gene mutations, with additional somatic aberrations resulting in the NF1 biallelic inactivation, leading to disease progression. Germline mutations in the NF1 gene alone primarily cause benign neurofibromatosis type 1 (NF1) tumours rather than malignant JMML, yet the underlying mechanism remains unclear. Here, we demonstrate that with reduced NF1 gene dose, immune cells are promoted in anti-tumour immune response. Comparing the biological properties of JMML and NF1 patients, we found that not only JMML but also NF1 patients driven by NF1 mutations could increase monocytes generation. But monocytes cannot further malignant development in NF1 patients. Utilizing haematopoietic and macrophage differentiation from iPSCs, we revealed that NF1 mutations or knockout (KO) recapitulated the classical haematopoietic pathological features of JMML with reduced NF1 gene dose. NF1 mutations or KO promoted the proliferation and immune function of NK cells and iMacs derived from iPSCs. Moreover, NF1-mutated iNKs had a high capacity to kill NF1-KO iMacs. NF1-mutated or KO iNKs administration delayed leukaemia progression in a xenograft animal model. Our findings demonstrate that germline NF1 mutations alone cannot directly drive JMML development and suggest a potential cell immunotherapy for JMML patients.

Identification of functional cooperative mutations of GNAO1 in human acute lymphoblastic leukemia.

Leukemogenesis is characterized by chromosomal rearrangements with additional molecular disruptions, yet the cooperative mechanisms are still unclear. Using whole-exome sequencing of a pair of monozygotic twins who were discordant for childhood acute lymphoblastic leukemia (ALL) with ETV6-RUNX1 (E/R) gene fusion successively after birth, we identified the R209C mutation of G protein subunit α o1 (GNAO1) as a new ALL risk loci. Moreover, GNAO1 missense mutations are recurrent in ALL patients and are associated with E/R fusion. Ectopic expression of the GNAO1 R209C mutant increased its GTPase activity and promoted cell proliferation and cell neoplastic transformation. Combined with the E/R fusion, the GNAO1 R209C mutation promoted leukemogenesis through activating PI3K/Akt/mTOR signaling. Reciprocally, activated mTORC1 phosphorylated p300 acetyltransferase, which acetylated E/R and thereby enhanced the E/R transcriptional activity of GNAO1 R209C. Thus, our study provides clinical evidence of the functional cooperation of GNAO1 mutations and E/R fusion, suggesting GNAO1 as a therapeutic target in human leukemia.

Snapshot hyperspectral imaging with quantum correlated photons.

Hyperspectral imaging (HSI) has a wide range of applications from environmental monitoring to biotechnology. Conventional snapshot HSI techniques generally require a trade-off between spatial and spectral resolution and are thus limited in their ability to achieve high resolutions in both simultaneously. Most techniques are also resource inefficient with most of the photons lost through spectral filtering. Here, we demonstrate a proof-of-principle snapshot HSI technique utilizing the strong spectro-temporal correlations inherent in entangled photons using a modified quantum ghost spectroscopy system, where the target is directly imaged with one photon and the spectral information gained through ghost spectroscopy from the partner photon. As only a few rows of pixels near the edge of the camera are used for the spectrometer, effectively no spatial resolution is sacrificed for spectral. Also since no spectral filtering is required, all photons contribute to the HSI process making the technique much more resource efficient.

HDAC3 controls male fertility through enzyme-independent transcriptional regulation at the meiotic exit of spermatogenesis.

