Lysyl oxidase-like 4 promotes the invasiveness of triple-negative breast cancer cells by orchestrating the invasive machinery formed by annexin A2 and S100A11 on the cell surface.

Background: Our earlier research revealed that the secreted lysyl oxidase-like 4 (LOXL4) that is highly elevated in triple-negative breast cancer (TNBC) acts as a catalyst to lock annexin A2 on the cell membrane surface, which accelerates invasive outgrowth of the cancer through the binding of integrin-ß1 on the cell surface. However, whether this machinery is subject to the LOXL4-mediated intrusive regulation remains uncertain. Methods: Cell invasion was assessed using a transwell-based assay, protein-protein interactions by an immunoprecipitation-Western blotting technique and immunocytochemistry, and plasmin activity in the cell membrane by gelatin zymography. Results: We revealed that cell surface annexin A2 acts as a receptor of plasminogen via interaction with S100A10, a key cell surface annexin A2-binding factor, and S100A11. We found that the cell surface annexin A2/S100A11 complex leads to mature active plasmin from bound plasminogen, which actively stimulates gelatin digestion, followed by increased invasion. Conclusion: We have refined our understanding of the role of LOXL4 in TNBC cell invasion: namely, LOXL4 mediates the upregulation of annexin A2 at the cell surface, the upregulated annexin 2 binds S100A11 and S100A10, and the resulting annexin A2/S100A11 complex acts as a receptor of plasminogen, readily converting it into active-form plasmin and thereby enhancing invasion.

Effectiveness of Low-frequency Pulse Electrical Stimulation Combined with Dexamethasone in Treating Facial Nerve Paralysis and Its Impact on Facial Nerve Function and Electromyography.

Objective: This study aimed to evaluate the efficacy of adjunct low-frequency pulse electrical stimulation alongside dexamethasone in the treatment of facial nerve paralysis and its subsequent effects on facial nerve function and electromyographic parameters. With the aim of addressing a knowledge gap in the field, this research provides valuable insights into the potential benefits of combining these treatments and their impact on clinical outcomes, facial nerve functionality, and electromyographic dynamics. Methods: A cohort of 66 patients with facial nerve paralysis treated at our institution between April 2018 and November 2021 were randomly assigned to either an observation (n=33) or an experimental group (n=33). The observation group received standard pharmacotherapy, including Western medications and Daqinjiao decoction, along with dexamethasone. The experimental group was administered low-frequency pulse electrical stimulation in addition to the observation group's regimen. Outcomes assessed were clinical efficacy, facial nerve paralysis scoring, facial nerve functional scoring and indices, electromyographic latency, amplitude ratios between affected and unaffected sides, as well as any adverse events. Results: The experimental group demonstrated a significant improvement over the observation group in clinical treatment outcomes, facial nerve paralysis scores, and facial nerve function scores (P < .05 for all). Furthermore, electromyographic analysis revealed shorter latency periods and greater amplitude ratios in the experimental group's facial muscles post-treatment (P < .05). No significant difference was observed in the incidence of adverse reactions between the two groups (P > .05). Conclusion: The integration of low-frequency pulse electrical stimulation with dexamethasone therapy significantly ameliorates the severity of facial nerve paralysis, enhances facial nerve function, and improves electromyographic signals in facial muscles without increasing adverse effects. These findings support the clinical value and safety of this combined treatment approach for facial nerve paralysis, suggesting its suitability for broader clinical application. These results suggest that this combined treatment approach holds promise for broader clinical application, potentially providing a more effective and safer therapeutic option for patients with facial nerve paralysis. Implementing this approach in clinical practice may lead to improved treatment outcomes, better functional recovery, and enhanced quality of life for affected individuals.

