Intrinsically disordered Meningioma-1 stabilizes the BAF complex to cause AML.

Meningioma-1 (MN1) overexpression in AML is associated with poor prognosis, and forced expression of MN1 induces leukemia in mice. We sought to determine how MN1 causes AML. We found that overexpression of MN1 can be induced by translocations that result in hijacking of a downstream enhancer. Structure predictions revealed that the entire MN1 coding frame is disordered. We identified the myeloid progenitor-specific BAF complex as the key interaction partner of MN1. MN1 over-stabilizes BAF on enhancer chromatin, a function directly linked to the presence of a long polyQ-stretch within MN1. BAF over-stabilization at binding sites of transcription factors regulating a hematopoietic stem/progenitor program prevents the developmentally appropriate decommissioning of these enhancers and results in impaired myeloid differentiation and leukemia. Beyond AML, our data detail how the overexpression of a polyQ protein, in the absence of any coding sequence mutation, can be sufficient to cause malignant transformation.

A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism.

Heterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy (DEE) as a result of a dominant-negative mechanism impeding vesicular fission. Thus far, pathogenic variants in DNM1 have been studied with a canonical transcript that includes the alternatively spliced exon 10b. However, after performing RNA sequencing in 39 pediatric brain samples, we find the primary transcript expressed in the brain includes the downstream exon 10a instead. Using this information, we evaluated genotype-phenotype correlations of variants affecting exon 10a and identified a cohort of eleven previously unreported individuals. Eight individuals harbor a recurrent de novo splice site variant, c.1197-8G>A (GenBank: NM_001288739.1), which affects exon 10a and leads to DEE consistent with the classical DNM1 phenotype. We find this splice site variant leads to disease through an unexpected dominant-negative mechanism. Functional testing reveals an in-frame upstream splice acceptor causing insertion of two amino acids predicted to impair oligomerization-dependent activity. This is supported by neuropathological samples showing accumulation of enlarged synaptic vesicles adherent to the plasma membrane consistent with impaired vesicular fission. Two additional individuals with missense variants affecting exon 10a, p.Arg399Trp and p.Gly401Asp, had a similar DEE phenotype. In contrast, one individual with a missense variant affecting exon 10b, p.Pro405Leu, which is less expressed in the brain, had a correspondingly less severe presentation. Thus, we implicate variants affecting exon 10a as causing the severe DEE typically associated with DNM1-related disorders. We highlight the importance of considering relevant isoforms for disease-causing variants as well as the possibility of splice site variants acting through a dominant-negative mechanism.

Decoding temporal heterogeneity in NSCLC through machine learning and prognostic model construction.

BACKGROUND: Non-small cell lung cancer (NSCLC) is a prevalent and heterogeneous disease with significant genomic variations between the early and advanced stages. The identification of key genes and pathways driving NSCLC tumor progression is critical for improving the diagnosis and treatment outcomes of this disease. METHODS: In this study, we conducted single-cell transcriptome analysis on 93,406 cells from 22 NSCLC patients to characterize malignant NSCLC cancer cells. Utilizing cNMF, we classified these cells into distinct modules, thus identifying the diverse molecular profiles within NSCLC. Through pseudotime analysis, we delineated temporal gene expression changes during NSCLC evolution, thus demonstrating genes associated with disease progression. Using the XGBoost model, we assessed the significance of these genes in the pseudotime trajectory. Our findings were validated by using transcriptome sequencing data from The Cancer Genome Atlas (TCGA), supplemented via LASSO regression to refine the selection of characteristic genes. Subsequently, we established a risk score model based on these genes, thus providing a potential tool for cancer risk assessment and personalized treatment strategies. RESULTS: We used cNMF to classify malignant NSCLC cells into three functional modules, including the metabolic reprogramming module, cell cycle module, and cell stemness module, which can be used for the functional classification of malignant tumor cells in NSCLC. These findings also indicate that metabolism, the cell cycle, and tumor stemness play important driving roles in the malignant evolution of NSCLC. We integrated cNMF and XGBoost to select marker genes that are indicative of both early and advanced NSCLC stages. The expression of genes such as CHCHD2, GAPDH, and CD24 was strongly correlated with the malignant evolution of NSCLC at the single-cell data level. These genes have been validated via histological data. The risk score model that we established (represented by eight genes) was ultimately validated with GEO data. CONCLUSION: In summary, our study contributes to the identification of temporal heterogeneous biomarkers in NSCLC, thus offering insights into disease progression mechanisms and potential therapeutic targets. The developed workflow demonstrates promise for future applications in clinical practice.

Telephoto achromatic camera based on optical-digital co-design.