The transition from meiotic spermatocytes to postmeiotic haploid germ cells constitutes an essential step in spermatogenesis. The epigenomic regulatory mechanisms underlying this transition remain unclear. Here, we find a prominent transcriptomic switch from the late spermatocytes to the early round spermatids during the meiotic-to-postmeiotic transition, which is associated with robust histone acetylation changes across the genome. Among histone deacetylases (HDACs) and acetyltransferases, we find that HDAC3 is selectively expressed in the late meiotic and early haploid stages. Three independent mouse lines with the testis-specific knockout of HDAC3 show infertility and defects in meiotic exit with an arrest at the late stage of meiosis or early stage of round spermatids. Stage-specific RNA-seq and histone acetylation ChIP-seq analyses reveal that HDAC3 represses meiotic/spermatogonial genes and activates postmeiotic haploid gene programs during meiotic exit, with associated histone acetylation alterations. Unexpectedly, abolishing HDAC3 catalytic activity by missense mutations in the nuclear receptor corepressor (NCOR or SMRT) does not cause infertility, despite causing histone hyperacetylation as HDAC3 knockout, demonstrating that HDAC3 enzyme activity is not required for spermatogenesis. Motif analysis of the HDAC3 cistrome in the testes identified SOX30, which has a similar spatiotemporal expression pattern as HDAC3 during spermatogenesis. Depletion of SOX30 in the testes abolishes the genomic recruitment of the HDAC3 to the binding sites. Collectively, these results establish the SOX30/HDAC3 signaling as a key regulator of the transcriptional program in a deacetylase-independent manner during the meiotic-to-postmeiotic transition in spermatogenesis.

Manipulating the symmetry of transverse momentum entangled biphoton states.

Bell states are a fundamental resource in photonic quantum information processing. These states have been generated successfully in many photonic degrees of freedom. Their manipulation, however, in the momentum space remains challenging. Here, we present a scheme for engineering the symmetry of two-photon states entangled in the transverse momentum degree of freedom through the use of a spatially variable phase object. We demonstrate how a Hong-Ou-Mandel interferometer must be constructed to verify the symmetry in momentum entanglement via photon "bunching/anti-bunching" observation. We also show how this approach allows generating states that acquire an arbitrary phase under the exchange operation.

High-speed imaging of spatiotemporal correlations in Hong-Ou-Mandel interference.

The Hong-Ou-Mandel interference effect lies at the heart of many emerging quantum technologies whose performance can be significantly enhanced with increasing numbers of entangled modes one could measure and thus utilize. Photon pairs generated through the process of spontaneous parametric down conversion are known to be entangled in a vast number of modes in the various degrees of freedom (DOF) the photons possess such as time, energy, and momentum, etc. Due to limitations in detection technology and techniques, often only one such DOFs can be effectively measured at a time, resulting in much lost potential. Here, we experimentally demonstrate, with the aid of a time tagging camera, high speed measurement and characterization of two-photon interference. With a data acquisition time of only a few seconds, we observe a bi-photon interference and coalescence visibility of ∼64% with potentially up to ∼2 × 103 spatial modes. These results open up a route for practical applications of using the high dimensionality of spatiotemporal DOF in two-photon interference, and in particular, for quantum sensing and communication.

The plant hormone abscisic acid stimulates megakaryocyte differentiation from human iPSCs in vitro.

In the clinic, the supply of platelets is frequently insufficient to meet transfusion needs. To address this issue, many scientists have established the derivation of functional platelets from CD34+ cells or human pluripotent stem cells (PSCs). However, the yield of platelets is still far below what is required. Here we found that the plant hormone abscisic acid (ABA) could increase the generation of megakaryocytes (MKs) and platelets from human induced PSCs (hiPSCs). During platelet derivation, ABA treatment promoted the generation of CD34+/CD45+ HPCs and CD41+ MKs on day 14 and then increased CD41+/CD42b+ MKs and platelets on day 19. Moreover, we found ABA-mediated activation of Akt and ERK1/2 signal pathway through receptors LANCL2 and GRP78 in a PKA-dependent manner on CD34+/CD45+ cells. In conclusion, our data suggest that ABA treatment can promote CD34+/CD45+ HPC proliferation and CD41+ MK differentiation.

MYCN protein stability is a better prognostic indicator in neuroblastoma.

OBJECTIVE: MYCN oncogene amplification is associated with treatment failure and poor prognosis in neuroblastoma. To date, most detection methods of MYCN focus on DNA copy numbers instead of protein expression, which is the real one performing biological function, for poor antibodies. The current investigation was to explore a fast and reliable way to detect MYCN protein expression and evaluate its performance in predicting prognosis. METHODS: Several MYCN antibodies were used to detect MYCN protein expression by immunohistochemistry (IHC), and one was chosen for further study. We correlated the IHC results of MYCN from 53 patients with MYCN fluorescence in situ hybridization (FISH) and identified the sensitivity and specificity of IHC. The relationship between patient prognosis and MYCN protein expression was detected from this foundation. RESULTS: MYCN amplification status detected by FISH was most valuable for INSS stage 3 patients. In the cohort of 53 samples, IHC test demonstrated 80.0-85.7% concordance with FISH results. Further analyzing those cases with inconsistent results, we found that patients with MYCN amplification but low protein expression tumors always had a favorable prognosis. In contrast, if patients with MYCN non-amplified tumors were positive for MYCN protein, they had a poor prognosis. CONCLUSION: MYCN protein level is better than MYCN amplification status in predicting the prognosis of neuroblastoma patients. Joint of FISH and IHC could confirm MYCN protein stability and achieve better prediction effect than the singular method.

