3D Chromatin Structures of Mature Gametes and Structural Reprogramming during Mammalian Embryogenesis.

High-order chromatin structure plays important roles in gene expression regulation. Knowledge of the dynamics of 3D chromatin structures during mammalian embryo development remains limited. We report the 3D chromatin architecture of mouse gametes and early embryos using an optimized Hi-C method with low-cell samples. We find that mature oocytes at the metaphase II stage do not have topologically associated domains (TADs). In sperm, extra-long-range interactions (>4 Mb) and interchromosomal interactions occur frequently. The high-order structures of both the paternal and maternal genomes in zygotes and two-cell embryos are obscure but are gradually re-established through development. The establishment of the TAD structure requires DNA replication but not zygotic genome activation. Furthermore, unmethylated CpGs are enriched in A compartment, and methylation levels are decreased to a greater extent in A compartment than in B compartment in embryos. In summary, the global reprogramming of chromatin architecture occurs during early mammalian development.

An artificial intelligence system using maximum intensity projection MR images facilitates classification of non-mass enhancement breast lesions.

OBJECTIVES: To build an artificial intelligence (AI) system to classify benign and malignant non-mass enhancement (NME) lesions using maximum intensity projection (MIP) of early post-contrast subtracted breast MR images. METHODS: This retrospective study collected 965 pure NME lesions (539 benign and 426 malignant) confirmed by histopathology or follow-up in 903 women. The 754 NME lesions acquired by one MR scanner were randomly split into the training set, validation set, and test set A (482/121/151 lesions). The 211 NME lesions acquired by another MR scanner were used as test set B. The AI system was developed using ResNet-50 with the axial and sagittal MIP images. One senior and one junior radiologist reviewed the MIP images of each case independently and rated its Breast Imaging Reporting and Data System category. The performance of the AI system and the radiologists was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: The AI system yielded AUCs of 0.859 and 0.816 in the test sets A and B, respectively. The AI system achieved comparable performance as the senior radiologist (p = 0.558, p = 0.041) and outperformed the junior radiologist (p < 0.001, p = 0.009) in both test sets A and B. After AI assistance, the AUC of the junior radiologist increased from 0.740 to 0.862 in test set A (p < 0.001) and from 0.732 to 0.843 in test set B (p < 0.001). CONCLUSION: Our MIP-based AI system yielded good applicability in classifying NME lesions in breast MRI and can assist the junior radiologist achieve better performance. KEY POINTS: • Our MIP-based AI system yielded good applicability in the dataset both from the same and a different MR scanner in predicting malignant NME lesions. • The AI system achieved comparable diagnostic performance with the senior radiologist and outperformed the junior radiologist. • This AI system can assist the junior radiologist achieve better performance in the classification of NME lesions in MRI.

Chromatin 3D structure reconstruction with consideration of adjacency relationship among genomic loci.

BACKGROUND: Chromatin 3D conformation plays important roles in regulating gene or protein functions. High-throughout chromosome conformation capture (3C)-based technologies, such as Hi-C, have been exploited to acquire the contact frequencies among genomic loci at genome-scale. Various computational tools have been proposed to recover the underlying chromatin 3D structures from in situ Hi-C contact map data. As connected residuals in a polymer, neighboring genomic loci have intrinsic mutual dependencies in building a 3D conformation. However, current methods seldom take this feature into account. RESULTS: We present a method called ShNeigh, which combines the classical MDS technique with local dependence of neighboring loci modeled by a Gaussian formula, to infer the best 3D structure from noisy and incomplete contact frequency matrices. We validated ShNeigh by comparing it to two typical distance-based algorithms, ShRec3D and ChromSDE. The comparison results on simulated Hi-C dataset showed that, while keeping the high-speed nature of classical MDS, ShNeigh can recover the true structure better than ShRec3D and ChromSDE. Meanwhile, ShNeigh is more robust to data noise. On the publicly available human GM06990 Hi-C data, we demonstrated that the structures reconstructed by ShNeigh are more reproducible between different restriction enzymes than by ShRec3D and ChromSDE, especially at high resolutions manifested by sparse contact maps, which means ShNeigh is more robust to signal coverage. CONCLUSIONS: Our method can recover stable structures in high noise and sparse signal settings. It can also reconstruct similar structures from Hi-C data obtained using different restriction enzymes. Therefore, our method provides a new direction for enhancing the reconstruction quality of chromatin 3D structures.

Aptamer pseudoknot-functionalized electronic sensor for reagentless and single-step detection of immunoglobulin E in human serum.