Rauwolfia polysaccharide can inhibit the progress of ulcerative colitis through NOS2-mediated JAK2/STAT3 pathway.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory disease of the digestive tract. Rauwolfia polysaccharide (Rau) has therapeutic effects on colitis in mice, but its mechanism of action needs to be further clarified. In the study, we explored the effect of Rau on the UC cell model induced by Lipopolysaccharide (LPS). METHODS: We constructed a UC cell model by stimulating HT-29 cells with LPS. Dextran sodium sulfate (DSS) was used to induce mice to construct an animal model of UC. Subsequently, we performed Rau administration on the UC cell model. Then, the therapeutic effect of Rau on UC cell model and was validated through methods such as Cell Counting Kit-8 (CCK8), Muse, Quantitative real­time polymerase chain reaction (RT-qPCR), Western blotting, and Enzyme-linked immunosorbent assay (ELISA). RESULTS: The results showed that Rau can promote the proliferation and inhibit the apoptosis of the HT-29 cells-induced by LPS. Moreover, we observed that Rau can inhibit the expression of NOS2/JAK2/STAT3 in LPS-induced HT-29 cells. To further explore the role of NOS2 in UC progression, we used siRNA technology to knock down NOS2 and search for its mechanism in UC. The results illustrated that NOS2 knockdown can promote proliferation and inhibit the apoptosis of LPS-induced HT-29 cells by JAK2/STAT3 pathway. In addition, in vitro and in vivo experiments, we observed that the activation of the JAK2/STAT3 pathway can inhibit the effect of Rau on DSS-induced UC model. CONCLUSION: In short, Rauwolfia polysaccharide can inhibit the progress of ulcerative colitis through NOS2-mediated JAK2/STAT3 pathway. This study provides a theoretical clue for the treatment of UC by Rau.

Identification of a distinct cluster of GDF15high macrophages induced by in vitro differentiation exhibiting anti-inflammatory activities.

Introduction: Macrophage-mediated inflammatory response may have crucial roles in the pathogenesis of a variety of human diseases. Growth differentiation factor 15 (GDF15) is a cytokine of the transforming growth factor-ß superfamily, with potential anti-inflammatory activities. Previous studies observed in human lungs some macrophages which expressed a high level of GDF15. Methods: In the present study, we employed multiple techniques, including immunofluorescence, flow cytometry, and single-cell RNA sequencing, in order to further clarify the identity of such GDF15high macrophages. Results: We demonstrated that macrophages derived from human peripheral blood mononuclear cells and rat bone marrow mononuclear cells by in vitro differentiation with granulocyte-macrophage colony stimulating factor contained a minor population (~1%) of GDF15high cells. GDF15high macrophages did not exhibit a typical M1 or M2 phenotype, but had a unique molecular signature as revealed by single-cell RNA sequencing. Functionally, the in vitro derived GDF15high macrophages were associated with reduced responsiveness to pro-inflammatory activation; furthermore, these GDF15high macrophages could inhibit the pro-inflammatory functions of other macrophages via a paracrine mechanism. We further confirmed that GDF15 per se was a key mediator of the anti-inflammatory effects of GDF15high macrophage. Also, we provided evidence showing that GDF15high macrophages were present in other macrophage-residing human tissues in addition to the lungs. Further scRNA-seq analysis in rat lung macrophages confirmed the presence of a GDF15high sub-population. However, these data indicated that GDF15high macrophages in the body were not a uniform population based on their molecular signatures. More importantly, as compared to the in vitro derived GDF15high macrophage, whether the tissue resident GDF15high counterpart is also associated with anti-inflammatory functions remains to be determined. We cannot exclude the possibility that the in vitro priming/induction protocol used in our study has a determinant role in inducing the anti-inflammatory phenotype in the resulting GDF15high macrophage cells. Conclusion: In summary, our results suggest that the GDF15high macrophage cells obtained by in vitro induction may represent a distinct cluster with intrinsic anti-inflammatory functions. The (patho)physiological importance of these cells in vivo warrants further investigation.

Multiplex nanozymatic biosensing of Salmonella on a finger-actuated microfluidic chip.

A colorimetric biosensor was elaboratively designed for fast, sensitive and multiplex bacterial detection on a single microfluidic chip using immune magnetic nanobeads for specific bacterial separation, immune gold@platinum palladium nanoparticles for specific bacterial labeling, a finger-actuated mixer for efficient immunoreaction and two coaxial rotatable magnetic fields for magnetic nanobead capture (outer one) and magnet-actuated valve control (inner one). First, preloaded bacteria, nanobeads and nanozymes were mixed through a finger actuator to form nanobead-bacteria-nanozyme conjugates, which were captured by the outer magnetic field. After the inner magnetic field was rotated to successively wash the conjugates and push the H2O2-TMB substrate for resuspending these conjugates, colorless TMB was catalyzed into blue TMBox products, followed by color analysis using ImageJ software for bacterial determination. This simple biosensor enabled multiplex Salmonella detection as low as 9 CFU per sample in 45 min.