The effect of pterostilbene and its active ingredients on experimental pulmonary fibrosis in asthma: a meta-analysis.

Introduction: Pulmonary fibrosis (PF) is a chronic progressive interstitial lung disease caused by a variety of factors. Aim: To systematically evaluate the therapeutic effect of pterostilbene (PTE) on experimental PF in asthma and other oxidative damage pathway-related diseases, and to provide evidence for clinical treatment. Material and methods: Chinese and English databases such as CNKI, Wanfang, VIP, PubMed, Embase, Cochrane Library, and CBM were searched by computer. The Chinese literature on pterostilbene for the treatment of asthma by evaluating experimental pulmonary fibrosis, diabetes, and myocardial infarction was collected from the establishment of a randomized controlled trial until May 2021.Outcome indicators include related physical and chemical indicators such as MDA and SOD. Data were analysed using Review Manager 5.4 software after screening by 2 researchers. Results: Seven randomized controlled animal experiments were included, with a total sample size of 62 cases. Meta-analysis results showed the following: 1) compared with pulmonary fibrosis, diabetes and other model groups, the pterostilbene intervention group were able to up-regulate SOD, and the effect was better than that of the model group (MD = 20.87, 95% CI: 19.41-22.33; n = 7, I 2 = 96%); the pterostilbene intervention group could also up-regulate the expression of GSH, and its effect was better than that of the model group (MD = 9.37, 95% CI: 8.67-10.07; n = 2, I 2 = 98%). The MDA level of the intervention group was significantly down regulated, and the intervention group was also better than the model group. Pterostilbene can prevent experimental PF by lowering the level of MDA. Conclusions: Pterostilbene can effectively improve experimental pulmonary fibrosis, diabetes, myocardial infarction, and other oxidative damage pathway-related diseases have certain guiding significance for clinical trials on asthma.

Two-photon interference: the Hong-Ou-Mandel effect.

Nearly 30 years ago, two-photon interference was observed, marking the beginning of a new quantum era. Indeed, two-photon interference has no classical analogue, giving it a distinct advantage for a range of applications. The peculiarities of quantum physics may now be used to our advantage to outperform classical computations, securely communicate information, simulate highly complex physical systems and increase the sensitivity of precise measurements. This separation from classical to quantum physics has motivated physicists to study two-particle interference for both fermionic and bosonic quantum objects. So far, two-particle interference has been observed with massive particles, among others, such as electrons and atoms, in addition to plasmons, demonstrating the extent of this effect to larger and more complex quantum systems. A wide array of novel applications to this quantum effect is to be expected in the future. This review will thus cover the progress and applications of two-photon (two-particle) interference over the last three decades.

Sox30 initiates transcription of haploid genes during late meiosis and spermiogenesis in mouse testes.

Transcription factors of the Sox protein family contain a DNA-binding HMG box and are key regulators of progenitor cell fate. Here, we report that expression of Sox30 is restricted to meiotic spermatocytes and postmeiotic haploids. Sox30 mutant males are sterile owing to spermiogenic arrest at the early round spermatid stage. Specifically, in the absence of Sox30, proacrosomic vesicles fail to form a single acrosomal organelle, and spermatids arrest at step 2-3. Although most Sox30 mutant spermatocytes progress through meiosis, accumulation of diplotene spermatocytes indicates a delayed or impaired transition from meiotic to postmeiotic stages. Transcriptome analysis of isolated stage-specific spermatogenic cells reveals that Sox30 controls a core postmeiotic gene expression program that initiates as early as the late meiotic cell stage. ChIP-seq analysis shows that Sox30 binds to specific DNA sequences in mouse testes, and its genomic occupancy correlates positively with expression of many postmeiotic genes including Tnp1, Hils1, Ccdc54 and Tsks These results define Sox30 as a crucial transcription factor that controls the transition from a late meiotic to a postmeiotic gene expression program and subsequent round spermatid development.

