The role of Ca2+ signalling and InsP3R in the pathogenesis of intrahepatic cholestasis of pregnancy.

BACKGROUND: In order to contribute new insights for future prevention and treatment of intrahepatic cholestasis of pregnancy (ICP), and to promote positive pregnancy outcomes, we evaluated serum Ca2+ levels and inositol 1,4,5-trisphosphate receptor (InsP3R) expression in the liver tissue of a rat ICP model. METHODS: After establishing the model by injection of oestradiol benzoate and progesterone into pregnant rats, animals were divided into normal control (n = 5) and ICP model groups (n = 5). The expression of InsP3R protein in the liver, and serum levels of Ca2+, glycocholic acid and bile acid were detected. RESULTS: InsP3R mRNA and protein were significantly lower in the ICP model group compared to the normal group, as determined by qPCR and immunohistochemistry, respectively. Serum enzyme-linked immunosorbent assay results revealed significantly higher levels of glycocholic acid and bile acid in the ICP model group compared to the normal group, while Ca2+ levels were significantly lower. The levers of Ca2+ were significantly and negatively correlated with the levels of glycocholic acid. The observed decrease in Ca2+ was associated with an increase in total bile acids, but there was no significant correlation. CONCLUSIONS: Our results revealed that the expression of InsP3R and serum Ca2+ levels was significantly decreased in the liver tissue of ICP model rats. Additionally, Ca2+ levels were found to be negatively correlated with the level of glycocholic acid.

This study investigated the relationship between serum Ca²⁺ levels, inositol 1,4,5-trisphosphate receptor (InsP3R) expression and intrahepatic cholestasis of pregnancy (ICP) in a rat model. The results indicated a significant decrease in InsP3R expression and Ca²⁺ in the disease group compared to the control group, alongside elevated levels of glycocholic acid and bile acid. The levels of Ca²⁺ exhibited a negative correlation with the levels of glycocholic acid. These findings indicated that the decrease of InsP3R expression and Ca²⁺ levels may be related to the pathogenesis of ICP. The study provides further insight into the treatment of this disease.

Modulating Driver Alertness via Ambient Olfactory Stimulation: A Wearable Electroencephalography Study.

Poor alertness levels and related changes in cognitive efficiency are common when performing monotonous tasks such as extended driving. Recent studies have investigated driver alertness decrement and possible strategies for modulating alertness with the goal of improving reaction times to safety critical events. However, most studies rely on subjective measures in assessing alertness changes, while the use of olfactory stimuli, which are known to be strong modulators of cognitive states, has not been commensurately explored in driving alertness settings. To address this gap, in the present study we investigated the effectiveness of olfactory stimuli in modulating the alertness state of drivers and explored the utility of electroencephalography (EEG) in developing objective brain-based tools for assessing the resulting changes in cortical activity. Olfactory stimulation induced a significant differential effect on braking reaction time. The corresponding effect to the cortical activity was characterized using EEG-derived metrics and the devised machine learning framework yielded a high discriminating accuracy (92.1%). Furthermore, neural activity in the alpha frequency band was found to be significantly associated with the observed drivers' behavioral changes. Overall, our results demonstrate the potential of olfactory stimuli to modulate the alertness state and the efficiency of EEG in objectively assessing the resulting cognitive changes.

The effect of sex differences on neointimal characteristics of in-stent restenosis in drug-eluting stents: An optical coherence tomography study.

Background: Previous studies have demonstrated that there are sex-related differences in atherosclerosis. However, in terms of the nature of in-stent restenosis (ISR) neointima, the effect of gender on the results is unclear. Methods: Patients with ISR of drug-eluting stents (DES) who underwent OCT examination in Senior Department of Cardiology of the Chinese People's Liberation Army General Hospital from March 2010 to March 2022 were included. The patients were divided into male and female groups. Results: In this study, a total of 230 DES-ISR patients and 249 DES-ISR target lesions were analyzed. OCT data showed that compared to females, males have a higher incidence of thin-cap fibrous atherosclerosis (TCFA) (37.4% [n = 77] vs. 9.3% [n = 4], p < 0.001) and in-stent neoatherosclerosis (ISNA) (82.0% [n = 169] vs. 62.8% [n = 27]). p = 0.005). In addition, a multivariate logistic regression analysis demonstrated that male was independently associated with a higher incidence of ISNA (OR: 2.659, 95% CI: 1.239-5.707; p = 0.012) and TCFA (OR: 4.216, 95% CI: 1.370-12.976; p = 0.012). Conclusion: For DES-ISR patients, the incidence of ISNA in female was significantly lower than that in male and vulnerability of neointimal pattern is lower in female than in male.

