A Noncoding A-to-U Kozak Site Change Related to the High Transmissibility of Alpha, Delta, and Omicron VOCs.

Three prevalent SARS-CoV-2 variants of concern (VOCs) emerged and caused epidemic waves. It is essential to uncover advantageous mutations that cause the high transmissibility of VOCs. However, viral mutations are tightly linked, so traditional population genetic methods, including machine learning-based methods, cannot reliably detect mutations conferring a fitness advantage. In this study, we developed an approach based on the sequential occurrence order of mutations and the accelerated furcation rate in the pandemic-scale phylogenomic tree. We analyzed 3,777,753 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata using the Coronavirus GenBrowser. We found that two noncoding mutations at the same position (g.a28271-/u) may be crucial to the high transmissibility of Alpha, Delta, and Omicron VOCs although the noncoding mutations alone cannot increase viral transmissibility. Both mutations cause an A-to-U change at the core position -3 of the Kozak sequence of the N gene and significantly reduce the protein expression ratio of ORF9b to N. Using a convergent evolutionary analysis, we found that g.a28271-/u, S:p.P681H/R, and N:p.R203K/M occur independently on three VOC lineages, suggesting that coordinated changes of S, N, and ORF9b proteins are crucial to high viral transmissibility. Our results provide new insights into high viral transmissibility co-modulated by advantageous noncoding and nonsynonymous changes.

Recent advances in the involvement of epigenetics in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease that manifests as skin rash, arthritis, lymphadenopathy, and multiple organ lesions. Epigenetics, including DNA methylation, histone modification, and non-coding RNA regulation, mainly affect the function and characteristics of cells through the regulation of gene transcription or translation. Increasing evidence indicates that there are a variety of complex epigenetic effects in patients with SLE, which interfere with the differentiation and function of T, and B lymphocytes, monocytes, and neutrophils, and enhance the expression of SLE-associated pathogenic genes. This paper summarizes our currently knowledge regarding pathogenesis of SLE, and introduces current advances in the epigenetic regulation of SLE from three aspects: immune function, inflammatory response, and lupus complications. We propose that epigenetic changes could be used as potential biomarkers and therapeutic targets of SLE.

Surface-Enriched Room-Temperature Liquid Bismuth for Catalytic CO2 Reduction.

Bismuth-based electrocatalysts are effective for carbon dioxide (CO2) reduction to formate. However, at room temperature, these materials are only available in solid state, which inevitably suffers from surface deactivation, declining current densities, and Faradaic efficiencies. Here, the formation of a liquid bismuth catalyst on the liquid gallium surface at ambient conditions is shown as its exceptional performance in the electrochemical reduction of CO2 (i.e., CO2RR). By doping a trace amount of bismuth (740 ppm atomic) in gallium liquid metal, a surface enrichment of bismuth by over 400 times (30 at%) in liquid state is obtained without atomic aggregation, achieving 98% Faradic efficiency for CO2 conversion to formate over 80 h. Ab initio molecular simulations and density functional theory calculations reveal that bismuth atoms in the liquid state are the most energetically favorable sites for the CO2RR intermediates, superior to solid Bi-sites, as well as joint GaBi-sites. This study opens an avenue for fabricating high-performing liquid-state metallic catalysts that cannot be reached by elementary metals under electrocatalytic conditions.

Protein engineering of lipase A from Candida antarctica to improve esterification of tertiary alcohols.

Chiral tertiary alcohols are important organic compounds in science as well as in industry. However, their preparation in enantiomerically pure form is still a challenge due to their complex structure and steric hindrances compared with primary and secondary alcohols, so kinetic resolution could be an attractive approach.  Lipase A from Candida antarctica (CAL-A) has been shown to catalyze the enantioselective esterification of various tertiary alcohols with excellent enantioselectivity but low activity. Here we report a mutagenesis study by rational design to improve CAL-A activity against tertiary alcohols. Single mutants of CAL-A were selected, expressed, immobilized and screened for esterification of the tertiary alcohol 1,2,3,4-tetrahydronaphthalene-1-ol. A double mutant V278S+S429G showed a 1.5-fold higher reaction rate than that of the wild type CAL-A, while maintaining excellent enantioselectivity.

