LPAD: using network construction and label propagation to detect topologically associating domains from Hi-C data.

With the development of chromosome conformation capture technique, the study of spatial conformation of a genome based on Hi-C technique has made a quantum leap. Previous studies reveal that genomes are folded into hierarchy of three-dimensional (3D) structures associated with topologically associating domains (TADs), and detecting TAD boundaries is of great significance in the chromosome-level analysis of 3D genome architecture. In this paper, we propose a novel TAD identification method, LPAD, which first extracts node correlations from global interactions of chromosomes based on the random walk with restart and then builds an undirected graph from Hi-C contact matrix. Next, LPAD designs a label propagation-based approach to discover communities and generates TADs. Experimental results verify the effectiveness and quality of TAD detections compared with existing methods. Furthermore, experimental evaluation of chromatin immunoprecipitation sequencing data shows that LPAD performs high enrichment of histone modifications remarkably nearby the TAD boundaries, and these results demonstrate LPAD's advantages on TAD identification accuracy.

HiBrowser: an interactive and dynamic browser for synchronous Hi-C data visualization.

With the development of chromosome conformation capture technology, the genome-wide investigation of higher-order chromatin structure by using high-throughput chromatin conformation capture (Hi-C) technology is emerging as an important component for understanding the mechanism of gene regulation. Considering genetic and epigenetic differences are typically used to explore the pathological reasons on the chromosome and gene level, visualizing multi-omics data and performing an intuitive analysis by using an interactive browser become a powerful and welcomed way. In this paper, we develop an effective sequence and chromatin interaction data display browser called HiBrowser for visualizing and analyzing Hi-C data and their associated genetic and epigenetic annotations. The advantages of HiBrowser are flexible multi-omics navigation, novel multidimensional synchronization comparisons and dynamic interaction system. In particular, HiBrowser first provides an out of the box web service and allows flexible and dynamic reconstruction of custom annotation tracks on demand during running. In order to conveniently and intuitively analyze the similarities and differences among multiple samples, such as visual comparisons of normal and tumor tissue samples, and pan genomes of multiple (consanguineous) species, HiBrowser develops a clone mode to synchronously display the genome coordinate positions or the same regions of multiple samples on the same page of visualization. HiBrowser also supports a pluralistic and precise search on correlation data of distal cis-regulatory elements and navigation to any region on Hi-C heatmap of interest according to the searching results. HiBrowser is a no-build tool, and could be easily deployed in local server. The source code is available at https://github.com/lyotvincent/HiBrowser.

PhiHER2: phenotype-informed weakly supervised model for HER2 status prediction from pathological images.

MOTIVATION: Human epidermal growth factor receptor 2 (HER2) status identification enables physicians to assess the prognosis risk and determine the treatment schedule for patients. In clinical practice, pathological slides serve as the gold standard, offering morphological information on cellular structure and tumoral regions. Computational analysis of pathological images has the potential to discover morphological patterns associated with HER2 molecular targets and achieve precise status prediction. However, pathological images are typically equipped with high-resolution attributes, and HER2 expression in breast cancer (BC) images often manifests the intratumoral heterogeneity. RESULTS: We present a phenotype-informed weakly supervised multiple instance learning architecture (PhiHER2) for the prediction of the HER2 status from pathological images of BC. Specifically, a hierarchical prototype clustering module is designed to identify representative phenotypes across whole slide images. These phenotype embeddings are then integrated into a cross-attention module, enhancing feature interaction and aggregation on instances. This yields a phenotype-based feature space that leverages the intratumoral morphological heterogeneity for HER2 status prediction. Extensive results demonstrate that PhiHER2 captures a better WSI-level representation by the typical phenotype guidance and significantly outperforms existing methods on real-world datasets. Additionally, interpretability analyses of both phenotypes and WSIs provide explicit insights into the heterogeneity of morphological patterns associated with molecular HER2 status. AVAILABILITY AND IMPLEMENTATION: Our model is available at https://github.com/lyotvincent/PhiHER2.

CRISPR-M: Predicting sgRNA off-target effect using a multi-view deep learning network.