High speed imaging of spectral-temporal correlations in Hong-Ou-Mandel interference.

In this work we demonstrate spectral-temporal correlation measurements of the Hong-Ou-Mandel (HOM) interference effect with the use of a spectrometer based on a photon-counting camera. This setup allows us to take, within seconds, spectral temporal correlation measurements on entangled photon sources with sub-nanometer spectral resolution and nanosecond timing resolution. Through post processing, we can observe the HOM behaviour for any number of spectral filters of any shape and width at any wavelength over the observable spectral range. Our setup also offers great versatility in that it is capable of operating at a wide spectral range from the visible to the near infrared and does not require a pulsed pump laser for timing purposes. This work offers the ability to gain large amounts of spectral and temporal information from a HOM interferometer quickly and efficiently and will be a very useful tool for many quantum technology applications and fundamental quantum optics research.

Molecular mechanism of c-Myc and PRPS1/2 against thiopurine resistance in Burkitt's lymphoma.

Patients with relapsed/refractory Burkitt's lymphoma (BL) have a dismal prognosis. Current research efforts aim to increase cure rates by identifying high-risk patients in need of more intensive or novel therapy. The 8q24 chromosomal translocation of the c-Myc gene, a main molecular marker of BL, is related to the metabolism by regulating phosphoribosyl pyrophosphate synthetase 2 (PRPS2). In our study, BL showed significant resistance to thiopurines. PRPS2 homologous isoenzyme, PRPS1, was demonstrated to play the main role in thiopurine resistance. c-Myc did not have direct effects on thiopurine resistance in BL for only driving PRPS2. PRPS1 wild type (WT) showed different resistance to 6-mercaptopurine (6-mp) in different metabolic cells because it could be inhibited by adenosine diphosphate or guanosine diphosphate negative feedback. PRPS1 A190T mutant could dramatically increase thiopurine resistance in BL. The interim analysis of the Treatment Regimen for Children or Adolescent with mature B cell non-Hodgkin's lymphoma in China (CCCG-B-NHL-2015 study) confirms the value of high-dose methotrexate (MTX) and cytarabine (ARA-C) in high-risk paediatric patients with BL. However, there remains a subgroup of patients with lactate dehydrogenase higher than four times of the normal value (4N) for whom novel treatments are needed. Notably, we found that the combination of thiopurines and the phosphoribosylglycinamide formyltransferase (GART) inhibitor lometrexol could serve as a therapeutic strategy to overcome thiopurine resistance in BL.

Theoretical analysis on spatially structured beam induced mass transport in azo-polymer films.

The radiation force from paraxial beams possessing helical phase fronts causes twists on the surface of an azobenzene polymer sample, and leads to the formation of micro-scale structures. Here, we theoretically investigate the radiation force generated by spatially structured optical beams on a dispersive-absorptive substrate. We derive an analytical expression for the radiation force from spatially structured polarized beams, including, lemon, star, monstar and vector vortex beams in the paraxial regime. Finally, we extend our calculation for non-paraxial beams - optical beams under the tight-focusing regime - and simulate the transverse radiation forces numerically at the focal plane.

Characterization of an underwater channel for quantum communications in the Ottawa River.

We examine the propagation of optical beams possessing different polarization states and spatial modes through the Ottawa River in Canada. A Shack-Hartmann wavefront sensor is used to record the distorted beam's wavefront. The turbulence in the underwater channel is analysed, and associated Zernike coefficients are obtained in real-time. Finally, we explore the feasibility of transmitting polarization states as well as spatial modes through the underwater channel for applications in quantum cryptography.

Interaction-free ghost-imaging of structured objects.