Relationship Between Family History and Quality of Life in Patients with Psoriasis: A Cross-Sectional Study from China.

Purpose: The purpose of this study was to investigate the comprehensive impact of family history of psoriasis, lesion size, disease severity, and the possibility of joint involvement on patients' quality of life(QoL). Patients and Methods: Data from 5961 patients with psoriasis recruited from 440 hospitals throughout China were analyzed. The effects of family history of psoriasis, Body Surface Area(BSA), Psoriasis Area and Severity Index(PASI), and Psoriasis Epidemiology Screening Tool(PEST) on their Dermatology Life Quality Index(DLQI) were studied using a moderated chained mediated effects test. Results: A total of 912 patients (15.30%) had a family history of psoriasis, and 5071 patients (85.10%) had plaque psoriasis. In patients with plaque psoriasis, the variables of family history, PASI, PEST, and DLQI were positively correlated with each other. Additionally, in patients with other types of psoriasis, PASI was positively correlated with PEST and DLQI. Age was positively correlated with PASI and PEST and negatively correlated with DLQI in patients with plaque psoriasis; their Body Mass Index(BMI) and disease duration were in positive correlation with PASI and PEST. The mediation effect of PASI and PEST between family history and DLQI was remarkable in patients with plaque psoriasis and not in those with other types of psoriasis. BSA moderated the association between family history and PASI in patients with plaque psoriasis. Conclusion: PASI and PEST play a chain mediating role in the relationship between family history and DLQI in patients with plaque psoriasis, and high levels of BSA increase the ability of family history to positively predict PASI in plaque psoriasis, thereby affecting the patient's QoL.

Photoinduced Decarboxylative Difluoroalkylation and Perfluoroalkylation of α-Fluoroacrylic Acids.

Herein, a novel and practical methodology for the photoinduced decarboxylative difluoroalkylation and perfluoroalkylation of α-fluoroacrylic acids is reported. A wide range of α-fluoroacrylic acids can be used as applicable feedstocks, allowing for rapid access to structurally important difluoroalkylated and polyfluoroalkylated monofluoroalkenes with high Z-stereoselectivity under mild conditions. The protocol demonstrates excellent functional group compatibility and provides a platform for modifying complex biologically active molecules.

An artificial intelligence model for detecting pathological lymph node metastasis in prostate cancer using whole slide images: a retrospective, multicentre, diagnostic study.

Background: The pathological examination of lymph node metastasis (LNM) is crucial for treating prostate cancer (PCa). However, the limitations with naked-eye detection and pathologist workload contribute to a high missed-diagnosis rate for nodal micrometastasis. We aimed to develop an artificial intelligence (AI)-based, time-efficient, and high-precision PCa LNM detector (ProCaLNMD) and evaluate its clinical application value. Methods: In this multicentre, retrospective, diagnostic study, consecutive patients with PCa who underwent radical prostatectomy and pelvic lymph node dissection at five centres between Sep 2, 2013 and Apr 28, 2023 were included, and histopathological slides of resected lymph nodes were collected and digitised as whole-slide images for model development and validation. ProCaLNMD was trained at a dataset from a single centre (the Sun Yat-sen Memorial Hospital of Sun Yat-sen University [SYSMH]), and externally validated in the other four centres. A bladder cancer dataset from SYSMH was used to further validate ProCaLNMD, and an additional validation (human-AI comparison and collaboration study) containing consecutive patients with PCa from SYSMH was implemented to evaluate the application value of integrating ProCaLNMD into the clinical workflow. The primary endpoint was the area under the receiver operating characteristic curve (AUROC) of ProCaLNMD. In addition, the performance measures for pathologists with ProCaLNMD assistance was also assessed. Findings: In total, 8225 slides from 1297 patients with PCa were collected and digitised. Overall, 8158 slides (18,761 lymph nodes) from 1297 patients with PCa (median age 68 years [interquartile range 64-73]; 331 [26%] with LNM) were used to train and validate ProCaLNMD. The AUROC of ProCaLNMD ranged from 0.975 (95% confidence interval 0.953-0.998) to 0.992 (0.982-1.000) in the training and validation datasets, with sensitivities > 0.955 and specificities > 0.921. ProCaLNMD also demonstrated an AUROC of 0.979 in the cross-cancer dataset. ProCaLNMD use triggered true reclassification in 43 (4.3%) slides in which micrometastatic tumour regions were initially missed by pathologists, thereby correcting 28 (8.5%) missed-diagnosed cases of previous routine pathological reports. In the human-AI comparison and collaboration study, the sensitivity of ProCaLNMD (0.983 [0.908-1.000]) surpassed that of two junior pathologists (0.862 [0.746-0.939], P = 0.023; 0.879 [0.767-0.950], P = 0.041) by 10-12% and showed no difference to that of two senior pathologists (both 0.983 [0.908-1.000], both P > 0.99). Furthermore, ProCaLNMD significantly boosted the diagnostic sensitivity of two junior pathologists (both P = 0.041) to the level of senior pathologists (both P > 0.99), and substantially reduced the four pathologists' slide reviewing time (-31%, P < 0.0001; -34%, P < 0.0001; -29%, P < 0.0001; and -27%, P = 0.00031). Interpretation: ProCaLNMD demonstrated high diagnostic capabilities for identifying LNM in prostate cancer, reducing the likelihood of missed diagnoses by pathologists and decreasing the slide reviewing time, highlighting its potential for clinical application. Funding: National Natural Science Foundation of China, the Science and Technology Planning Project of Guangdong Province, the National Key Research and Development Programme of China, the Guangdong Provincial Clinical Research Centre for Urological Diseases, and the Science and Technology Projects in Guangzhou.