Using the CRISPR-Cas9 system to perform base substitutions at the target site is a typical technique for genome editing with the potential for applications in gene therapy and agricultural productivity. When the CRISPR-Cas9 system uses guide RNA to direct the Cas9 endonuclease to the target site, it may misdirect it to a potential off-target site, resulting in an unintended genome editing. Although several computational methods have been proposed to predict off-target effects, there is still room for improvement in the off-target effect prediction capability. In this paper, we present an effective approach called CRISPR-M with a new encoding scheme and a novel multi-view deep learning model to predict the sgRNA off-target effects for target sites containing indels and mismatches. CRISPR-M takes advantage of convolutional neural networks and bidirectional long short-term memory recurrent neural networks to construct a three-branch network towards multi-views. Compared with existing methods, CRISPR-M demonstrates significant performance advantages running on real-world datasets. Furthermore, experimental analysis of CRISPR-M under multiple metrics reveals its capability to extract features and validates its superiority on sgRNA off-target effect predictions.

DupScan: predicting and visualizing vertebrate genome duplication database.

Duplicated genes prevail in vertebrates and are important in the acquisition of new genes and novelties. Whole genome duplication (WGD) is one of the sources of duplicated genes. It can provide raw materials for natural selection by increasing the flexibility and complexity of the genome. WGDs are the driving force for the evolution of vertebrates and contribute greatly to their species diversity, especially in fish species with complicated WGD patterns. Here, we constructed the DupScan database (https://dupscan.sysumeg.com/) by integrating 106 chromosomal-level genomes, which can analyze and visualize synteny at both the gene and genome scales, visualize the Ka, Ks, and 4DTV values, and browse genomes. DupScan was used to perform functional adaptation for the intricate WGD investigation based on synteny matching. DupScan supports the analysis of five WGD rounds (R): VGD2 (vertebrate genome duplication 2), Ars3R (Acipenser-ruthenus-specific 3R), Pss3R (Polyodon-spathula-specific 3R), Ts3R (teleost-specific duplication 3R), Ss4R (salmonid-specific 4R), and Cs4R (carp-specific 4R). DupScan serves as one-stop analysis platform for synteny and WGD research in which users can analyze and predict synteny and WGD patterns across 106 species of whole genome sequences. This further aided us in elucidating genome evolutionary patterns across over 60,000 vertebrate species with synteny and WGD events.

2.1 µm multi-quantum well laser epitaxially grown on on-axis (001) InP/SiO2/Si substrate fabricated by ion-slicing.

A cost-effective method to achieve a 2-3 µm wavelength light source on silicon represents a major challenge. In this study, we have developed a novel approach that combines an epitaxial growth and the ion-slicing technique. A 2.1 µm wavelength laser on a wafer-scale heterogeneous integrated InP/SiO2/Si (InPOI) substrate fabricated by ion-slicing technique was achieved by epitaxial growth. The performance of the lasers on the InPOI are comparable with the InP, where the threshold current density (Jth) was 1.3 kA/cm2 at 283 K when operated under continuous wave (CW) mode. The high thermal conductivity of Si resulted in improved high-temperature laser performance on the InPOI. The proposed method offers a novel means of integrating an on-chip light source.

{Ru(C6 H6 )}-Decorating Heteropolymolybdate for Highly Activity Photocatalytic Oxidation of Benzyl Alcohol to Benzaldehyde.

An unclassical structure of {Ru(C6 H6 )}-based polyoxometalate, Cs6 H4 [Te2 Mo12 O46 {Ru(C6 H6 )}] ⋅ 16.5H2 O (1), has been successfully constructed from {Te2 Mo12 O46 }-type heteropolymolybdate and {Ru(C6 H6 )} group, which structure type was discovered for the first time. Compound 1 not only possesses strong light-harvesting ability, but also exhibits high carrier separation efficiency and lower charge transfer resistance. Under visible light irradiation, compound 1 displayed excellent catalytic activity and circularity in the conversion of benzyl alcohol to benzaldehyde (yield=94 %; turnover number=500; turnover frequency=20.8 h-1 ). Finally, the electron paramagnetic resonance measurement and energy level matching analysis provide theoretical basis for the derivation of the reaction mechanism.

High-speed compact folded Michelson interferometer modulator.