Quantum - or classically correlated - light can be employed in various ways to improve resolution and measurement sensitivity. In an "interaction-free" measurement, a single photon can be used to reveal the presence of an object placed within one arm of an interferometer without being absorbed by it. With a technique known as "ghost-imaging", entangled photon pairs are used for detecting an opaque object with significantly improved signal-to-noise ratio while preventing over-illumination. Here, we integrate these two methods to obtain a new imaging technique which we term "interaction-free ghost-imaging" (IFGI). With this new technique, we reduce photon illumination on the object by up to 26.5% while still maintaining at least the same image quality of conventional ghost-imaging. Alternatively, IFGI can improve image signal-to-noise ratio by 18% when given the same number of interacting photons as in standard ghost-imaging. IFGI is also sensitive to phase and polarisation changes of the photons introduced by a structured object. These advantages make IFGI superior for probing light-sensitive materials and biological tissues.

A germline-specific role for the mTORC2 component Rictor in maintaining spermatogonial differentiation and intercellular adhesion in mouse testis.

STUDY QUESTION: What is the physiological role of Rictor in spermatogenic cells? SUMMARY ANSWER: Germline expression of Rictor regulates spermatogonial differentiation and has an essential role in coordinating germ cells and Sertoli cells in maintaining intact cell-cell adhesion dynamics and cytoskeleton-based architecture in the seminiferous epithelium. WHAT IS KNOWN ALREADY: The mechanistic target of rapamycin (mTOR) resides in its functions as the catalytic subunits of the structurally and functionally distinct mTORC1 and mTORC2 complexes. In the mammalian testis, mTORC1 regulates spermatogonial stem cell self-renewal and differentiation, whereas mTORC2 is required for Sertoli cell function. In contrast to mTORC1, mTORC2 has been much less well studied. Rictor is a distinct component of the mTORC2 complex. STUDY DESIGN, SIZE, DURATION: We investigated the effects of germ cell-specific ablation of Rictor on testicular development by using a mouse model of germline-specific ablation of Rictor. PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed the in-vivo functions of Rictor through different methods including histology, immunofluorescent staining, chromosome spreads, blood-testis barrier (BTB) integrity assays and RNA sequencing. MAIN RESULTS AND THE ROLE OF CHANCE: Mutant mice did not show a defect in meiotic synapsis or recombination, but exhibited compromised spermatogonial differentiation potential, disorganized cell-cell junctions, impaired BTB dynamics and defective spermiogenesis. Concomitantly, RNA-seq profiling revealed that many genes involved in adhesion and migration were expressed inappropriately. LARGE SCALE DATA: RNA-seq data are published in the SRA database (PRJNA419273). LIMITATIONS REASONS FOR CAUTION: A detailed analysis of the mechanisms underlying the phenotype needs further investigations. WIDER IMPLICATIONS OF THE FINDINGS: Our work provides previously unidentified in-vivo evidence that germline expression of Rictor plays a role in maintaining spermatogonial differentiation and cell-cell adhesion. These findings are important for understanding the regulation of spermatogenesis and have clinical implications for the effect of mTOR inhibitors on human fertility. STUDY FUNDING AND COMPETING INTEREST(S): This study was supported by National Key R&D Program of China (2016YFA0500902), National Natural Science Foundation of China (31471228 and 31771653), Jiangsu Science Foundation for Distinguished Young Scholars (BK20150047), and Natural Science Foundation of Jiangsu Province (BK20140897, 14KJA180005 and 14KJB310004) to K.Z. The authors declare no competing or financial interests.

Quantum cryptography with twisted photons through an outdoor underwater channel.

Quantum communication has been successfully implemented in optical fibres and through free-space. Fibre systems, though capable of fast key and low error rates, are impractical in communicating with destinations without an established fibre link. Free-space quantum channels can overcome such limitations and reach long distances with the advent of satellite-to-ground links. However, turbulence, resulting from local fluctuations in refractive index, becomes a major challenge by adding errors and losses. Recently, an interest in investigating the possibility of underwater quantum channels has arisen. Here, we investigate the effect of turbulence on an underwater quantum channel using twisted photons in outdoor conditions. We study the effect of turbulence on transmitted error rates, and compare different quantum cryptographic protocols in an underwater quantum channel, showing the feasibility of high-dimensional encoding schemes. Our work may open the way for secure high-dimensional quantum communication between submersibles, and provides important input for potential submersibles-to-satellite quantum communication.