High-resolution X-ray luminescence extension imaging.

Current X-ray imaging technologies involving flat-panel detectors have difficulty in imaging three-dimensional objects because fabrication of large-area, flexible, silicon-based photodetectors on highly curved surfaces remains a challenge1-3. Here we demonstrate ultralong-lived X-ray trapping for flat-panel-free, high-resolution, three-dimensional imaging using a series of solution-processable, lanthanide-doped nanoscintillators. Corroborated by quantum mechanical simulations of defect formation and electronic structures, our experimental characterizations reveal that slow hopping of trapped electrons due to radiation-triggered anionic migration in host lattices can induce more than 30 days of persistent radioluminescence. We further demonstrate X-ray luminescence extension imaging with resolution greater than 20 line pairs per millimetre and optical memory longer than 15 days. These findings provide insight into mechanisms underlying X-ray energy conversion through enduring electron trapping and offer a paradigm to motivate future research in wearable X-ray detectors for patient-centred radiography and mammography, imaging-guided therapeutics, high-energy physics and deep learning in radiology.

A computational approach for detecting physiological homogeneity in the midst of genetic heterogeneity.

The human genetic dissection of clinical phenotypes is complicated by genetic heterogeneity. Gene burden approaches that detect genetic signals in case-control studies are underpowered in genetically heterogeneous cohorts. We therefore developed a genome-wide computational method, network-based heterogeneity clustering (NHC), to detect physiological homogeneity in the midst of genetic heterogeneity. Simulation studies showed our method to be capable of systematically converging genes in biological proximity on the background biological interaction network, and capturing gene clusters harboring presumably deleterious variants, in an efficient and unbiased manner. We applied NHC to whole-exome sequencing data from a cohort of 122 individuals with herpes simplex encephalitis (HSE), including 13 individuals with previously published monogenic inborn errors of TLR3-dependent IFN-α/ß immunity. The top gene cluster identified by our approach successfully detected and prioritized all causal variants of five TLR3 pathway genes in the 13 previously reported individuals. This approach also suggested candidate variants of three reported genes and four candidate genes from the same pathway in another ten previously unstudied individuals. TLR3 responsiveness was impaired in dermal fibroblasts from four of the five individuals tested, suggesting that the variants detected were causal for HSE. NHC is, therefore, an effective and unbiased approach for unraveling genetic heterogeneity by detecting physiological homogeneity.

iLSGRN: inference of large-scale gene regulatory networks based on multi-model fusion.

MOTIVATION: Gene regulatory networks (GRNs) are a way of describing the interaction between genes, which contribute to revealing the different biological mechanisms in the cell. Reconstructing GRNs based on gene expression data has been a central computational problem in systems biology. However, due to the high dimensionality and non-linearity of large-scale GRNs, accurately and efficiently inferring GRNs is still a challenging task. RESULTS: In this article, we propose a new approach, iLSGRN, to reconstruct large-scale GRNs from steady-state and time-series gene expression data based on non-linear ordinary differential equations. Firstly, the regulatory gene recognition algorithm calculates the Maximal Information Coefficient between genes and excludes redundant regulatory relationships to achieve dimensionality reduction. Then, the feature fusion algorithm constructs a model leveraging the feature importance derived from XGBoost (eXtreme Gradient Boosting) and RF (Random Forest) models, which can effectively train the non-linear ordinary differential equations model of GRNs and improve the accuracy and stability of the inference algorithm. The extensive experiments on different scale datasets show that our method makes sensible improvement compared with the state-of-the-art methods. Furthermore, we perform cross-validation experiments on the real gene datasets to validate the robustness and effectiveness of the proposed method. AVAILABILITY AND IMPLEMENTATION: The proposed method is written in the Python language, and is available at: https://github.com/lab319/iLSGRN.

Identifying Genetic Factors of Polycystic Ovary Syndrome in Women with Epilepsy: A Whole-Genome Sequencing Study.