Due to the difficulty of correcting chromatic aberration (CA) in telephoto cameras, recent studies have combined image algorithms with simple optical structures, such as single-spherical lenses, for high-quality photography, moving away from complex optics. However, this approach often struggles to comprehensively address compounded issues arising from optical aberrations of simple optical systems, including defocus blur and multi-channel misalignment. To tackle this challenge, this manuscript presents an approach for developing a telephoto imaging system by leveraging the distinct characteristics of axial and lateral chromatic aberrations (ACA, LCA) over the visible spectrum. The optical design is limited to a specific wavelength range to preserve high-frequency information of the green channel. A cross-channel fitting method is presented to suppress the LCA. Subsequently, the powerful capabilities of deep learning are utilized to correct ACA, defocus blur, and other residual optical aberrations. Simulation experiments demonstrate the effectiveness of the proposed approach in mitigating the CA inherent in telephoto systems, thereby delivering high-quality imaging results over the whole visible waveband.

Off-axis four-mirror telescope with a wide field of view and a long focal length using double integrated mirrors.

An off-axis four-mirror optical system has the advantages of a wide field of view (FOV) and a small telephoto ratio. However, it will bring difficulties in assembly and detection. Here we report an off-axis four-mirror free-form telescope with a long focal length and a wide field of view based on two integration mirrors. The initial structure of a coaxial four-mirror optical system is established based on the Seidel aberration theory. A Zernike Fringe free-form surface is introduced to correct aberrations. By gradually increasing the entrance pupil diameter and the FOV, we finally obtain an off-axis four-mirror telescope with a FOV of 0.4∘×20∘, an F-number of 11.5, a long focal length of 2000 mm, and a volume of 360×400×600m m 3. In addition, four mirrors remain coaxially aligned, remarkably facilitating detection and adjustment. The proposed off-axis four-mirror telescope, with double integration mirrors, holds great potential for application in aerospace remote sensing observations.

FOCAD Indel in a Family With Juvenile Polyposis Syndrome.

Juvenile polyposis syndrome (JPS) is a childhood polyposis syndrome with up to a 50% lifetime risk of gastrointestinal cancer. Germline pathogenic variants in BMPR1A and SMAD4 are responsible for around 40% of cases of JPS, but for the majority of individuals, the underlying genetic cause is unknown. We identified a family for which polyposis spanned four generations, and the proband had a clinical diagnosis of JPS. Next-generation sequencing was conducted, followed by Sanger sequencing confirmation. We identified an internal deletion of the FOCAD gene in all family members tested that altered the reading frame and is predicted to be pathogenic. We conclude that inactivation of the FOCAD gene is likely to cause JPS in this family.

Gustatory event-related potential alterations in olfactory dysfunction patients.

The phenomenon that longstanding impaired olfactory function is associated with the decreased gustatory function was described in present studies, which was seems attributed to mutual chemosensory interactions. And the interaction between olfaction and gustation still needs more research to figure out. The objective of the study was to investigate how the taste was influenced by olfactory impairment in the central pathway. We tested 33 subjects with normal (n = 19) or impaired (n = 14) olfactory function for their gustatory event-related potentials (gERPs). Validated tests were used for olfactory and gustatory testing (Sniffin' Sticks, gERPs, and three-drop test). This study reported an objective gustatory function decline in olfactory dysfunction participants. However, it also reported the increased gustatory event-related potentials of olfactory dysfunction participants, especially at the frontal electrode (FZ) and electrode 16 (E16), and the reduced latency of P2 peak of them at electrode 21 (E21), while no obvious difference was observed at the centro-parietal electrode (PZ). Inferior insula might be the main response area for the increase in gERPs, and this increase averaged amplitude of the P2 component may attribute to compensation of the secondary gustatory response that occurred in the gustatory processing of olfactory-impaired patients.

Two-Dimensional Frank-Kasper Z Phase with One Unit-Cell Thickness.

Z phase is one of the three basic units by which the Frank-Kasper (F-K) phases are generally assembled. Compared to the other two basic units, that is, A15 and C15 structures, the Z structure is rarely experimentally observed because of a relatively large volume ratio among the constituents to inhibit its formation. Moreover, the discovered Z structures are generally the three-dimensional ordered Gibbs bulk phases to conform to their thermodynamic stability. Here, we confirmed the existence of a metastable two-dimensional F-K Z phase that has only one unit-cell height in the crystallography in a model Mg-Sm-Zn system, using atomic-scale scanning transmission electron microscopy combined with the first-principles calculations. Self-adapted atomic shuffling can convert the simple hexagonal close-packed structure to the topologically close-packed F-K Z phase. This finding provides new insight into understanding the formation mechanism and clustering behavior of the F-K phases and even quasicrystals in general condensed matters.