Insufficient Sleep is Associated With Increasing Trends in Adolescent Suicidal Behaviors.

PURPOSE: Youth suicide has been increasing and became a public health concern worldwide. Identifying insufficient sleep as the potential risk factor is critical to reducing suicide risk and increasing trends. This study aimed to determine whether insufficient sleep is associated with increasing trends in suicidal behaviors and disparities by sex, age, and race/ethnicity among school adolescents. METHODS: The present study used biennial data from the US nationally representative Youth Risk Behavior Survey from 2007 to 2019. Joinpoint regression models were used to estimate biennial percent changes (BPCs) and average BPCs (ABPCs) of suicidal behaviors by sleep duration. Logistic regression models were used to examine the association between insufficient sleep and suicidal behaviors. RESULTS: Of 73,356 adolescent students included (mean [standard deviation] age, 16.11 [1.23] years), 50.03% were female. Suicidal ideation and suicide plan among insufficient sleep group increased from 2007 to 2019 (BPC = 2.88% [95% confidence interval {CI}: 1.65%, 4.13%]; BPC = 3.42% [95% CI: 2.09%, 4.77%]), but were nonsignificant among sufficient sleep group. Trends in suicidal ideation (ABPC = 3.03% [95% CI: 1.35%, 4.73%]) and suicide plan (ABPC = 4.03% [95% CI: 2.47%, 5.62%]) among female adolescents with insufficient sleep increased, but nonsignificant among male adolescents with insufficient sleep. Suicidal ideation (ABPC = 1.73% [95% CI: 0.51%, 2.97%]) and suicide plan (ABPC = 2.31% [95% CI: 0.70%, 3.95%]) increased among younger adolescents only with insufficient sleep, whereas suicide trends by sleep duration were similar among older adolescents. Suicide plan among insufficient sleep group increased across the four racial groups, with BPC highest for the White (BPC = 3.48% [95% CI: 1.31%, 5.69%]), and lowest for the Hispanic/Latino (BPC = 1.18% [95% CI: 0.15%, 2.23%]), but were nonsignificant among sufficient sleep group except for the White (BPC = 2.83% [95% CI: 0.62%, 5.09%]). DISCUSSION: Insufficient sleep was disproportionately associated with increasing trends in suicidal behaviors among female, younger, and non-White adolescent students. Ensuring sufficient sleep can potentially reduce suicide among school adolescents.

Personal versus therapist perioperative music intervention: a randomized controlled trial.