We propose and experimentally demonstrate a novel compact folded Michelson interferometer (FMI) modulator with high modulation efficiency. By folding the 0.5 mm-long phase shift arms, the length of the modulation area of the FMI modulator is only 0.25 mm. Meanwhile, the traveling wave electrode (TWE) is also shorter, which decreases the propagation loss of the RF signal and contributes to a small footprint. The Vπ-L of the present device is as low as 0.87 V·cm at -8 V bias voltage. The minimum optical insertion loss is 3.7 dB, and the static extinction ratio (ER) is over 25 dB. The measured 3-dB electro-optical (EO) bandwidth is 17.3 GHz at a -6 V bias. The OOK eye diagram up to 40 Gb/s is demonstrated under 2 V driver voltage.

Long-term, low-dose macrolide antibiotic treatment in pediatric chronic airway diseases.

Macrolide antibiotics are one of the most commonly used broad-spectrum antibiotics. They have an inhibitory effect on a variety of respiratory pathogens; besides, they have non-anti-infective effects, including anti-inflammatory, regulating airway secretion, immune regulation, and other effects. A growing number of studies have shown that the non-anti-infective effects of macrolides have important and potential value in the treatment of pediatric chronic airway diseases; the therapy was described as "long-term, low-dose usage"; unfortunately, there is no guideline or consensus that applies to children. To better carry out the mechanism and clinical research of non-anti-infective effect and promote its rational use in children, the authors summarize the evidence of the usage of long-term, low-dose macrolide antibiotic therapy (LLMAT) in the treatment of chronic airway diseases in children and the progress in recent years. IMPACT: This review summarizes the evidence (mostly in recent 5 years) of the usage of long-term, low-dose macrolide antibiotic therapy in the treatment of chronic airway diseases. The recent studies and guidelines support and enrich the point that long-term, low-dose macrolide antibiotic therapy has potential benefit for children with severe asthma, CF, non-CF bronchiectasis, and BO, which provides clinical references and is of clinical interest. Long-term, low-dose macrolide antibiotic therapy has good safety, and no serious events have been reported; however, potential cardiac side effects and macrolide resistance should be clinically noted.

Systematic Infection of Chlamydia Pneumoniae.

BACKGROUND: Chlamydia pneumoniae (Cpn) is one of the most common respiratory pathogens in children and adults. It is characterized as an obligate intracellular parasite. Peripheral blood monocytes (PBMC), lymphocytes, and macrophages are involved in spreading chlamydia infection to extrapulmonary organs indicating that Cpn infection can cause systematic symptoms in vivo via blood transmission. METHODS: This review summarizes the mechanisms of Cpn infection in host cells, the immune response of the body, and the relationship between Cpn infection and some chronic diseases. RESULTS: Cpn participation in extrapulmonary chronic diseases has been proven owing to the presence of Cpn DNA in AS plaque, nerve tissues, and synovium tissues of the joints. CONCLUSIONS: Cpn infection is related to the development of chronic diseases such as atherosclerosis, Alzheimer's Disease (AD), and reactive arthritis through in vivo and in vitro experiments.

InAs/GaAs quantum dot laser epitaxially grown on on-axis (001) GaAsOI substrate.

Quantum dot (QD) laser as a light source for silicon optical integration has attracted great research attention because of the strategic vision of optical interconnection. In this paper, the communication band InAs QD ridge waveguide lasers were fabricated on GaAs-on-insulator (GaAsOI) substrate by combining ion-slicing technique and molecular beam epitaxy (MBE) growth. On the foundation of optimizing surface treatment processes, the InAs/In0.13Ga0.87As/GaAs dot-in-well (DWELL) lasers monolithically grown on a GaAsOI substrate were realized under pulsed operation at 20 °C. The static device measurements reveal comparable performance in terms of threshold current density, slope efficiency and output power between the QD lasers on GaAsOI and GaAs substrates. This work shows great potential to fabricate highly integrated light source on Si for photonic integrated circuits.

UHRF2 promotes intestinal tumorigenesis through stabilization of TCF4 mediated Wnt/ß-catenin signaling.