Coronavirus GenBrowser for monitoring the transmission and evolution of SARS-CoV-2.

Genomic epidemiology is important to study the COVID-19 pandemic, and more than two million severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic sequences were deposited into public databases. However, the exponential increase of sequences invokes unprecedented bioinformatic challenges. Here, we present the Coronavirus GenBrowser (CGB) based on a highly efficient analysis framework and a node-picking rendering strategy. In total, 1,002,739 high-quality genomic sequences with the transmission-related metadata were analyzed and visualized. The size of the core data file is only 12.20 MB, highly efficient for clean data sharing. Quick visualization modules and rich interactive operations are provided to explore the annotated SARS-CoV-2 evolutionary tree. CGB binary nomenclature is proposed to name each internal lineage. The pre-analyzed data can be filtered out according to the user-defined criteria to explore the transmission of SARS-CoV-2. Different evolutionary analyses can also be easily performed, such as the detection of accelerated evolution and ongoing positive selection. Moreover, the 75 genomic spots conserved in SARS-CoV-2 but non-conserved in other coronaviruses were identified, which may indicate the functional elements specifically important for SARS-CoV-2. The CGB was written in Java and JavaScript. It not only enables users who have no programming skills to analyze millions of genomic sequences, but also offers a panoramic vision of the transmission and evolution of SARS-CoV-2.

Novel Iminocoumarin-substituted Tetraphenylethylene-based Near-infrared Fluorescent Probe for Ratiometric Detection of F- and H2S.

An iminocoumarin and tetraphenylethylene compound that exhibits aggregation-induced emission (AIE) and a significant Stokes shift (Δλ = 135 nm) in THF was created via the Knoevenagel condensation method. TPICBT could also be used as a ratiometric near-infrared fluorescent probe for the naked color identification of F- and H2S. It showed a large red shift (˃ 90 nm), good selectivity, and anti-interference. Test strip detection and cell imaging had both been accomplished using the probe. In addition, the probe could conveniently detect H2S produced during food spoilage without laboratory instruments.

Adult mice with noise-induced hearing loss exhibited temporal ordering memory deficits accompanied by microglia-associated neuroplastic changes in the medial prefrontal cortex.

Acquired peripheral hearing loss in midlife is considered the primary modifiable risk factor for dementia, while the underlying pathological mechanism remains poorly understood. Excessive noise exposure is the most common cause of acquired peripheral hearing loss in modern society. This study was designed to investigate the impact of noise-induced hearing loss (NIHL) on cognition, with a focus on the medial prefrontal cortex (mPFC), a brain region that is involved in both auditory and cognitive processes and is highly affected in patients with cognitive impairment. Adult C57BL/6 J mice were randomly assigned to a control group and seven noise groups: 0HPN, 12HPN, 1DPN, 3DPN, 7DPN, 14DPN, and 28DPN, which were exposed to broadband noise at a 123 dB sound pressure level (SPL) for 2 h and sacrificed immediately (0 h), 12 h, or 1, 3, 7, 14, or 28 days post-noise exposure (HPN, DPN), respectively. Hearing assessment, behavioral tests, and neuromorphological studies in the mPFC were performed in control and 28DPN mice. All experimental animals were included in the time-course analysis of serum corticosterone (CORT) levels and mPFC microglial morphology. The results illustrated that noise exposure induced early-onset transient serum CORT elevation and permanent moderate-to-severe hearing loss in mice. 28DPN mice, in which permanent NIHL has been verified, exhibited impaired performance in temporal order object recognition tasks concomitant with reduced structural complexity of mPFC pyramidal neurons. The time-course immunohistochemical analysis in the mPFC revealed significantly higher morphological microglial activation at 14 and 28 DPN, preceded by a remarkably higher amount of microglial engulfed postsynaptic marker PSD95 at 7 DPN. Additionally, lipid accumulation in microglia was observed in 7DPN, 14DPN and 28DPN mice, suggesting a driving role of lipid handling deficits following excessive phagocytosis of synaptic elements in delayed and sustained microglial abnormalities. These findings provide fundamentally novel information concerning mPFC-related cognitive impairment in mice with NIHL and empirical evidence suggesting the involvement of microglial malfunction in the mPFC neurodegenerative consequences of NIHL.