Twin Boundary Superstructures Assembled by Periodic Segregation of Solute Atoms.

Twinning is a common deformation mechanism in metals, and twin boundary (TB) segregation of impurities/solutes plays an important role in the performances of alloys such as thermostability, mobility, and even strengthening. The occurrence of such segregation phenomena is generally believed as a one-layer coverage of solutes alternately distributed at extension/compression sites, in an orderly, continuous manner. However, in the Mn-free and Mn-containing Mg-Nd model systems, we reported unexpected three- and five-layered discontinuous segregation patterns of the coherent {101̅1} TBs, and not all the extension sites occupied by solutes larger in size than Mg, and even some larger sized solutes taking the compression sites. Nd/Mn solutes selectively segregate at substitutional sites and thus to generate two new types of ordered two-dimensional TB superstructures or complexions. These findings refresh the understanding of solute segregation in the perfect coherent TBs and provide a meaningful theoretical guidance for designing materials via targeted TB segregation.

Nonsymmetrical Segregation of Solutes in Periodic Misfit Dislocations Separated Tilt Grain Boundaries.

Interfacial segregation is ubiquitous in mulit-component polycrystalline materials and plays a decisive role in material properties. So far, the discovered solute segregation patterns at special high-symmetry interfaces are usually located at the boundary lines or are distributed symmetrically at the boundaries. Here, in a model Mg-Nd-Mn alloy, we confirm that elastic strain minimization facilitated nonsymmetrical segregation of solutes in four types of linear tilt grain boundaries (TGBs) to generate ordered interfacial superstructures. Aberration-corrected high-angle annular dark-field scanning transmission electron microscopy observations indicate that the solutes selectively segregate at substitutional sites at the linear TGBs separated by periodic misfit dislocations to form such two-dimensional planar structures. These findings are totally different from the classical McLean-type segregation which has assumed the monolayer or submonolayer coverage of a grain boundary and refresh understanding on strain-driven interface segregation behaviors.

Oxidation ruled transition from normal to anomalous periodic structures with femtosecond laser irradiation on Cr/Si films.

Elucidation of the underlying physics for laser-induced periodic surface structures (LIPSSs) is of great importance for their controllable fabrication. We here demonstrate a periodic structure transition from normal to anomalous morphology, upon femtosecond laser irradiation on 50-nm thick Cr/Si films in an air pressure-tunable chamber. As the air pressure gradually decreases, the amount of surface oxide induced by preceding laser pulses is found to reduce, and eventually triggering the structure evolution from the anomalously oriented subwavelength to normally oriented deep-subwavelength LIPSSs. The intriguing structure transition is explained in terms of the competitive excitation between the transverse-electric scattered surface wave and transverse-magnetic hybrid plasmon wave, which is ruled by the thickness of the preformed oxide layer indeed.

Precision treatment exploration of breast cancer based on heterogeneity analysis of lncRNAs at the single-cell level.

BACKGROUND: Breast cancer (BC) is a complex disease with high heterogeneity, which often leads to great differences in treatment results. Current common molecular typing method is PAM50, which shows positive results for precision medicine; however, room for improvement still remains because of the different prognoses of subtypes. Therefore, in this article, we used lncRNAs, which are more tissue-specific and developmental stage-specific than other RNAs, as typing markers and combined single-cell expression profiles to retype BC, to provide a new method for BC classification and explore new precise therapeutic strategies based on this method. METHODS: Based on lncRNA expression profiles of 317 single cells from 11 BC patients, SC3 was used to retype BC, and differential expression analysis and enrichment analysis were performed to identify biological characteristics of new subtypes. The results were validated for survival analysis using data from TCGA. Then, the downstream regulatory genes of lncRNA markers of each subtype were searched by expression correlation analysis, and these genes were used as targets to screen therapeutic drugs, thus proposing new precision treatment strategies according to the different subtype compositions of patients. RESULTS: Seven lncRNA subtypes and their specific biological characteristics are obtained. Then, 57 targets and 210 drugs of 7 subtypes were acquired. New precision medicine strategies were proposed according to the different compositions of patient subtypes. CONCLUSIONS: For patients with different subtype compositions, we propose a strategy to select different drugs for different patients, which means using drugs targeting multi subtype or combinations of drugs targeting a single subtype to simultaneously kill different cancer cells by personalized treatment, thus reducing the possibility of drug resistance and even recurrence.

Construction and application of color fundus image segmentation algorithm based on Multi-Scale local combined global enhancement.