INTRODUCTION: Women with epilepsy (WWE) are more likely to develop reproductive endocrine disorders, especially polycystic ovary syndrome (PCOS). This study aimed to explore the genetic factors of PCOS in WWE in hope of improving individual precision diagnosis and treatment. METHODS: WWE registered at West China Hospital between January 2022 and October 2022 were enrolled in this study. Demographic and epilepsy-related characteristics were recorded, and blood samples were collected for hormones, glucose metabolism testing, and whole-genome sequencing. RESULTS: After sample sequencing, quality control, and variants selection, association analyses were performed. Pathway analysis was performed to identify involved biological pathways. The overall and PCOS "burden score" of each individual were calculated to count the deleterious variants. A total of 95 WWE were included in this study and 19 patients were diagnosed with PCOS. WWE with PCOS showed a significantly different hormone profiles and a tendency of impaired glucose metabolism. The most commonly associated genes were ZFYVE28, COL19A1, SIK3, ANKK1, PPIG, and REPIN1. The top 3 canonical pathways are adipogenesis pathway, epoxysqualene biosynthesis signaling, and glutamate degradation signaling. The most significant common variant was rs11914038 located in gene CELSR1 and rs651748 located in gene ZBTB16. In human gene connectome prioritizations, ITGA9, PNPLA2, and DAB2 are the top 3 genes having the shortest distance to known PCOS genes. CONCLUSION: Genetic factors involved in the abnormal regulation of glucose and insulin metabolism are likely to be associated with the comorbidity of PCOS in WWE. Interventions targeting these processes should be given more priority in clinical practice.

Tandem Sulfonylative Annulation/Halogenation of 1,7-Enynes with Sodium Sulfinate and TBAX for the Assembly of 4-Methylenechromanes.

An effective and stereoselective synthesis of halogenated (E)-4-methylenechromanes with a sulfonyl group was developed via the copper-catalyzed sulfonylative annulation/halogenation of 1,7-enynes, in which sodium sulfinates were used as the sulfonyl reagents and tetrabutylammonium halide provided the halogen sources. The formed alkenyl C-X bonds were valuable and can efficiently undergo the subsequent hydrolysis, alkenylation, alkynylation, arylation, alkylthiolation, and alkoxylation to furnish a series of highly functionalized 4-methylenechromanes.

A SU6668 pure nanoparticle-based eyedrops: toward its high drug Accumulation and Long-time treatment for corneal neovascularization.

Corneal neovascularization (CNV) is one of the common blinding factors worldwide, leading to reduced vision or even blindness. However, current treatments such as surgical intervention and anti-VEGF agent therapy still have some shortcomings or evoke some adverse effects. Recently, SU6668, an inhibitor targeting angiogenic tyrosine kinases, has demonstrated growth inhibition of neovascularization. But the hydrophobicity and low ocular bioavailability limit its application in cornea. Hereby, we proposed the preparation of SU6668 pure nanoparticles (NanoSU6668; size ~135 nm) using a super-stable pure-nanomedicine formulation technology (SPFT), which possessed uniform particle size and excellent aqueous dispersion at 1 mg/mL. Furthermore, mesenchymal stem cell membrane vesicle (MSCm) was coated on the surface of NanoSU6668, and then conjugated with TAT cell penetrating peptide, preparing multifunctional TAT-MSCm@NanoSU6668 (T-MNS). The T-MNS at a concentration of 200 µg/mL was treated for CNV via eye drops, and accumulated in blood vessels with a high targeting performance, resulting in elimination of blood vessels and recovery of cornea transparency after 4 days of treatment. Meanwhile, drug safety test confirmed that T-MNS did not cause any damage to cornea, retina and other eye tissues. In conclusion, the T-MNS eye drop had the potential to treat CNV effectively and safely in a low dosing frequency, which broke new ground for CNV theranostics.

Isolation and Biological Characteristics of a Novel Phage and Its Application to Control Vibrio Parahaemolyticus in Shellfish Meat.