Effect of perioperative acupoint electrical stimulation on macrophages in mice under operative stress.

The strong perioperative stress response caused by surgical anesthesia can significantly suppress immune function, and the body is in a state of immunosuppression for 3 to 4 days after surgery, which leads to an increase in the probability of postoperative infection. Traditional Chinese medicine believes that acupuncture points can "reconcile yin and yang", promote the recovery of immune function, and help reduce the incidence of postoperative infection. Macrophages are an important type of immune cells that participate in the body's innate immunity. They have powerful phagocytosis and clearance functions. They can be polarized into M1 and M2 types under the regulation of the body, and play different roles in fighting microbial infections. Among them, the M1 type can participate in the elimination of pathogens. In this study, we will investigate the perioperative acupoint electrical stimulation to alleviate the immunosuppressive state of surgical stress mice, clarify the regulation of perioperative acupoint electrical stimulation on glucocorticoids and the relationship between NF-κB molecules and macrophage polarization.The key molecules of related pathways were verified by glucocorticoid receptor inhibitors, and it was found that electrical stimulation of acupoints during the perioperative period can affect the polarization of macrophages in surgically stressed mice to the M1 type by reducing the level of glucocorticoids and promoting the expression of NF κB molecules. Further reveal the partial mechanism of electroacupuncture regulating the anti-inflammatory and pro-inflammatory processes of macrophages in the immune response.

Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84.

GPR84 is an orphan class A G protein-coupled receptor (GPCR) that is predominantly expressed in immune cells and plays important roles in inflammation, fibrosis, and metabolism. Here, we present cryo-electron microscopy (cryo-EM) structures of Gαi protein-coupled human GPR84 bound to a synthetic lipid-mimetic ligand, LY237, or a putative endogenous ligand, a medium-chain fatty acid (MCFA) 3-hydroxy lauric acid (3-OH-C12). Analysis of these two ligand-bound structures reveals a unique hydrophobic nonane tail -contacting patch, which forms a blocking wall to select MCFA-like agonists with the correct length. We also identify the structural features in GPR84 that coordinate the polar ends of LY237 and 3-OH-C12, including the interactions with the positively charged side chain of R172 and the downward movement of the extracellular loop 2 (ECL2). Together with molecular dynamics simulations and functional data, our structures reveal that ECL2 not only contributes to direct ligand binding, but also plays a pivotal role in ligand entry from the extracellular milieu. These insights into the structure and function of GPR84 could improve our understanding of ligand recognition, receptor activation, and Gαi-coupling of GPR84. Our structures could also facilitate rational drug discovery against inflammation and metabolic disorders targeting GPR84.

As-Grown Miniaturized True Zero-Order Waveplates Based on Low-Dimensional Ferrocene Crystals.

As basic optical elements, waveplates with anisotropic electromagnetic responses are imperative for manipulating light polarization. Conventional waveplates are manufactured from bulk crystals (e.g., quartz and calcite) through a series of precision cutting and grinding steps, which typically result in large size, low yield, and high cost. In this study, a bottom-up method is used to grow ferrocene crystals with large anisotropy to demonstrate self-assembled ultrathin true zero-order waveplates without additional machining processing, which is particularly suited for nanophotonic integration. The van der Waals ferrocene crystals exhibit high birefringence (Δn (experiment) = 0.149  ±  0.002 at 636 nm), low dichroism Δκ (experiment) = -0.0007 at 636 nm), and a potentially broad operating range (550 nm to 20 µm) as suggested by Density Functional Theory (DFT) calculations. In addition, the grown waveplate's highest and the lowest principal axes (n1 and n3 , respectively) are in the a-c plane, where the fast axis is along one natural edge of the ferrocene crystal, rendering them readily usable. The as-grown, wavelength-scale-thick waveplate allows the development of further miniaturized systems via tandem integration.

Greatly Enhanced Resonant Exciton-Trion Conversion in Electrically Modulated Atomically Thin WS2 at Room Temperature.