Intestinal tumors mainly originate from transformed crypt stem cells supported by Wnt signaling, which functions through downstream critical factors enriched in the intestinal stem/progenitor compartment. Here, we show Uhrf2 is predominantly expressed in intestinal crypts and adenomas in mice and is transcriptionally regulated by Wnt signaling. Upregulated UHRF2 correlates with poor prognosis in colorectal cancer patients. Although loss of Uhrf2 did not affect intestinal homeostasis and regeneration, tumor initiation and progression were inhibited, leading to a markedly prolonged life span in Uhrf2 null mice on an ApcMin background. Uhrf2 deficiency also strongly reduced primary tumor organoid formation suggesting impairment of tumor stem cells. Moreover, ablation of Uhrf2 suppressed tumor cell proliferation through downregulation of the Wnt/ß-catenin pathway. Mechanistically, Uhrf2 directly interacts with and sumoylates Tcf4, a critical intranuclear effector of the Wnt pathway. Uhrf2 mediated SUMOylation stabilized Tcf4 and further sustained hyperactive Wnt signaling. Together, we demonstrate that Wnt-induced Uhrf2 expression promotes tumorigenesis through modulation of the stability of Tcf4 for maintaining oncogenic Wnt/ß-catenin signaling. This is a new reciprocal feedforward regulation between Uhrf2 and Wnt signaling in tumor initiation and progression.

Verticillium dahliae VdTHI20, Involved in Pyrimidine Biosynthesis, Is Required for DNA Repair Functions and Pathogenicity.

Verticillium dahliae (V. dahliae) infects roots and colonizes the vascular vessels of host plants, significantly reducing the economic yield of cotton and other crops. In this study, the protein VdTHI20, which is involved in the thiamine biosynthesis pathway, was characterized by knocking out the corresponding VdTHI20 gene in V. dahliae via Agrobacterium tumefaciens-mediated transformation (ATMT). The deletion of VdTHI20 resulted in several phenotypic defects in vegetative growth and conidiation and in impaired virulence in tobacco seedlings. We show that VdTHI20 increases the tolerance of V. dahliae to UV damage. The impaired vegetative growth of ΔVdTHI20 mutant strains was restored by complementation with a functional copy of the VdTHI20 gene or by supplementation with additional thiamine. Furthermore, the root infection and colonization of the ΔVdTHI20 mutant strains were suppressed, as indicated by green fluorescent protein (GFP)-labelling under microscope observation. When the RNAi constructs of VdTHI20 were used to transform Nicotiana benthamiana, the transgenic lines expressing dsVdTHI20 showed elevated resistance to V. dahliae. Together, these results suggest that VdTHI20 plays a significant role in the pathogenicity of V. dahliae. In addition, the pathogenesis-related gene VdTHI20 exhibits potential for controlling V. dahliae in important crops.

Measurements and Clinical Application of Anatomical Space for Transfrontal Pituitary Surgery Through Magnetic Resonance Imaging Reconstruction.

OBJECTIVE: This study aims to clarify the relative position of the normal important structures and anatomical spaces formed by the structures passed through during the transfrontal pituitary surgery, and discuss how to avoid some eloquent structures. METHODS: A total of 120 cases of magnetic resonance imaging images from normal adult brains were selected as the object of study and divided into male and female groups. The important adjacent structures of the pituitary passed through during the transfrontal pituitary surgery were marked on the reconstructed images. In all planes of the spaces passing through successively during the pituitary surgery, the morphological parameters such as the size, boundary, structure, and spatial extent of the spaces were measured. RESULTS: The size, boundary, structure, and spatial extent of the space between the 2 optic nerves, the space between the optic nerves and the pituitary stalk, and the space between the tuber cinereum and the interal carotid artery in the plane of the pituitary stalk were measured, the anterior part and the posterior part in male were shorter than those in female (P = 0.021; P = 0.029); no statistically significant difference was found in the measurements of the lengths and angles of these spaces. CONCLUSIONS: The authors' findings provide the surgeons with the detailed anatomical data and help to provide a morphological basis for intraoperative protection of the pituitary and vital adjacent structures and surgical approach.

Using Transcriptome Analysis to Screen for Key Genes and Pathways Related to Cytoplasmic Male Sterility in Cotton (Gossypium hirsutum L.).