Vibrio parahaemolyticus is a common foodborne pathogenic bacterium. With the overuse of antibiotics, an increasing proportion of drug-resistant strains are emerging, which puts enormous pressure on public health. In this study, a V. parahaemolyticus-specific phage, VP41s3, was isolated. The head length, width, and tail length of the phage were 77.7 nm, 72.2 nm, and 17.5 nm, respectively. It remained active in the temperature range of 30-50°C and pH range of 4-11. The lytic curve of phage VP41s3 showed that the host bacteria did not grow until 11 h under phage treatment at MOI of 1000, indicating that the phage had good bacteriostatic ability. When it was added to shellfish contaminated with V. parahaemolyticus (15°C, 48 h), the number of bacteria in the experimental group was 2.11 log10 CFU/mL lower than that in the control group at 24 h. Furthermore, genomic characterization and phylogenetic analysis indicated that phage VP41s3 was a new member of the Podoviridae family. The genome contained 50 open reading frames (ORFs), in which the ORF19 (thymidine kinase) was an enzyme involved in the pyrimidine salvage pathway, which might lead to the accelerated DNA synthesis efficiency after phage entered into host cells. This study not only contributed to the improvement of phage database and the development of beneficial phage resources but also revealed the potential application of phage VP41s3 in food hygiene and safety.

A neural network model to screen feature genes for pancreatic cancer.

All the time, pancreatic cancer is a problem worldwide because of its high degree of malignancy and increased mortality. Neural network model analysis is an efficient and accurate machine learning method that can quickly and accurately predict disease feature genes. The aim of our research was to build a neural network model that would help screen out feature genes for pancreatic cancer diagnosis and prediction of prognosis. Our study confirmed that the neural network model is a reliable way to predict feature genes of pancreatic cancer, and immune cells infiltrating play an essential role in the development of pancreatic cancer, especially neutrophils. ANO1, AHNAK2, and ADAM9 were eventually identified as feature genes of pancreatic cancer, helping to diagnose and predict prognosis. Neural network model analysis provides us with a new idea for finding new intervention targets for pancreatic cancer.

Cryo-EM reveals the structure and dynamics of a 723-residue malate synthase G.

Determination of sub-100 kDa (kDa) structures by cryo-electron microscopy (EM) is a longstanding but not straightforward goal. Here, we present a 2.9-Å cryo-EM structure of a 723-amino acid apo-form malate synthase G (MSG) from Escherichia coli. The cryo-EM structure of the 82-kDa MSG exhibits the same global folding as structures resolved by crystallography and nuclear magnetic resonance (NMR) spectroscopy, and the crystal and cryo-EM structures are indistinguishable. Analyses of MSG dynamics reveal consistent conformational flexibilities among the three experimental approaches, most notably that the α/ß domain exhibits structural heterogeneity. We observed that sidechains of F453, L454, M629, and E630 residues involved in hosting the cofactor acetyl-CoA and substrate rotate differently between the cryo-EM apo-form and complex crystal structures. Our work demonstrates that the cryo-EM technique can be used to determine structures and conformational heterogeneity of sub-100 kDa biomolecules to a quality as high as that obtained from X-ray crystallography and NMR spectroscopy.

Identifying shared genetic factors underlying epilepsy and congenital heart disease in Europeans.

Epilepsy (EP) and congenital heart disease (CHD) are two apparently unrelated diseases that nevertheless display substantial mutual comorbidity. Thus, while congenital heart defects are associated with an elevated risk of developing epilepsy, the incidence of epilepsy in CHD patients correlates with CHD severity. Although genetic determinants have been postulated to underlie the comorbidity of EP and CHD, the precise genetic etiology is unknown. We performed variant and gene association analyses on EP and CHD patients separately, using whole exomes of genetically identified Europeans from the UK Biobank and Mount Sinai BioMe Biobank. We prioritized biologically plausible candidate genes and investigated the enriched pathways and other identified comorbidities by biological proximity calculation, pathway analyses, and gene-level phenome-wide association studies. Our variant- and gene-level results point to the Voltage-Gated Calcium Channels (VGCC) pathway as being a unifying framework for EP and CHD comorbidity. Additionally, pathway-level analyses indicated that the functions of disease-associated genes partially overlap between the two disease entities. Finally, phenome-wide association analyses of prioritized candidate genes revealed that cerebral blood flow and ulcerative colitis constitute the two main traits associated with both EP and CHD.

Pair-Density-Wave and Chiral Superconductivity in Twisted Bilayer Transition Metal Dichalcogenides.