Excitonic resonance in atomically thin semiconductors offers a favorite platform to study 2D nanophotonics in both classical and quantum regimes and promises potentials for highly tunable and ultra-compact optical devices. The understanding of charge density dependent exciton-trion conversion is the key for revealing the underlaying physics of optical tunability. Nevertheless, the insufficient and inefficient light-matter interactions hinder the observation of trionic phenomenon and the development of excitonic devices for dynamic power-efficient electro-optical applications. Here, by engaging an optical cavity with atomically thin transition metal dichalcogenides (TMDCs), greatly enhanced exciton-trion conversion is demonstrated at room temperature (RT) and achieve electrical modulation of reflectivity of ≈40% at exciton and 7% at trion state, which correspondingly enables a broadband large phase tuning in monolayer tungsten disulfide. Besides the absorptive conversion, ≈100% photoluminescence conversion from excitons to trions is observed at RT, illustrating a clear physical mechanism of an efficient exciton-trion conversion for extraordinary optical performance. The results indicate that both excitons and trions can play significant roles in electrical modulation of the optical parameters of TMDCs at RT. The work shows the real possibility for realizing electrical tunable and multi-functional ultra-thin optical devices using 2D materials.

Exploiting refractory organic matter for advanced nitrogen removal from mature landfill leachate via anammox in an expanded granular sludge bed reactor.

Anammox is an efficient low-carbon nitrogen removal technology for mature landfill leachate (MLL). However, it produces 11 % nitrate theoretically, which needs further removal. In this study, the mechanisms of exploiting refractory organic matter (ROM) from an MLL as an inner carbon source for advanced nitrogen removal via anammox were systematically analyzed, and the effects of hydraulic retention time on nitrogen and ROM removal/utilization were investigated. Without any external carbon source, a total nitrogen and organic carbon removal efficiency of 94.50 % and 27.12 %, respectively, were achieved, with a nitrogen loading rate of 2.4 kg N/(m3·d). The abundances of norank_f_norank_o_SBR1031, OLB13, and norank_f_A4b, which had the capacity to degrade ROM, increased from 21.63 % to 49.21 %. This study reveals that the ROM in an MLL can be exploited for synchronous advanced nitrogen and organic matter removal.

Comprehensive breathing variability indices enhance the prediction of extubation failure in patients on mechanical ventilation.

BACKGROUND AND OBJECTIVE: Despite the numerous studies on extubation readiness assessment for patients who are invasively ventilated in the intensive care unit, a 10-15% extubation failure rate persists. Although breathing variability has been proposed as a potential predictor of extubation failure, it is mainly assessed using simple statistical metrics applied to basic respiratory parameters. Therefore, the complex pattern of breathing variability conveyed by continuous ventilation waveforms may be underexplored. METHODS: Here, we aimed to develop novel breathing variability indices to predict extubation failure among invasively ventilated patients. First, breath-to-breath basic and comprehensive respiratory parameters were computed from continuous ventilation waveforms 1 h before extubation. Subsequently, the basic and advanced variability methods were applied to the respiratory parameter sequences to derive comprehensive breathing variability indices, and their role in predicting extubation failure was assessed. Finally, after reducing the feature dimensionality using the forward search method, the combined effect of the indices was evaluated by inputting them into the machine learning models, including logistic regression, random forest, support vector machine, and eXtreme Gradient Boosting (XGBoost). RESULTS: The coefficient of variation of the dynamic mechanical power per breath (CV-MPd[J/breath]) exhibited the highest area under the receiver operating characteristic curve (AUC) of 0.777 among the individual indices. Furthermore, the XGBoost model obtained the best AUC (0.902) by combining multiple selected variability indices. CONCLUSIONS: These results suggest that the proposed novel breathing variability indices can improve extubation failure prediction in invasively ventilated patients.

Dual antiplatelet therapy after percutaneous coronary intervention in patients at high bleeding risk: A systematic review and meta-analysis.

BACKGROUND: To date, it has not been ascertained whether shortening the duration of dual antiplatelet therapy (DAPT) can benefit high bleeding risk (HBR) patients. This systematic review and meta-analysis was performed to investigate the safety and efficacy of short (≤ 3 months) DAPT in HBR patients after percutaneous coronary intervention (PCI). METHODS: The PubMed, Embase, and Clinical Trials databases were searched from inception until November 2021 to identify studies that evaluated the safety and efficacy of short DAPT in HBR patients implanted with new-generation drug-eluting stents (DES). Primary endpoints included major bleeding, definite or probable stent thrombosis (ST), and myocardial infarction (MI), while secondary endpoints included all-cause death and ischemic stroke. Based on the fixed and random effect model, the risk ratio (RR) and 95% confidence interval of each endpoint were measured. RESULTS: Five observational studies and one randomized controlled trial were included, involving 15,432 HBR patients. Short DAPT for HBR patients undergoing PCI had a lower incidence of major bleeding in comparison with standard (> 3 months) DAPT (2.3% vs. 3.2%, RR 0.64 [0.44, 0.95], p = 0.03), while short DAPT was comparable to standard DAPT with regard to definite or probable ST (0.4% vs. 0.3%, RR 1.31 [0.77, 2.23], p = 0.32) and MI (2.4% vs. 2.0%, RR 1.17 [0.95, 1.45], p = 0.14). CONCLUSIONS: Among HBR patients implanted with new-generation DES, short DAPT was associated with reduced risk of major bleeding without significantly increasing the risk of definite or probable ST and MI in comparison with standard DAPT.