INTRODUCTION: Music interventions can alleviate patient anxiety and improve post-surgical satisfaction. However, it remains uncertain whether music personal preferences affect efficacy. We tested whether personal music intervention with patient-selected songs played ad libitum is more effective than standard therapist-designed treatment with classical music. METHODS: A prospective, parallel-group, single-blinded, randomized controlled trial with 229 participants (aged 18 to 60 y) previously scheduled for elective surgery. Data analyses followed a modified intention-to-treat principle. The patients were randomized into three groups: Standard care without music (Control), therapist-designed classic music treatment (TT), or personal music intervention with patient-selected songs played ad libitum by the patient (PI). All patients received standard post-anesthesia care, and music intervention was started upon arrival at the post-anesthesia care unit. Primary outcomes were anxiety and overall satisfaction at discharge. In contrast, secondary outcomes were systolic blood pressure during music intervention, the sleep quality of the night after surgery, and the occurrence of postoperative nausea and vomiting within the first 24 hours after surgery. RESULTS: Compared with therapist-designed music treatment, personal intervention decreased systolic blood pressure (T 0 : 124.3±13.7, 95%CI:121-127.7; T 20min : 117.6±10.4, 95%CI:115-120.1; T 30min : 116.9±10.6, 95%CI:114.3-119.4), prevented postoperative nausea and vomiting (Control: 55.9%, TT: 64.6%, PI: 77.6%), including severe postoperative nausea (VAS score>4; Control:44.1%; TT:33.8%; PI:20.9%) and severe emesis (Frequency≥3, Control:13.2%; TT:7.7%; PI:4.5%). None of the treatments affected sleep quality at night after surgery (Median, Q1-Q3, Control:3,1-3; TT:3,1-4; PI:3,1-3.5). Personal, but not therapist, music intervention significantly prevented anxiety (Control: 36.4±5.9, 95% CI:35.0-37.9; TT: 36.2±7.1, 95%CI: 34.4-37.9; PI: 33.8±5.6, 95%CI: 32.4-35.2) and emesis (Control:23.9%; TT:23.4%; PI:13.2%) and improved patient satisfaction (Median, Q1-Q3, C:8, 6-8; TT:8,7-9; PI:8,7-9). CONCLUSIONS: Personal music intervention improved postoperative systolic blood pressure, anxiety, nausea, emesis, and overall satisfaction, but not sleep quality, as compared to therapist-designed classic intervention.

Nursing Based on Humanistic Care Concept for Continuous Blood Purification for Patients with Severe Sepsis in the Intensive Care Unit.

Context: Mortality from severe sepsis has been declining in recent years but remains a challenge worldwide because it remains the most frequent cause of death in ICUs. High-quality nursing care during a patient's CBP can play an important role in promoting a patient's physical condition. Objective: The study intended to explore the effects of nursing based on a humanistic care concept on continuous blood purification (CBP) treatment for patients with severe sepsis in an intensive care unit (ICU). Design: The research team performed a prospective randomized controlled study. Setting: The study took place at Minhang Hospital at Fudan University in Shanghai, China. Participants: Participants were 80 patients with severe sepsis who had been admitted to the ICU of the hospital and who were receiving CBP between April 2021 and December 2022. Intervention: The research team randomly divided participants into two groups according to their admission sequence, with 40 participants in each group: (1) an intervention group, the humanistic care group, who received CBP under humanistic care, and (2) a control group who received CBP under routine nursing. Outcome Measures: At baseline and postintervention, the research team: (1) measured participants' negative emotions using the Self-rating Anxiety Scale (SAS) and the Self-rating Depression scale (SDS), (2) assessed participants' hope levels using the Herth Hope Index (HHI), and (3) evaluated participants' health statuses using the Acute Physiology and Chronic Health Evaluation (APACHE-II). The team also measured the complication rate and determined participants' treatment compliance. Results: Postintervention compared to the control group, the humanistic care group's: (1) SAS and SDS scores were significantly lower, with P < .001 and P < .001, respectively; (2) HHI score was significantly higher, with P < .001; (3) APACHE-II scores and complication rate were significantly lower, with P < .001 and < .001, respectively; and (4) treatment compliance was significantly higher, with P = .0186. Conclusions: Nursing based on a humanistic care concept in ICUs can effectively alleviate the negative mood of patients with severe sepsis receiving CBP, enhance their hope levels and the treatment effect, improve their health statuses and treatment compliance, and reduce the occurrence of complications.

Interbrain substrates of role switching during mother-child interaction.