We theoretically explore possible orders induced by weak repulsive interactions in twisted bilayer transition metal dichalcogenides (e.g., WSe_{2}) in the presence of an out-of-plane electric field. Using renormalization group analysis, we show that superconductivity survives even with the conventional van Hove singularities. We find that topological chiral superconducting states with Chern number N=1, 2, 4 (namely, p+ip, d+id, and g+ig) appear over a large parameter region with a moiré filling factor around n=1. At some special values of applied electric field and in the presence of a weak out-of-plane Zeeman field, spin-polarized pair-density-wave (PDW) superconductivity can emerge. This spin-polarized PDW state can be probed by experiments such as spin-polarized STM measuring spin-resolved pairing gap and quasiparticle interference. Moreover, the spin-polarized PDW could lead to a spin-polarized superconducting diode effect.

Emergence of the Chern Supermetal and Pair-Density Wave through Higher-Order Van Hove Singularities in the Haldane-Hubbard Model.

While advances in electronic band theory have brought to light new topological systems, understanding the interplay of band topology and electronic interactions remains a frontier question. In this work, we predict new interacting electronic orders emerging near higher-order Van Hove singularities present in the Chern bands of the Haldane model. We classify the nature of such singularities and employ unbiased renormalization group methods that unveil a complex landscape of electronic orders, which include ferromagnetism, density waves, and superconductivity. Importantly, we show that repulsive interactions can stabilize the long-sought pair-density-wave state and an exotic Chern supermetal, which is a new class of non-Fermi liquid with anomalous quantum Hall response. This framework opens a new path to explore unconventional electronic phases in two-dimensional chiral bands through the interplay of band topology and higher-order Van Hove singularities.

Pair Density Wave Order from Electron Repulsion.

A pair density wave (PDW) is a superconductor whose order parameter is a periodic function of space, without an accompanying spatially uniform component. Since PDWs are not the outcome of a weak-coupling instability of a Fermi liquid, a generic pairing mechanism for PDW order has remained elusive. We describe and solve models having robust PDW phases. To access the intermediate coupling limit, we invoke large-N limits of Fermi liquids with repulsive BCS interactions that admit saddle point solutions. We show that the requirements for long-range PDW order are that the repulsive BCS couplings must be nonmonotonic in space and that their strength must exceed a threshold value. We obtain a phase diagram with both finite temperature transitions to PDW order and a T=0 quantum critical point, where non-Fermi liquid behavior occurs.

The application of new gastric cancer screening score system for gastric cancer screening and risk assessment of gastric precancerous lesions in China.

Objective: To evaluate the value of new gastric cancer screening score system for risk assessment of gastric precancerous lesions.Methods: A total of 520 patients were enrolled after the examination of endoscopy at Endoscopy Center, Department of Gastroenterology, from June 2018 to December 2021. The patients were divided into three groups according to age, gender, serum helicobacter pylori antibody test, pepsinogen I (PGI), pepsinogen II (PGII), pepsinogen I/II ratio (PGR) and gastrin-17 test results before endoscopy: Group A defined as low-risk group (0-11 points), Group B defined as middle-risk group (12-16 points), Group C defined as high-risk group (17-23 points). The detection rates of gastric cancer and atrophic gastritis in three groups were analyzed. According to the range and degree of atrophy/intestinal metaplasia, patients were divided into five groups on the basis of OLGA/OLGIM staging system. The levels of PG I, PG II and PGR were compared between different groups, and the correlation between new gastric cancer screening score system and OLGA/OLGIM staging system were evaluated. Statistical analysis was accomplished by ANOVA, chi-square test and Gamma coefficient analysis.Results: A total of 520 patients were enrolled. 268 patients were classified into group A,222 patients into group B and 30 patients into group C, respectively. According to the pathological results, 281 cases were non-atrophic gastritis, 230 cases atrophic gastritis and 9 cases gastric cancer. For OLGA staging system, 281 patients were divided into stage-0 group, 121 patients into stage-I group, 72 patients into stage-II group, 33 patients into stage-III group and 13 patients into stage-IV groups. The PGI and PGR level correlated inversely with the rising OLGA stages (F = 3.028, p = .016, F = 6.036, p < .001). For OLGIM staging system, 252 patients were divided into stage-0 group, 137 patients into stage-I group, 80 patients into stage-II group, 36 patients into stage-III group and 15 patients into stage-IV group. The PGR level correlated inversely with the rising OLGIM stages (F = 3.466, p＝.007). The detection rates of gastric cancer and atrophic gastritis in Group C were much higher than other groups. (X2 = 14.727, p < .001; X2 = 51.280, p < .001). Gamma coefficient analysis showed significant correlations between OLGA/OLGIM and the new gastric cancer screening score system (p < .001).Conclusions: The new gastric cancer screening score system is closely linked with histological OLGA/OLGIM staging system in the risk assessment of gastric precancerous lesions. The role of new gastric cancer screening score system in future gastric precancerous lesions screening and high risk population identifying was promising.