Cotton (Gossypium hirsutum L.) is one of the most important cash crops worldwide. Cytoplasmic male sterility (CMS) is an excellent breeding system for exploitation of heterosis, which has great potential to increase crop yields. To understand the molecular mechanism of CMS in cotton, we compared transcriptome, cytomorphological, physiological and bioinformatics data between the CMS line C2P5A and its maintainer line C2P5B. By using high-throughput sequencing technology, 178,166 transcripts were assembled and 2013 differentially expression genes (DEGs) were identified at three different stages of C2P5A anther development. In this study, we identified DEGs associated with reactive oxygen species (ROS), peroxisomes, aldehyde dehydrogenases (ALDH), cytochrome oxidase subunit VI, and cytochrome P450, and DEGs associated with tapetum development, Jojoba acyl-CoA reductase-related male sterility protein, basic helix-loop-helix (bHLH) and MYB transcription factors. The abnormal expression of one of these genes may be responsible for the CMS C2P5A line. In gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, DEGs were mainly related to carbohydrate metabolism, amino acid metabolism, transport and catabolism, and signal transduction. Carbohydrate metabolism provides energy for anther development, starch and sucrose metabolism, fatty acid biosynthesis and metabolism and ascorbate and aldarate metabolism. These results showed that numerous genes and multiple complex metabolic pathways regulate cotton anther development. Weighted correlation network analysis (WGCNA) indicated that three modules, 'turquoise,' 'blue,' and 'green,' were specific for the CMS C2P5A line. The 'turquoise' and 'blue' modules were mainly related to carbohydrate metabolism, amino acid metabolism, energy metabolism, peroxisomes, pyruvate metabolism as well as fatty acid degradation. The 'green' module was mainly related to energy metabolism, carbon metabolism, translation, and lipid metabolism. RNA-sequencing and WGCNA polymerization modules were screened for key genes and pathways related to CMS in cotton. This study presents a new perspective for further research into the metabolic pathways of pollen abortion in the CMS C2P5A line and also provides a theoretical basis for its breeding and production.

Elevation of GPRC5A expression in colorectal cancer promotes tumor progression through VNN-1 induced oxidative stress.

The clearance of oxidative stress compounds is critical for the protection of the organism from malignancy, but how this key physiological process is regulated is not fully understood. Here, we found that the expression of GPRC5A, a well-characterized tumor suppressor in lung cancer, was elevated in colorectal cancer tissues in patients. In both cancer cell lines and a colitis-associated cancer model in mice, we found that GPRC5A deficiency reduced cell proliferation and increased cell apoptosis as well as inhibited tumorigenesis in vivo. Through RNA-Seq transcriptome analysis, we identified oxidative stress associated pathways were dysregulated. Moreover, in GPRC5A deficient cells and mouse tissues, the oxidative agents were reduced partially due to increased glutathione (GSH) level. Mechanistically, GPRC5A regulates NF-κB mediated Vanin-1 expression which is the predominant enzyme for cysteamine generation. Administration of cystamine (the disulfide form of cysteamine) in GPRC5A deficient cell lines inhibited γ-GCS activity, leading to reduction of GSH level and increase of cell growth. Taken together, our studies suggest that GPRC5a is a potential biomarker for colon cancer and promotes tumorigenesis through stimulation of Vanin-1 expression and oxidative stress in colitis associated cancer. This study revealed an unexpected oncogenic role of GPRC5A in colorectal cancer suggesting there are complicated functional and molecular mechanism differences of this gene in distinct tissues.

Morphologic Study of Positional Relationship Between Transverse-Sigmoid Sinus and Extracranial Bony Landmarks With Reconstructed Computed Tomographic Image.

OBJECTIVE: By using the line between the lowest point of the mastoid process and the external occipital protuberance as landmarks, to locate the projection of the transverse-sigmoid sinus (TSS) on the skull surface using three-dimensional reconstruction technique, to provide morphological basis for avoiding TSS injuries during surgeries. METHODS: A total of 120 volunteers underwent computed tomography scan, and computed tomography reconstruction was used to reconstruct the 3D model of the skull for structural landmark and measurement. The line between the most prominent point (A) of external occipital protuberance and the lowest point (B) of mastoid process was used as the landmark to depict distance between the TSS sulcus and the landmarks, as well as the width of the TSS sulcus. RESULTS: The widths of the transverse sinus sulcus, denoted as d, at its central landmark J were measured to be significantly different between the right and left sides (t = 6.291, P < 0.05); no statistically significant difference was found in the measurements of indicators including h1, h2, h3, h4, h5, h6, h7, h8, d1, α, s1, s2, s3, s4, s5, s6 between the right and left sides (P > 0.05), or between the males and females (P > 0.05). CONCLUSIONS: These above-mentioned results can help to locate the projection of the TSS sulcus on the skull surface accurately, which is simple and convenient in guiding the surgeons to protect the TSS during surgeries.