The development of electronic sensors with minimized usage of reagents and washing steps in the sensing protocols will significantly facilitate the detection of biomolecules. In this work, by using a new pseudoknot design of the aptamer probes, the construction of an electronic sensor for reagentless and single-step detection of immunoglobulin E (IgE) in human serum is described. The pseudoknot aptamer probes are self-assembled on the disposable electrode surface. The association of IgE with the aptamer probes leads to conformational changes of the pseudoknot aptamer structures and brings the redox-tags in close proximity to the electrode, resulting in amplified current response for monitoring IgE. The effects of the pseudoknot structure and the immobilization concentration of the aptamer probes on the sensor performance are evaluated. Under optimal conditions, the detection limit for IgE is estimated to be 60 pM. The sensor is also selective and can be employed to detect IgE in human serum samples. The developed sensor can achieve reagentless, washing-free and low-cost (with the disposable electrode) electrochemical detection of proteins, making this device a convenient sensing platform for the monitoring of different biomarkers when coupled with the appropriate aptamer probes.

[Study on the Hemoglobin levels among the Tibetan pregnant women in rural Lhasa].

OBJECTIVE: To understand the level of hemoglobin (Hb) and determine the risk factors of Hb concentration among the Tibetan pregnant women in rural Lhasa. METHODS: Between August 2008 and May 2011, a hospital-based study was conducted among 1 530 Tibetan pregnant women after getting their informed consent in agricultural and pastoral areas in maternity clinic or hospital in city, county and township level of Lhasa. Their blood samples were tested and related socio-demographic information was collected. Blood was collected on tip of finger and the Hb concentration was measured using B-Hemoglobin photometer. American Centers for Disease Control and Prevention(CDC) method was used to adjust the Hb measurements based on altitude for estimating the prevalence of anemia. Anemia was assessed according to WHO criteria. A hemoglobin concentration of less than 110 g/L in a pregnant woman was considered an indication of anemia. RESULTS: From August 2008 to May 2011, 1 530 Tibetan pregnant women living at (3 716.4 ± 69.1) m above sea level in rural Lhasa were examined. The findings indicated that average Hb concentration was (122.0 ± 17.5) g/L; the Hb concentration of 1(st), 2(nd) and 3(rd) trimester were (125.5 ± 18.0), (122.5 ± 16.9) and (120.6 ± 17.4) g/L, respectively. The Hb concentration of pregnant women decreased with the increase of gestational age(P < 0.05). Based onCDC method and the adjusted Hb level, the prevalence of anemia in pregnant women were 85.6% (1 310/1 530), the prevalence of anemia of 1(st), 2(nd), and 3(rd)rd trimester were 79.5% (206/259) , 86.1% (395/459)and 87.3% (698/800), respectively (P < 0.05) . The rate of moderate and severe anemia were 46.7% (612/1 310) among pregnant women. Multiple linear regression analysis showed that high Hb level was associated significantly with low family income status (ß = 2.74, 95%CI:1.73-3.74), no bad habits (drinking or smoking) (ß = 7.34, 95%CI:4.87-9.81) and fewer times of pregnancies(ß = -1.62, 95%CI:-2.93--0.31) after adjusting for potential confounding factors. CONCLUSION: Hb concentration level in pregnancy was rather low in rural Lhasa. The increase of family income, reduction the intervals of pregnancies and no bad habits might benefit for the improvement of Hb level of pregnant women in this region.

Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells.

The peptidyl-prolyl cis-trans isomerase Pin1 is a pivotal therapeutic target in cancers, but the regulation of Pin1 protein stability is largely unknown. High Pin1 expression is associated with SUMO1-modified protein hypersumoylation in glioma stem cells (GSCs), but the underlying mechanisms remain elusive. Here we demonstrate that Pin1 is deubiquitinated and stabilized by USP34, which promotes isomerization of the sole SUMO E2 enzyme Ubc9, leading to SUMO1-modified hypersumoylation to support GSC maintenance. Pin1 interacts with USP34, a deubiquitinase with preferential expression and oncogenic function in GSCs. Such interaction is facilitated by Plk1-mediated phosphorylation of Pin1. Disruption of USP34 or inhibition of Plk1 promotes poly-ubiquitination and degradation of Pin1. Furthermore, Pin1 isomerizes Ubc9 to upregulate Ubc9 thioester formation with SUMO1, which requires CDK1-mediated phosphorylation of Ubc9. Combined inhibition of Pin1 and CDK1 with sulfopin and RO3306 most effectively suppresses orthotopic tumor growth. Our findings provide multiple molecular targets to induce Pin1 degradation and suppress hypersumoylation for cancer treatment.

Chromosome Three-Dimensional Structure Reconstruction: An Iterative ShRec3D Algorithm.