Chimeric deletion mutation of rpoC2 underlies the leaf-patterning of Clivia miniata var. variegata.

KEY MESSAGE: The deletion mutated rpoC2 leads to yellow stripes of Clivia miniata var. variegata by down regulating the transcription of 28 chloroplast genes and disturbing chloroplast biogenesis and thylakoid membrane development. Clivia miniata var. variegata (Cmvv) is a common mutant of Clivia miniata but its genetic basis is unclear. Here, we found that a 425 bp deletion mutation of chloroplast rpoC2 underlies the yellow stripes (YSs) of Cmvv. Both RNA polymerase PEP and NEP coexist in seed-plant chloroplasts and the ß″ subunit of PEP is encoded by rpoC2. The rpoC2 mutation changed the discontinuous cleft domain required to form the PEP central cleft for DNA binding from 1103 to 59 aa. RNA-Seq revealed that 28 chloroplast genes (cpDEGs) were all down-regulated in YSs, of which, four involved in chloroplast protein translation and 21 of photosynthesis system (PS)I, PSII, cytochrome b6/f complex and ATP synthase are crucial for chloroplast biogenesis/development. The accuracy and reliability of RNA-Seq was verified by qRT-PCR. Moreover, the chlorophyll (Chl) a/b content, ratio of Chla/Chlb and photosynthetic rate (Pn) of YS decreased significantly. Meanwhile, chloroplasts of the YS mesophyll cells were smaller, irregular in shape, contain almost no thylakoid membrane, and even proplastid was found in YS. These findings indicate that the rpoC2 mutation down-regulated expression of the 28 cpDEGs, which disturb chloroplast biogenesis and its thylakoid membrane development. Thus, there are not enough PSI and II components to bind Chl, so that the corresponding areas of the leaf are yellow and show a low Pn. In this study, the molecular mechanism of three phenotypes of F1 (Cmvv ♀ × C. miniata ♂) was revealed, which lays a foundation for the breeding of variegated plants.

ICG-based laser treatments for ophthalmic diseases: Toward their safe and rapid strategy.

The eye is a very important organ, and keratitis, corneal neovascularization, floaters, age-related macular degeneration, and other vision problems have seriously affected people's quality of life. Among the ophthalmic treatments, laser photocoagulations have been proposed and have shown therapeutic effects in clinical settings. However, corneal thinning and bleeding lesions induced by laser damage have led to limit its applications. To treat the issues of traditional hyperthermia treatments, photosensitizers [e.g., indocyanine green (ICG)] have been investigated to increase the therapeutic effects of corneal neovascularization and choroidal neovascularization. In the recent study, with the help of ICG, laser-induced nanobubble was proposed to treat vitreous opacities. The developed strategies could enlarge the effect of laser irradiation and reduce the side effects, so as to expand the scope of laser treatments in clinical ophthalmic diseases.

Common and Rare Variant Prediction and Penetrance of IBD in a Large, Multi-ethnic, Health System-based Biobank Cohort.