Mother-child interaction is highly dynamic and reciprocal. Switching roles in these back-and-forth interactions serves as a crucial feature of reciprocal behaviors while the underlying neural entrainment is still not well-studied. Here, we designed a role-controlled cooperative task with dual EEG recording to explore how differently two brains interact when mothers and children hold different roles. When children were actors and mothers were observers, mother-child interbrain synchrony emerged primarily within the theta oscillations and the frontal lobe, which highly correlated with children's attachment to their mothers (self-reported by mothers). When their roles were reversed, this synchrony was shifted to the alpha oscillations and the central area and associated with mothers' perception of their relationship with their children. The results suggested an observer-actor neural alignment within the actor's oscillations, which was related to the actor-toward-observer emotional bonding. Our findings contribute to the understanding of how interbrain synchrony is established and dynamically changed during mother-child reciprocal interaction.

Pickering emulsions stabilized by starch nanocrystals prepared from various crystalline starches by ultrasonic assisted acetic acid: Stability and delivery of curcumin.

Ultrasonic assisted acetic acid hydrolysis was applied to prepare starch nanocrystals (SNCs) from native starches with different crystalline structures (A, B, and C types). The structure properties, morphology, Pickering emulsion stability and curcumin deliver capacity of both SNCs and native starches were investigated and compared. Compared with native starches, SNCs showed smaller size and higher crystallinity. The size of SNCs varied with different crystalline types, with C-type starch exhibiting the smallest SNCs (107.4 nm), followed by A-type (113.8 nm), and B-type displaying the largest particle size (149.0 nm). SNCs-Pickering emulsion showed enhanced stability with smaller emulsion droplets, higher static stability, and denser oil/water interface. SNCs-Pickering emulsions displayed higher curcumin loading efficiency (53.53 %-61.41 %) compared with native starch-Pickering emulsions (13.93 %-19.73 %). During in vitro digestion, SNCs-Pickering emulsions proved to be more proficient in protecting and prolonging the biological activity of curcumin due to their smaller size and better interfacial properties. These findings demonstrated the potential of SNCs for application in Pickering emulsion and delivery of bioactive components.

Enhancement of low gamma oscillations by volitional conditioning of local field potential in the primary motor and visual cortex of mice.

Volitional control of local field potential oscillations in low gamma band via brain machine interface can not only uncover the relationship between low gamma oscillation and neural synchrony but also suggest a therapeutic potential to reverse abnormal local field potential oscillation in neurocognitive disorders. In nonhuman primates, the volitional control of low gamma oscillations has been demonstrated by brain machine interface techniques in the primary motor and visual cortex. However, it is not clear whether this holds in other brain regions and other species, for which gamma rhythms might involve in highly different neural processes. Here, we established a closed-loop brain-machine interface and succeeded in training mice to volitionally elevate low gamma power of local field potential in the primary motor and visual cortex. We found that the mice accomplished the task in a goal-directed manner and spiking activity exhibited phase-locking to the oscillation in local field potential in both areas. Moreover, long-term training made the power enhancement specific to direct and adjacent channel, and increased the transcriptional levels of NMDA receptors as well as that of hypoxia-inducible factor relevant to metabolism. Our results suggest that volitionally generated low gamma rhythms in different brain regions share similar mechanisms and pave the way for employing brain machine interface in therapy of neurocognitive disorders.

Polymerase chain reaction-based methods for the rapid identification of Amanita exitialis.

Amanita exitialis, a deadly mushroom found in eastern Asia, causes the highest death rates among all poisonous mushrooms in China. The aim of the present study was to develop an efficient, accurate, and user-friendly PCR-based method for identifying A. exitialis that could facilitate the prevention, diagnosis, and treatment of associated food poisoning. A. exitialis-specific primers and probes were designed based on the internal transcribed spacer region variations of 27 mushroom species. Specificity was confirmed using conventional and real-time PCR for 23 non-target mushroom species, including morphologically similar and closely related species. Compared to conventional PCR, real-time PCR was more sensitive (detectable DNA concentration: 1.36 × 10-2 ng/µL vs. 1.36 × 10-3) and efficient (analysis time: 1 h vs. 40 min). Furthermore, the real-time PCR results could be immediately visualized using amplification curve analysis. The results present two robust PCR-based methods for A. exitialis identification that can facilitate food safety.

Active control of an electromagnetically induced transparency analogue in a coupled dual bound states in the continuum system integrated with graphene.