Broadband electrically controlled reflective metasurface for reconfigurable circularly polarized wavefront manipulation.

A broadband, electrically controlled, reconfigurable, circularly polarized reflective metasurface is presented. The chirality of the metasurface structure is changed by switching active elements, which benefits from the tunable current distributions generated by the elaborately designed structure under x-polarized and y-polarized waves. Notably, the proposed metasurface unit cell maintains a good circular-polarization efficiency in a broadband range of 6.82-9.96 GHz (fractional bandwidth of 37%) with a phase difference of π between the two states. As a demonstration, a reconfigurable circularly polarized metasurface containing 8 × 8 elements was simulated and measured. The results verify that the proposed metasurface can flexibly control circularly polarized waves in a broadband, realizing beam splitting, mirror reflection, and other beam manipulations from 7.4 GHz to 9.9 GHz (fractional bandwidth of 28.9%) by simply adjusting the loaded active elements. The proposed reconfigurable metasurface may offer a promising approach to electromagnetic wave manipulation or communication systems.

Identification of Endometrial Cancer-Specific microRNA Biomarkers in Endometrial Fluid.

Abnormal uterine bleeding is a common benign gynecological complaint and is also the most common symptom of endometrial cancer (EC). Although many microRNAs have been reported in endometrial carcinoma, most of them were identified from tumor tissues obtained at surgery or from cell lines cultured in laboratories. The objective of this study was to develop a method to detect EC-specific microRNA biomarkers from liquid biopsy samples to improve the early diagnosis of EC in women. Endometrial fluid samples were collected during patient-scheduled in-office visits or in the operating room prior to surgery using the same technique performed for saline infusion sonohysterography (SIS). The total RNA was extracted from the endometrial fluid specimens, followed by quantification, reverse transcription, and real-time PCR arrays. The study was conducted in two phases: exploratory phase I and validation phase II. In total, endometrial fluid samples from 82 patients were collected and processed, with 60 matched non-cancer versus endometrial carcinoma patients used in phase I and 22 in phase II. The 14 microRNA biomarkers, out of 84 miRNA candidates, with the greatest variation in expression from phase I, were selected to enter phase II validation and statistical analysis. Among them, three microRNAs had a consistent and substantial fold-change in upregulation (miR-429, miR-183-5p, and miR-146a-5p). Furthermore, four miRNAs (miR-378c, miR-4705, miR-1321, and miR-362-3p) were uniquely detected. This research elucidated the feasibility of the collection, quantification, and detection of miRNA from endometrial fluid with a minimally invasive procedure performed during a patient in-office visit. The screening of a larger set of clinical samples was necessary to validate these early detection biomarkers for endometrial cancer.

Epilepsy-related white matter network changes in patients with frontal lobe glioma.

PURPOSE: Epilepsy is a common symptom in patients with frontal lobe glioma. Tumor-related epilepsy was recently considered a type of network disease. Glioma can severely influence the integrity of the white matter network. The association between white matter network changes and presurgical epilepsy remains unclear in glioma patients. This study aims to identify alterations to the subcortical brain networks caused by glioma and glioma-related epilepsy. METHODS: Sixty-one patients with frontal lobe gliomas were enrolled and stratified into the epileptic and non-epileptic groups. Additionally, 14 healthy participants were enrolled after matching for age, sex, and education level. All participants underwent diffusion tensor imaging. Graph theoretical analysis was applied to reveal topological changes in their white matter networks. Regions affected by tumors were excluded from the analysis. RESULTS: Global efficiency was significantly decreased (p = 0.008), while the shortest path length increased (p = 0.02) in the left and right non-epileptic groups compared to the controls. A total of five edges exhibited decreased fiber count in the non-epileptic group (p < 0.05, false discovery rate-corrected). The topological properties and connectional edges showed no significant differences when comparing the epileptic groups and the controls. Additionally, the degree centrality of several nodes connected to the alternated edges was also diminished. CONCLUSIONS: Compared to the controls, the epilepsy groups showed raletively intact WM networks, while the non-epileptsy groups had damaged network with lower efficiency and longer path length. These findings indicated that the occurrence of glioma related epilepsy have association with white matter network intergrity.