BACKGROUND AND AIMS: Polygenic risk scores (PRS) may soon be used to predict inflammatory bowel disease (IBD) risk in prevention efforts. We leveraged exome-sequence and single nucleotide polymorphism (SNP) array data from 29,358 individuals in the multiethnic, randomly ascertained health system-based BioMe biobank to define effects of common and rare IBD variants on disease prediction and pathophysiology. METHODS: PRS were calculated from European, African American, and Ashkenazi Jewish (AJ) reference case-control studies, and a meta-GWAS run using all three association datasets. PRS were then combined using regression to assess which combination of scores best predicted IBD status in European, AJ, Hispanic, and African American cohorts in BioMe. Additionally, rare variants were assessed in genes associated with very early-onset IBD (VEO-IBD), by estimating genetic penetrance in each BioMe population. RESULTS: Combining risk scores based on association data from distinct ancestral populations improved IBD prediction for every population in BioMe and significantly improved prediction among European ancestry UK Biobank individuals. Lower predictive power for non-Europeans was observed, reflecting in part substantially lower African IBD case-control reference sizes. We replicated associations for two VEO-IBD genes, ADAM17 and LRBA, with high dominant model penetrance in BioMe. Autosomal recessive LRBA risk alleles are associated with severe, early-onset autoimmunity; we show that heterozygous carriage of an African-predominant LRBA protein-altering allele is associated with significantly decreased LRBA and CTLA-4 expression with T-cell activation. CONCLUSIONS: Greater genetic diversity in African populations improves prediction across populations, and generalizes some VEO-IBD genes. Increasing African American IBD case-collections should be prioritized to reduce health disparities and enhance pathophysiological insight.

High quality quasi-parallel x-ray microbeams based on a parabolic capillary.

High quality quasi-parallel x-ray microbeams have an appreciable application value in the x-ray diffraction analysis technique, which is currently one of the most significant non-destructive analysis techniques. A simulation of a parabolic single capillary is carried out based on the Monte Carlo simulation toolkit Geant4. The simulation results show that it is feasible to obtain high quality quasi-parallel x-ray microbeams based on a parabolic capillary and a traditional laboratorial x-ray source. We manufacture a parabolic capillary based on the simulation results. The physical parameters of the obtained x-ray beams are characterized by building an x-ray imaging system. The experimental results show that the x-ray beam with submicrometer size and almost zero divergence can be obtained from the traditional laboratorial x-ray source by utilizing a parabolic single capillary as a collimator.

Multiphoton Upconversion Enhanced by Deep Subwavelength Near-Field Confinement.

Efficient generation of anti-Stokes emission within nanometric volumes enables the design of ultracompact, miniaturized photonic devices for a host of applications. Many subwavelength crystals, such as metal nanoparticles and two-dimensional layered semiconductors, have been coupled with plasmonic nanostructures for augmented anti-Stokes luminescence through multiple-harmonic generation. However, their upconversion process remains inefficient due to their intrinsic low absorption coefficients. Here, we demonstrate on-chip, site-specific integration of lanthanide-activated nanocrystals within gold nanotrenches of sub-25 nm gaps via bottom-up self-assembly. Coupling of upconversion nanoparticles to subwavelength gap-plasmon modes boosts 3.7-fold spontaneous emission rates and enhances upconversion by a factor of 100 000. Numerical investigations reveal that the gap-mode nanocavity confines incident excitation radiation into nanometric photonic hotspots with extremely high field intensity, accelerating multiphoton upconversion processes. The ability to design lateral gap-plasmon modes for enhanced frequency conversion may hold the potential to develop on-chip, background-free molecular sensors and low-threshold upconversion lasers.

The Role of Ectodysplasin A on the Ocular Surface Homeostasis.

Ectodysplasin A (EDA), a ligand of the TNF family, plays an important role in maintaining the homeostasis of the ocular surface. EDA is necessary for the development of the meibomian gland, the lacrimal gland, as well as the proliferation and barrier function of the corneal epithelium. The mutation of EDA can induce the destruction of the ocular surface resulting in keratopathy, abnormality of the meibomian gland and maturation of the lacrimal gland. Experimental animal studies showed that a prenatal ultrasound-guided intra-amniotic injection or postnatal intravenous administration of soluble recombinant EDA protein can efficiently prevent the development of ocular surface abnormalities in EDA mutant animals. Furthermore, local application of EDA could restore the damaged ocular surface to some extent. Hence, a recombinant EDA-based therapy may serve as a novel paradigm to treat ocular surface disorders, such as meibomian gland dysfunction and corneal epithelium abnormalities.