The three-dimensional (3D) structure of chromosomes is of great significance to ensure that the genome performs various functions (e.g., gene expression) correctly and replicates and separates correctly in mitosis. Since the emergence of Hi-C in 2009, a new experimental technique in molecular biology, researchers have been paying more and more attention to the reconstruction of chromosome 3D structure. To reconstruct the 3D structure of chromosomes based on Hi-C experimental data, many algorithms have been proposed, among which ShRec3D is one of the most outstanding. In this article, an iterative ShRec3D algorithm is presented to greatly improve the native ShRec3D algorithm. Experimental results show that our algorithm can significantly promote the performance of ShRec3D, and this improvement is applicable to almost all data noise range and signal coverage range, so it is universal.

A comparative study of interfacial thermal conductance between metal and semiconductor.

To understand and control thermal conductance of interface between metal and semiconductor has now become a crucial task for the thermal design and management of nano-electronic and micro-electronic devices. The interfacial alignments and electronic characteristics of the interfaces between metal and semiconductor are studied using a first-principles calculation based on hybrid density functional theory. The thermal conductance of interfaces between metal and semiconductor were calculated and analyzed using diffuse mismatch model, acoustic mismatch model and nonequilibrium molecular dynamics methods. Especially, according to nonequilibrium molecular dynamics, the values of thermal conductance were obtained to be 32.55 MW m-2 K-1 and 341.87 MW m-2 K-1 at C-Cu and Si-Cu interfaces, respectively. These results of theoretical simulation calculations are basically consistent with the current experimental data, which indicates that phonon-phonon interaction play a more important role than electron-phonon interaction during heat transport. It may be effective way to improve the interfacial thermal conductance through enhancing the interface coupling strength at the metal-semiconductor interface because the strong interfacial scattering plays a role in suppressing in the weaker interface coupling heterostructure, leading to the lower thermal conductance of interfaces. This could provide a beneficial reference for the design of the Schottky diode and thermal management at the interfaces between metal and semiconductor.

Performance assessment of protein multiple sequence alignment algorithms based on permutation similarity measurement.

Protein multiple sequence alignment is an important bioinformatics tool. It has important applications in biological evolution analysis and protein structure prediction. A variety of alignment algorithms in this field have achieved great success. However, each algorithm has its own inherent deficiencies. In this paper, permutation similarity is proposed to evaluate several protein multiple sequence alignment algorithms that are widely used currently. As the permutation similarity method only concerns the relative order of different protein evolutionary distances, without taking into account the slight difference between the evolutionary distances, it can get more robust evaluations. The longest common subsequence method is adopted to define the similarity between different permutations. Using these methods, we assessed Dialign, Tcoffee, ClustalW and Muscle and made comparisons among them.

Three-dimensional reconstruction and quantitative analysis of the brain stem nuclei based on fast centroid auto-registration.

This paper introduces a three-dimensional (3D) reconstruction algorithm of the brain stem nuclei based on fast centroid auto-registration. The research is based on methods and theories of computer stereo vision, and by image information processing three-point pattern local search, registration and auto-tracing for the centroids of the brain stem nuclei were accomplished. We adopt two-peak threshold, edge detection and grayscale image enhancement to extract contours of the nuclei's structures. The experimental results obtain the spatial structure information and 3D image of the brain stem nuclei, show spatial relationship between 14 pairs of nuclei, and quantitate morphological parameters of each type of nuclei's 3D structure. This work is significant to neuroanatomy research and clinic applications. Furthermore, a software system named BRAIN.HUK is established.

Studies on quantitative analysis and automatic recognition of cell types of lung cancer.

Recognition of lung cancer cells is very important to the clinical diagnosis of lung cancer. In this paper we present a novel method to extract the structure characteristics of lung cancer cells and automatically recognize their types. Firstly soft mathematical morphology methods are used to enhance the grayscale image, to improve the definition of images, and to eliminate most of disturbance, noise and information of subordinate images, so the contour of target lung cancer cell and biological shape characteristic parameters can be extracted accurately. Then the minimum distance classifier is introduced to realize the automatic recognition of different types of lung cancer cells. A software system named "CANCER.LUNG" is established to demonstrate the efficiency of this method. The clinical experiments show that this method can accurately and objectively recognize the type of lung cancer cells, which can significantly improve the pathology research on the pathological changes of lung cancer and clinical assistant diagnoses.

Development of the aza-crown ether metal complexes as artificial hydrolase.