Arylboronic Acid-Catalyzed Racemization of Secondary and Tertiary Alcohols.

The use of 2-carboxyphenylboronic acid (5 mol %) and oxalic acid (10 mol %) with 2-butanone as a solvent for the racemization of a range of enantiomerically pure secondary and tertiary alcohols is demonstrated. The process is postulated to proceed via reversible Brønsted acid-catalyzed C-O bond cleavage through an achiral carbocation intermediate.

Prognostic significance of tumor deposits in radically resected gastric cancer: a retrospective study of a cohort of 1915 Chinese individuals.

BACKGROUND: Tumor deposits (TDs) have been identified as an independent prognostic factor in gastric cancer (GC). However, the associated clinicopathological factors and how to simply and reasonably incorporate TD into the TNM staging system remain undetermined. The aim of the current study was therefore to assess the significance of TD among radically resected GC patients. METHODS: We retrospectively reviewed 1915 patients undergoing radical resection between 2007 and 2012. The patients were classified into two groups according to TD status (absent vs. present), and the clinicopathologic characteristics, DFS, and OS were compared. Associations of TD presence with other clinicopathologic factors were evaluated by logistic regression analysis. Univariate and multivariate Cox regression analyses were performed to determine the prognostic factors for DFS and OS in the primary cohort. Propensity score matching (PSM) was performed to reduce the possibility of selection bias according to the presence of TD. External validation of previously proposed modified staging systems incorporating TD was conducted. RESULTS: The detection rate of TD was 10.5% (201/1915). The presence of TD was significantly related to unfavorable clinicopathologic variables, including advanced T and N categories. According to the multivariate Cox regression analysis, the presence of TD was identified as an independent prognostic factor for DFS and OS in the primary cohort (both P < 0.001). In the after-PSM cohort, TD presence also significantly shortened DFS and OS. In the external validation, one system that incorporated TD into the pTNM stage had the best performance. CONCLUSIONS: The presence of TD was significantly associated with poor survival in radically resected GC patients. The incorporation of TD into the TNM staging system can further improve the predictive capability. A multicenter cohort with a large sample size is needed to determine the appropriate method of incorporation.

Development and validation of a novel survival prediction model for newly diagnosed lower-grade gliomas.

OBJECTIVE: Diffuse gliomas are the most common primary gliomas with a poor prognosis. This study aimed to develop and validate prognostic models for predicting the survival probability in newly diagnosed lower-grade glioma (LGG) patients. METHODS: Detailed data were obtained for newly diagnosed LGG from The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) cohorts. Survival was assessed using Cox proportional hazards regression with adjustment for known prognostic factors. The model was established using the TCGA cohort, and independently validated using the CGGA cohort, to predict the 3-, 5-, and 10-year survival probabilities of patients. RESULTS: Data from 293 patients with newly diagnosed LGG from the TCGA cohort were used to establish a prognostic model, and from 232 patients with primary LGG in the CGGA cohort to validate the model. Age, tumor grade, molecular subtype, tumor resection, and preoperative neurological deficits were included in the prediction model. The Cox regression model had a satisfactory corrected concordance index of 0.8508, 0.8510, and 0.8516 in the internal bootstrap validation at 3, 5, and 10 years, respectively. The calibration plots demonstrated high consistency of the predicted and observed outcomes. The CGGA cohort was used for external validation and showed satisfactory discrimination of 0.7776, 0.7682, and 0.7051 at 3, 5, and 10 years, respectively. The calibration plots demonstrated an acceptable calibration capability in the external validation. CONCLUSIONS: This study established and validated a prognostic model to predict the survival probability of patients with newly diagnosed LGG. The model performed well in discrimination and calibration with ease of use, speed, accessibility, interpretability, and generalizability. An easily used nomogram based on the Cox model was established for clinical application. Moreover, a free, easy-to-use software interface based on the nomogram is provided online.

A Robust Laser Stripe Extraction Method for Structured-Light Vision Sensing.