High-power, electrically-driven continuous-wave 1.55-µm Si-based multi-quantum well lasers with a wide operating temperature range grown on wafer-scale InP-on-Si (100) heterogeneous substrate.

A reliable, efficient and electrically-pumped Si-based laser is considered as the main challenge to achieve the integration of all key building blocks with silicon photonics. Despite the impressive advances that have been made in developing 1.3-µm Si-based quantum dot (QD) lasers, extending the wavelength window to the widely used 1.55-µm telecommunication region remains difficult. In this study, we develop a novel photonic integration method of epitaxial growth of III-V on a wafer-scale InP-on-Si (100) (InPOS) heterogeneous substrate fabricated by the ion-cutting technique to realize integrated lasers on Si substrate. This ion-cutting plus epitaxial growth approach decouples the correlated root causes of many detrimental dislocations during heteroepitaxial growth, namely lattice and domain mismatches. Using this approach, we achieved state-of-the-art performance of the electrically-pumped, continuous-wave (CW) 1.55-µm Si-based laser with a room-temperature threshold current density of 0.65 kA/cm-2, and output power exceeding 155 mW per facet without facet coating in CW mode. CW lasing at 120 °C and pulsed lasing at over 130 °C were achieved. This generic approach is also applied to other material systems to provide better performance and more functionalities for photonics and microelectronics.

Remodeling the immune microenvironment for gastric cancer therapy through antagonism of prostaglandin E2 receptor 4.

Gastric cancer is highly prevalent among digestive tract tumors. Due to the intricate nature of the gastric cancer immune microenvironment, there is currently no effective treatment available for advanced gastric cancer. However, there is promising potential for immunotherapy targeting the prostaglandin E2 receptor subtype 4 (EP4) in gastric cancer. In our previous study, we identified a novel small molecule EP4 receptor antagonist called YY001. Treatment with YY001 alone demonstrated a significant reduction in gastric cancer growth and inhibited tumor metastasis to the lungs in a mouse model. Furthermore, administration of YY001 stimulated a robust immune response within the tumor microenvironment, characterized by increased infiltration of antigen-presenting cells, T cells, and M1 macrophages. Additionally, our research revealed that YY001 exhibited remarkable synergistic effects when combined with the PD-1 antibody and the clinically targeted drug apatinib, rather than fluorouracil. These findings suggest that YY001 holds great promise as a potential therapeutic strategy for gastric cancer, whether used as a standalone treatment or in combination with other drugs.

Ginkgo biloba extract and ginkgolide antiarrhythmic potential by targeting hERG and ICa-L channel.

We investigated the effects of Ginkgo biloba extract (GBE) and ginkgolide (GLD) on human ether-a-go-go-related gene (hERG)-encoded K(+) channels and its underlying mechanisms in the hERG-HEK293 cell line by determining GBE- and GLD-induced changes in action potential duration (APD), L-type calcium currents (ICa-L), and the intracellular calcium concentration ([Ca(2+)]i) in guinea-pig ventricular myocytes. hERG currents, APD and ICa-L were recorded using the whole-cell patch clamp technique, the [Ca(2+)]i was examined by an immunofluorescence experiment. In the present study, we found that a low concentration of GBE (0.005 mg/ml) increased hERG currents, but the high concentration of GBE (from 0.05 to 0.25 mg/ml) reduced hERG currents. GLD reduced hERG currents in a concentration-dependent manner (from 0.005 to 0.25 mg/ml). Both GBE and GLD altered kinetics of the hERG channel. GBE accelerated the activation of hERG channels without changing the inactivation curve, but reduced the time constant of inactivation; GLD did not shift the activation or the inactivation curve, but only reduced the time constant of inactivation. Both GBE and GLD shortened the APD, inhibited the ICa-L currents, and decreased the [Ca(2+)]i in isolated guinea-pig ventricular myocytes. The results indicate that GBE and GLD can prevent ischemic arrhythmias and have an antiarrhythmic effect potential via inhibition of IKr and ICa-L currents.