Hydrolases play a crucial role in the biochemical process, which can catalyze the hydrolysis of various compounds like carboxylic esters, phosphoesters, amides, nucleic acids, peptides, and so on. The design of artificial hydrolases has attracted extensive attention due to their scientific significance and potential applications in the field of gene medicine and molecular biology. Numerous macrocyclic metal complexes have been used as artificial hydrolase in the catalytic hydrolysis of the organic substrate. Aza-crown ether for this comment is a special class of the macrocyclic ligand containing both the nitrogen atoms and oxygen atoms in the ring. The studies showed that the aza-crown complexes exhibited high activity of hydrolytic enzyme. However, the aza-crown ether metal complex as artificial hydrolase is still very limited because of its difficulty in synthesis. This review summarizes the development of the aza-crown ether metal complexes as the artificial hydrolase, including the synthesis and catalysis of the transition metal complexes and lanthanide metal complexes of aza-crown ethers. The purpose of this review is to highlight: (1) the relationship between the structure and hydrolytic activity of synthetic hydrolase; (2) the synergistic effect of metal sites and ligands in the course of organic compound hydrolysis; and (3) the design strategies of the aza-crown ethers as hydrolase.

Multiplexed electrochemical coding of DNA-protein bindings.

A simple, sensitive and multiplexed electrochemical sensor for the detection of DNA-protein binding based on the exonuclease protection strategy is described. Two electroactive species, methylene blue (MB)- and ferrocene (Fc)-labeled dsDNA probes are self-assembled on a gold electrode to prepare the sensor surface. The target proteins, vascular endothelial growth factor (VEGF) and estrogen receptor (ERα), bind to the dsDNA probes and protect the probes from digesting by exonuclease III due to the steric hindrance of the bound proteins. These protein-protected, MB/Fc-labeled sequences remaining on the sensor surface display two distinct voltammetric peaks, whose peak potentials (MB: -0.27 V; Fc: +0.27 V) and intensities reflect the identities and amounts of the corresponding target proteins, for simultaneous and multiplexed detection of DNA-protein bindings. The proposed sensor is also selective to the target proteins against other interference molecules. By using labels with distinct voltammetric peaks, the developed method can be easily expanded for simultaneous detection of multiple DNA-protein bindings.

Automatic recognition of small cell carcinoma based on the self-organizing neural network.

In this paper the recognition of Small Cell Carcinoma (SCC) is studied. For each type we select 128 samples for training, and randomly measure 200 cells in each sample. We introduce multi-scale morphology based on centroid coordinates to extract the boundaries of nuclei and obtain feature images of nuclei. The features of lung cancer cells are described by morphological and colorimetrical parameters, which is valuable to recognize SCC. Then the architecture of self-organizing feature mapping (SOFM) neural network is studied for recognition of SCC. The weights of the network are adjusted by self-organizing competition, and finally inputted patterns are classified. This algorithm has the advantage of parallelism and fast-convergence, and may simplify the analysis of SCC. Clinical experiment results show that the correctness ratio of this system may reach 95.3% while recognizing lung cancer cell types. Our work is significant to the pathological researches of lung cancer, assistant clinic diagnosis, and assessment of therapeutic effects. Meanwhile a software system named as SCC. LUNG is established for automatic analysis.

The synthesis and activities of novel mononuclear or dinuclear cyclen complexes bearing azole pendants as antibacterial and antifungal agents.

A series of novel compounds containing 1,4,7,10-tetraazacyclododecane and azoles were synthesized and characterized by (1)H NMR, MS and elemental analysis. Bioactive assay manifested that some target compounds, such as 11a, 11b and 11d, displayed good and broad spectrum antimicrobial activities with relative low MIC values against most of tested strains. These dinuclear complexes gave comparable or even better antimicrobial efficiencies than the reference drugs Fluconazole and Chloromycin. The result showed that the metal ions were the key factors to enhance the antimicrobial activities for mononuclear or dinuclear complexed in varying degrees. The interaction evaluation of compound 11b with bovine serum albumin (BSA) as an example was tested by fluorescence method. The thermodynamic parameters indicated that the hydrogen bonds and van der waals forces played the major roles in the strong association between dinuclear compound and BSA. The CCK-8 tests also confirmed the safeties of these dinuclear compounds in vitro.

Protein-protein networks construction and their relevance measurement based on multi-epitope-ligand-kartographie and gene ontology data of T-cell surface proteins for polymyositis.

Polymyositis is an inflammatory myopathy characterized by muscle invasion of T-cells penetrating the basal lamina and displacing the plasma membrane of normal muscle fibers. In order to understand the different adhesive mechanisms at the T-cell surface, Schubert randomly selected 19 proteins expressed at the T-cell surface and studied them using MELK technique [4], among which 15 proteins are picked up for further study by us. Two types of functional similarity networks are constructed for these proteins. The first type is MELK similarity network, which is constructed based on their MELK data by using the McNemar's test [24]. The second type is GO similarity network, which is constructed based on their GO annotation data by using the RSS method to measuring functional similarity. Then the subset surprisology theory is employed to measure the degree of similarity between two networks. Our computing results show that these two types of networks are high related. This conclusion added new values on MELK technique and expanded its applications greatly.