Environmental sensing is a key technology for the development of unmanned cars, drones and robots. Many vision sensors cannot work normally in an environment with insufficient light, and the cost of using multiline LiDAR is relatively high. In this paper, a novel and inexpensive visual navigation sensor based on structured-light vision is proposed for environment sensing. The main research contents of this project include: First, we propose a laser-stripe-detection neural network (LSDNN) that can eliminate the interference of reflective noise and haze noise and realize the highly robust extraction of laser stripes region. Then we use a gray-gravity approach to extract the center of laser stripe and used structured-light model to reconstruct the point clouds of laser center. Then, we design a single-line structured-light sensor, select the optimal parameters for it and build a car-platform for experimental evaluation. This approach was shown to be effective in our experiments and the experimental results show that this method is more accurate and robust in complex environment.

Broadband low-scattering metasurface using a combination of phase cancellation and absorption mechanisms.

In this paper, a broadband low-scattering metasurface is proposed by using a combination of phase cancellation and absorption mechanisms. The metasurface is composed of two structural layers. One layer adopts the geometric phase cell that can obtain a different reflection phase by changing its orientation. Through the random phase distribution design, electromagnetic diffusion can be realized to reduce the backward scattering energy. The other layer is made of a resistive frequency selective surface (RFSS) that can absorb the incident wave by converting it into Ohmic loss. The above two physical mechanisms respectively play the great roles at two distinct frequency bands, and finally make our metasurface achieve the RCS reduction over a wide frequency band ranging from 13 to 31.5 GHz. Both simulation and experimental results are in good agreement, which fully demonstrates our design method. The analysis of the scattering patterns, electric-field distribution and power loss density are given to explain the hybrid RCS-reduction mechanism of our metasurface.

Cascaded metasurface for simultaneous control of transmission and reflection.

Due to the strong capability to control electromagnetic (EM) wave, metasurfaces have garnered considerable interest and brought in many intriguing EM functional devices. However, most of such devices can only work in either transmitted or reflected mode, and it is still very challenging to achieve a simultaneous control of reflection and transmission in one device. Here, we present a cascaded metasurface which integrates the resonant and geometrical phase cells, to manipulate the transmitted and reflected wave independently. By specific design of phase distribution, the reflected and transmitted wavefront can be respectively reshaped on the shared aperture at two different frequency bands. As a proof of concept, a bidirectional beam deflector is realized by our metasurface and experimentally demonstrated at the microwave region. Both simulated and experimental results show that the transmitted and reflected beams can be simultaneously deflected to the predesigned angles. Furthermore, this metasurface exhibits isotropic EM responses under the different linear polarized wave in the reflected mode, while behaves anisotropic EM responses under the different circular polarized waves in the transmitted mode. Our approach provides a simple way to realize full-space EM manipulation, which could be developed for potential applications in mutlifunctional devices and integrated systems.

Cell sheet-based multilayered liver tumor models for anti-cancer drug screening.

OBJECTIVE: To fabricate in vitro cell-dense, three-dimensional (3D) tumor models by employing a cell sheet technology for testing anti-cancer drug efficacy. RESULTS: The stratified liver tumor models were fabricated by stacking contiguous HepG2 cell sheets. Triple-layer (3L), double-layer (2L), single-layer (1L) cell sheet-based liver tumor models (CSLTMs) demonstrated 106, 96, 85% cell viability, respectively, after 3 days treatment of 10 µM doxorubicin hydrochloride (DOX), while cell viability in two-dimensional (2D) conventional culture (control) was 27%. After 7 days of DOX treatment, the viabilities of 3L, 2L, 1L, control were 24, 14, 3 and 4%, respectively. Probable explanations were blocked diffusion of DOX by the intact and multilayered structure and also hypoxia in the bottom of multilayered cell sheets. CONCLUSION: CSLTMs showed a thickness-dependent cytotoxic efficacy of DOX and greater drug resistance than the control, thereby providing useful information toward the development of improved biomimetic tumor models.

[Butein promotes the role of mH2A in MAPK signaling pathway through targeting GRP78 in regulating biological behaviors of melanoma].