OBJECTIVE: Aiming at the problem of low accuracy in extracting small blood vessels from existing retinal blood vessel images, a retinal blood vessel segmentation method based on a combination of a multi-scale linear detector and local and global enhancement is proposed. METHODS: The multi-scale line detector is studied, and it is divided into two parts: small scale and large scale. The small scale is used to detect the locally enhanced image and the large scale is used to detect the globally enhanced image. Fusion the response functions at different scales to get the final retinal vascular structure. RESULTS: Experiments on two databases STARE and DRIVE, show that the average vascular accuracy rates obtained by the algorithm reach 96.62% and 96.45%, and the average true positive rates reach 75.52% and 83.07%, respectively. CONCLUSION: The segmentation accuracy is high, and better blood vessel segmentation results can be obtained.

A pilot-scale three-dimensional electrochemical reactor combined with anaerobic-anoxic-oxic system for advanced treatment of coking wastewater.

Coking wastewater is highly concentrated and extremely toxic, greatly challenging the treatment technologies. Conventional biological technology such as anaerobic-anoxic-oxic (A2O) system is inefficient, since various biological reactions are inhibited by toxicants in coking wastewater. In this work, a pilot-scale three-dimensional electrochemical reactor (3DER) is integrated into the A2O system as a pretreatment unit to improve the treatment efficiency of coking wastewater. The results indicate that 3DER pretreatment increased the biodegradability of coking wastewater, promoting the degradation of coking wastewater in A2O system. The integrated 3DER-A2O system can remove 94.4% of COD and 76.2% of TN from coking wastewater, and the energy consumption was only 0.22 kWh/kg COD and 4.69 kWh/kg TN. The components of coking wastewater were significantly simplified and the acute toxicity was reduced from 99% to 12% after the treatment. The integrated 3DER-A2O system provides a new solution for coking wastewater treatment, showing a promising application potential.

Optically injected intensity-stable pulse source for secure quantum key distribution.

The security of decoy-state quantum key distribution (QKD) highly depends on the accurate control of multiple intensity states. Although several theoretical studies on the QKD with loosely controlled source intensities have been proposed, there is still a large gap between the experimental realization and the theoretical analysis. In this paper, we adopt the gain-switching method to generate short optical pulses, and the corresponding intensity stabilities are quantitatively measured. The method via optical injection is proposed to make effective reductions of the intensity fluctuations from 6.47%∼1.59% to 1.95%∼1.15% at different optical powers. QKD performance adopting the experimental results is also analyzed and discussed. For a typical 40 dB high-attenuation QKD system, the relative increase on the secure key rates reaches 51.89% for the corresponding intensity fluctuations of 1.15% with optical injection and 1.59% without optical injection. The presented intensity-stable optical pulse source can find wide applications in different QKD protocols, such as BB84, DPS, COW, etc.

High-speed robust polarization modulation for quantum key distribution.

Polarization modulation plays a key role in polarization-encoding quantum key distribution (QKD). Here, we report a new, to the best of our knowledge, polarization modulation scheme based on an inherently stable Sagnac interferometer. The presented scheme is free of polarization mode dispersion and calibration as well as insensitive to environmental influences. Successful experiments at a repetition frequency of 1.25 GHz have been conducted to demonstrate the feasibility and stability of the scheme. The measured average quantum bit-error rate of the four polarization states is as low as 0.27% for 80 consecutive minutes without any adjustment. This high-speed intrinsically stable polarization modulation can be widely applied to many polarization-encoding QKD systems, such as BB84, MDI, etc.

Biological evaluation and energetic analyses of novel GSK-3ß inhibitors.

Glycogen synthase kinase-3 beta (GSK-3ß) is involved in multiple signaling pathways. Consistent with its critical roles in normal cells, abnormalities in GSK-3ß activity have been implicated in diabetes, heart disease, Parkinson disease, and Alzheimer's disease. In this study, a series of new scaffolds of small molecule inhibitors of GSK-3ß were identified by virtual screening and bioassay. Candidates that adhere to drug-like criteria from a virtual library of compounds were tested using computational docking studies. Twenty selected compounds were tested, which led to the discovery of two hits. Compound 14 (IC50 = 8.48 µM) and compound 19 (IC50 = 2.19 µM) were identified with high affinity. Molecular dynamics (MD) simulations, in conjunction with molecular mechanics/Poisson-Boltzmann surface area binding free-energy analysis, were employed to gain insight into the binding modes and energetics of GSK-3ß inhibitors. The detailed analysis of molecular dynamics results shows that Ile62, Val70, Tyr134, and Leu188 in GSK-3ß are key residues responsible to the binding of compound 14 and compound 19. Importantly, our results also validated this combined virtual screening and biophysical technique approach to discovery kinase inhibitors, which may be applied for future inhibitor discovery work for GSK-3ß.