Electronically induced transparency (EIT) is a coherent optical phenomenon that induces interference within atoms, allowing certain specific frequencies of light to pass through atomic media without being absorbed. However, EIT systems face challenges related to narrow transparency windows and precise control of slow light. We propose an interference structure based on a coupled dual bound states in the continuum (BIC) system to emulate the EIT-like effect. By integrating quasi-BIC (bright mode) with BIC (dark mode), our design successfully achieves an EIT-like effect in a narrow bright mode with a full width at half maximum (FWHM) of less than 1 nm. Its notable features are the bright mode's wide tunability achieved through structural parameter adjustment and a significant group delay of up to 14.43 ps. Additionally, integrating graphene into the BIC structure introduced a form of active tunability akin to the EIT-like effect. We numerically calculate the coupling structure, and its intrinsic mechanism is analyzed. Analysis based on coupled-mode theory confirms that this active modulation primarily stems from changes in the BIC structure's loss. Due to its special frequency selectivity and insensitivity to the polarization of the light source, this narrow-band EIT-like structure is particularly suitable for high-precision optical sensing and spectroscopy. The significant group delay of this structure enhances the interaction between light and matter, improving the accuracy and efficiency of optical signal control and data transmission, opening up new avenues for slow light applications and making significant progress in the development of active tunable optical switches and modulators.

Transcriptomic divergence of the Rheum palmatum complex derived from top-geoherb and non-geoherb areas provides the insights into geoherbalism properties of rhubarb.

Geoherb usually represents high-quality medicinal herbs with better clinical therapeutic effects, and elucidating the geoherbalism is essential for the quality improvement of traditional Chinese Medicine. However, few researches were conducted to clarify the geoherbalism based on a large scale of transcriptomics. In the present study, we compared the transcriptomes of Rheum palmatum complex derived from top-geoherb and non-geoherb areas to show the geoherbalism properties of rhubarb. A total of 412.32 Gb clean reads were obtained with unigene numbers of 100,615 after assembly. Based on the obtained transcriptome datasets, key enzyme-encoding genes involved in the anthraquinones biosynthesis were also obtained. We also found that 21 anthraquinone-related unigenes were differentially expressed between two different groups, and some of these DEGs were correlated to the content accumulation of five free anthraquinones, indicating that the gene expression profiles may promote the geoherbalism formation of rhubarb. In addition, the selective pressure analyses indicated that most paired orthologous genes between these two groups were subject to negative selection, and only a low proportion of orthologs under positive selection were detected. Functional annotation analyses indicated that these positive-selected genes related to the functions such as gene expression, substance transport, stress response and metabolism, indicating that discrepant environment also enhanced the formation of geoherbalism. Our study not only provided insights for the genetic mechanism of geoherbalism of rhubarb, but also laid more genetic cues for the future rhubarb germplasms improvement and utilization.

40 Hz light flickering promotes sleep through cortical adenosine signaling.

Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. Here, we demonstrate that light flickering triggered an immediate and sustained increase (up to 3 h after flickering) in extracellular adenosine levels in the primary visual cortex (V1) and other brain regions, as a function of light frequency and intensity, with maximal effects observed at 40 Hz frequency and 4000 lux. We uncovered cortical (glutamatergic and GABAergic) neurons, rather than astrocytes, as the cellular source, the intracellular adenosine generation from AMPK-associated energy metabolism pathways (but not SAM-transmethylation or salvage purine pathways), and adenosine efflux mediated by equilibrative nucleoside transporter-2 (ENT2) as the molecular pathway responsible for extracellular adenosine generation. Importantly, 40 Hz (but not 20 and 80 Hz) light flickering for 30 min enhanced non-rapid eye movement (non-REM) and REM sleep for 2-3 h in mice. This somnogenic effect was abolished by ablation of V1 (but not superior colliculus) neurons and by genetic deletion of the gene encoding ENT2 (but not ENT1), but recaptured by chemogenetic inhibition of V1 neurons and by focal infusion of adenosine into V1 in a dose-dependent manner. Lastly, 40 Hz light flickering for 30 min also promoted sleep in children with insomnia by decreasing sleep onset latency, increasing total sleep time, and reducing waking after sleep onset. Collectively, our findings establish the ENT2-mediated adenosine signaling in V1 as the neurochemical basis for 40 Hz flickering-induced sleep and unravel a novel and non-invasive treatment for insomnia, a condition that affects 20% of the world population.

The causal effects of genetically predicted alcohol consumption on endometrial cancer risk from a Mendelian randomization study.