OBJECTIVE: To investigate the effect of mH2A and Butein on mitogen-activation protein kinase (MAPK) signaling pathway through targeting glucose regulated protein of 78 (GRP78) in regulating the biological behavior of melanoma.
 Methods: Immunohistochemistry was used to detect the expressions of mH2A and GRP78 in melanoma and adjacent normal tissues. The relationship between mH2A and GRP78, and the clinicopathological data was analyzed. The relationship between GRP78 and mH2A protein was detected by immunoprecipitation assay. The protein expressions of mH2A and GRP78 was detected by Western blot. The invasion ability of melanoma after sliencing mH2A was detected by Transwell invasion assay. The migration ability of melanoma after sliencing mH2A was detected by wound healing assays. The protein expressions of MEK and ERK1 after sliencing mH2A was detected by Western blot.
 Results: The expressions of mH2A and GRP78 in melanoma tissues was significantly lower than that in adjacent normal tissues (P<0.05). Butein enhanced the expression of mH2A (P<0.05). The mH2A regulated the GRP78 protein (P<0.05). Silencing mH2A promoted the invasion and migration of melanoma A375 cells. The MEK and ERK1 protein expressions were up-regulated after silencing Butein.
 Conclusion: Butein promotes the role of mH2A in regulating GRP78 and modulating the biological behavior of melanoma cells through MAPK signaling pathway.

Anti-Inflammatory Effects of TRAF-Interacting Protein in Rheumatoid Arthritis Fibroblast-Like Synoviocytes.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by inflammatory cell infiltration, synovial inflammation, and cartilage destruction. Proliferative fibroblast-like synoviocytes (FLS) play crucial roles in both propagation of inflammation and joint damage because of their production of great amount of proinflammatory cytokines and proteolytic enzymes. In this study, we investigate the role of TRAF-interacting protein (TRIP) in regulating inflammatory process in RA-FLS. TRIP expression was attenuated in RA-FLS compared with osteoarthritis- (OA-) FLS. Overexpression of TRIP significantly inhibited the activation of NF-κB signaling and decreased the production of proinflammatory cytokines and matrix metalloproteinases (MMPs) in TNFα-stimulated RA-FLS. Furthermore, TRIP was found to interact with transforming growth factor ß-activated kinase 1 (TAK1) and promoting K48-linked polyubiquitination of TAK1 in RA-FLS. Our results demonstrate that TRIP has anti-inflammatory effects on RA-FLS and suggest TRIP as a potential therapeutic target for human RA.

Racial differences in false-positive mammogram rates: results from the ACRIN Digital Mammographic Imaging Screening Trial (DMIST).

BACKGROUND: Mammography screening reduces breast cancer mortality, but false-positive tests are common. Few studies have assessed racial differences in false-positive rates. OBJECTIVES: We compared false-positive mammography rates for black and white women, and the effect of patient and facility characteristics on false positives. RESEARCH DESIGN AND SUBJECTS: A prospective cohort study. From a sample of the American College of Radiology Imaging Network (ACRIN) Digital Mammographic Imaging Screening Trial (DMIST), we identified black/African American (N=3176) or white (N=26,446) women with no prior breast surgery or breast cancer. MEASURES: Race, demographics, and breast cancer risk factors were self-reported. Results of initial digital and film mammograms were assessed. False positives were defined as a positive mammogram (Breast Imaging Reporting and Data System category 0, 4, 5) with no cancer diagnosis within 15 months. RESULTS: The false-positive rate for digital mammograms was 9.2% for black women compared with 7.8% for white women (P=0.009). After adjusting for age, black women had 17% increased odds of false-positive digital mammogram compared with whites (OR=1.17; 95% CI, 1.01-1.35; P=0.033). This association was attenuated after adjusting for patient factors, prior films, and study site (OR=1.04; 95% CI, 0.91-1.20; P=0.561). There was no difference in the occurrence of false positives by race for film mammography. CONCLUSIONS: Black women had higher frequency of false-positive digital mammograms explained by lack of prior films and study site.The variation in the disparity between the established technique (film) and the new technology (digital) raises the possibility that racial differences in screening quality may be greatest for new technologies.