New Structured Laves Phase in the Mg-In-Ca System with Nontranslational Symmetry and Two Unit Cells.

All of the AB_{2} Laves phases discovered so far satisfy the general crystalline structure characteristic of translational symmetry; however, we report here a new structured Laves phase directly precipitated in an aged Mg-In-Ca alloy by using aberration-corrected scanning transmission electron microscopy. The nanoprecipitate is determined to be a (Mg,In)_{2}Ca phase, which has a C14 Laves structure (hcp, space group: P6_{3}/mmc, a=6.25 Å, c=10.31 Å) but without any translational symmetry on the (0001)_{p} basal plane. The (Mg,In)_{2}Ca Laves phase contains two separate unit cells promoting the formation of five tiling patterns. The bonding of these patterns leads to the generation of the present Laves phase, followed by the Penrose geometrical rule. The orientation relationship between the Laves precipitate and Mg matrix is (0001)_{p}//(0001)_{α} and [11[over ¯]00]_{p}//[112[over ¯]0]_{α}. More specifically, in contrast to the traditional view that the third element would orderly replace other atoms in a manner of layer by layer on the close-packed (0001)_{L} plane, the In atoms here have orderly occupied certain position of Mg atomic columns along the [0001]_{L} zone axis. The finding would be interesting and important for understanding the formation mechanism of Laves phases, and even atom stacking behavior in condensed matter.

Association of Single-Nucleotide Polymorphisms of C-Reactive Protein Gene with Susceptibility to Infantile Sepsis in Southern China.

BACKGROUND C-reactive protein (CRP) is an important biomarker of sepsis. Several single-nucleotide polymorphisms (SNPs) in the CRP gene can determine plasma CRP levels and are risk factors in many diseases, such as cancer, arteritis, and diabetes. However, it is unknown whether polymorphisms in CRP are associated with susceptibility to and outcome of infantile sepsis. We explored the effect of these SNPs on CRP response in infantile sepsis, and compared genetic data on patients with sepsis. MATERIAL AND METHODS A total of 49 infants with sepsis and 20 healthy infants were enrolled during hospitalization, and 3 SNPs in the CRP gene region (rs1205, rs2808530, and rs3091244) were genotyped and then analyzed for associations with CRP levels and sepsis. RESULTS The CRP means concentration results showed that mean CRP concentration was different in the 4 groups (healthy, sepsis, severe sepsis, and septic shock) and was positively correlated with the severity of infantile sepsis. There was also a difference in CRP SNP rs1205 between infants with septic shock and healthy infants, and between infants with septic shock and infants with sepsis. No differences were observed in SNP rs2808630 and SNP rs3091244. CONCLUSIONS Our study suggests that rs1205 genetic variability in the CRP gene determines the CRP levels in sepsis of different severities, while SNP rs3091244 and SNP rs2808630 are not associated with sepsis. However, the results of the present study on SNP rs1205, rs3091244, and rs2808630 in the CRP gene should be interpreted with caution due to limited sample size and sample heterogeneity. Large-scale, well-designed studies are needed to validate our findings.

Copy-number variation is an important contributor to the genetic causality of inherited retinal degenerations.

PURPOSE: Despite substantial progress in sequencing, current strategies can genetically solve only approximately 55-60% of inherited retinal degeneration (IRD) cases. This can be partially attributed to elusive mutations in the known IRD genes, which are not easily identified by the targeted next-generation sequencing (NGS) or Sanger sequencing approaches. We hypothesized that copy-number variations (CNVs) are a major contributor to the elusive genetic causality of IRDs. METHODS: Twenty-eight cases previously unsolved with a targeted NGS were investigated with whole-genome single-nucleotide polymorphism (SNP) and comparative genomic hybridization (CGH) arrays. RESULTS: Deletions in the IRD genes were detected in 5 of 28 families, including a de novo deletion. We suggest that the de novo deletion occurred through nonallelic homologous recombination (NAHR) and we constructed a genomic map of NAHR-prone regions with overlapping IRD genes. In this article, we also report an unusual case of recessive retinitis pigmentosa due to compound heterozygous mutations in SNRNP200, a gene that is typically associated with the dominant form of this disease. CONCLUSIONS: CNV mapping substantially increased the genetic diagnostic rate of IRDs, detecting genetic causality in 18% of previously unsolved cases. Extending the search to other structural variations will probably demonstrate an even higher contribution to genetic causality of IRDs.Genet Med advance online publication 13 October 2016.