Endometrial cancer (EC) is a common gynecological tumor in females with an increasing incidence over the past few decades. Alcohol consumption has been linked to the occurrence of various cancers; However, epidemiological studies have shown inconsistent associations between alcohol consumption and EC risk. In order to avoid the influence of potential confounding factors and reverse causality in traditional epidemiological studies, we used a method based on genetic principles-Mendelian randomization (MR) analysis to test whether there is a causal relationship between alcohol consumption and EC. MR analysis was conducted using publicly available summary-level data from genome-wide association studies (GWAS). Fifty-seven single nucleotide polymorphisms (SNPs) were extracted as instrumental variables for alcohol exposure from the GWAS and Sequencing Consortium of Alcohol and Nicotine GWAS summary data involving 941,287 participants of European ancestry. SNPs for EC were obtained from the Endometrial Cancer Association Consortium, the Endometrial Cancer Epidemiology Consortium, and the UK Biobank, involving 121,885 European participants. The inverse variance weighted (IVW) method was used as the primary method to estimate the causal effect, and the MR-Egger regression and weighted median method were used as supplementary methods. Sensitivity analyses were conducted using the Mendelian Randomization Pleiotropy RESidual Sum and Outlier global test, MR-Egger intercept test, and leave-one-out analysis to evaluate the impact of pleiotropy on causal estimates. An increase of 1 standard deviation of genetically predicted log-transformed alcoholic drinks per day was associated with a 43% reduction in EC risk [odds ratio (OR) = 0.57, 95% confidence interval (CI) 0.41-0.79, P < 0.001]. Subgroup analysis of EC revealed that alcohol consumption was a protective factor for endometrioid endometrial cancer (EEC) (OR = 0.56, 95% CI 0.38-0.83, P = 0.004) but not for non-endometrioid endometrial cancer (NEC) (OR = 1.36, 95% CI 0.40-4.66, P = 0.626). The MR-Egger regression and weighted median method yielded consistent causal effects with the IVW method. The consistent results of sensitivity analyses indicated the reliability of our causal estimates. Additionally, alcohol consumption was associated with decreased human chorionic gonadotropin (HCG) and insulin-like growth factor 1 (IGF1) levels. This MR study suggests that genetically predicted alcohol consumption is a protective factor for EC, particularly for EEC, and this protective effect may be mediated through the reduction of HCG and IGF1.

Single-domain antibodies against SARS-CoV-2 RBD from a two-stage phage screening of universal and focused synthetic libraries.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an evolving global pandemic, and nanobodies, as well as other single-domain antibodies (sdAbs), have been recognized as a potential diagnostic and therapeutic tool for infectious diseases. High-throughput screening techniques such as phage display have been developed as an alternative to in vivo immunization for the discovery of antibody-like target-specific binders. METHODS: We designed and constructed a highly diverse synthetic phage library sdAb-U (single-domain Antibody - Universal library ) based on a human framework. The SARS-CoV-2 receptor-binding domain (RBD) was expressed and purified. The universal library sdAb-U was panned against the RBD protein target for two rounds, followed by monoclonal phage ELISA (enzyme-linked immunosorbent assay) to identify RBD-specific binders (the first stage). High-affinity binders were sequenced and the obtained CDR1 and CDR2 sequences were combined with fully randomized CDR3 to construct a targeted (focused) phage library sdAb-RBD, for subsequent second-stage phage panning (also two rounds) and screening. Then, sequences with high single-to-background ratios in phage ELISA were selected for expression. The binding affinities of sdAbs to RBD were measured by an ELISA-based method. In addition, we conducted competition ELISA (using ACE2 ectodomain S19-D615) and SARS-CoV-2 pseudovirus neutralization assays for the high-affinity RBD-binding sdAb39. RESULTS: Significant enrichments were observed in both the first-stage (universal library) and the second-stage (focused library) phage panning. Five RBD-specific binders were identified in the first stage with high ELISA signal-to-background ratios. In the second stage, we observed a much higher possibility of finding RBD-specific clones in phage ELISA. Among 45 selected RBD-positive sequences, we found eight sdAbs can be well expressed, and five of them show high-affinity to RBD (EC50 < 100nM). We finally found that sdAb39 (EC50 ~ 4nM) can compete with ACE2 for binding to RBD. CONCLUSION: Overall, this two-stage strategy of synthetic phage display libraries enables rapid selection of SARS-CoV-2 RBD sdAb with potential therapeutic activity, and this two-stage strategy can potentially be used for rapid discovery of sdAbs against other targets.