Lipoprotein (a) is related to In-Stent neoatherosclerosis incidence rate and plaque vulnerability: Optical Coherence Tomography Study.

BACKGROUND: In-stent neoatherosclerosis (ISNA) is an important reason for stent failure. High lipoprotein (a) [Lp (a)] level is an independent predictor of in-stent restenosis (ISR). To date, the relationship between the level of serum Lp (a) and the incidence rate and vulnerability of ISNA has never been verified. METHODS: A total of 119 patients with 125 drug-eluting stent ISR lesions who underwent percutaneous coronary intervention guided by optical coherence tomography were enrolled in this study. According to their Lp (a) level, the patients were divided into two groups [high Lp (a) group ≥ 30 mg/dL, n = 47; or low Lp (a) group < 30 mg/dL, n = 72]. The clinical baseline, angiographic characteristics, and optical coherence tomography data of both groups were recorded and analyzed. RESULTS: No significant differences in clinical and angiographic characteristics were found between the two groups (P > 0.05). The incidence rate of ISNA in the high Lp (a) group was significantly higher than that in the low Lp (a) group (94.0% [n = 47] vs. 52.0% [n = 39], P < 0.001). The incidence rate of thin-cap fibroatheroma in ISR lesions was significantly higher in the high Lp (a) group than in the low Lp (a) group (42% [n = 21] vs. 5.3% [n = 4], P < 0.001). CONCLUSION: A high Lp (a) level is associated with the high incidence rate and plaque vulnerability of ISNA.

[Genetic diagnosis of a Chinese pedigree affected with Alazami syndrome].

OBJECTIVE: To explore the genetic etiology for a Chinese pedigree affected with Alazami syndrome. METHODS: Genomic DNA was extracted for 2 patients and 2 unaffected members from the pedigree. Whole exome sequencing was carried out to detect potential variant in the proband, and the result was verified by Sanger sequencing. RESULTS: The proband and her sister were both found to harbor compound heterozygous variants of LARP7 gene, namely c.94A>T (p.Lys32*) and c.1141A>G (p.Lys381Glu), which were inherited from their father and mother, respectively. Both variants were predicted to be pathogenic based on bioinformatic analysis. CONCLUSION: The two variants of the LARP7 gene, both were unreported previously, probably underlay the Alazami syndrome in this pedigree. Above finding has expanded the mutational spectrum of the LARP7 gene.

Multilayer Network Framework Reveals Cross-Frequency Coupling Hubs in Cortical Olfactory Perception.

Olfactory perception is shaped by dynamic in-teractions among networks of widely distributed brain regions involved in several neurocognitive processes. However, the neural mechanisms that enable effective coordination and integrative processing across these brain regions, which have different functions and operating characteristics, are not yet fully understood. In this study we use electroencephalography (EEG) signals and a multilayer network formalism to model cross-frequency coupling across the brain and identify brain regions that operate as connecting hubs, thus facilitating inte-grative function. To this goal, we investigate α-γ coupling and θ-γ coupling during exposure to olfactory stimuli of different pleasantness levels. We found that a wider distributed network of hubs emerges in the higher pleasantness condition and that significant differences in the hub connectivity are located in the middle frontal and central regions. Our results indicate the consistent functional role that γ band activity plays in information integration in olfactory perception.

Structural and biochemical mechanism for increased infectivity and immune evasion of Omicron BA.2 variant compared to BA.1 and their possible mouse origins.

The Omicron BA.2 variant has become a dominant infective strain worldwide. Receptor binding studies show that the Omicron BA.2 spike trimer exhibits 11-fold and 2-fold higher potency in binding to human ACE2 than the spike trimer from the wildtype (WT) and Omicron BA.1 strains. The structure of the BA.2 spike trimer complexed with human ACE2 reveals that all three receptor-binding domains (RBDs) in the spike trimer are in open conformation, ready for ACE2 binding, thus providing a basis for the increased infectivity of the BA.2 strain. JMB2002, a therapeutic antibody that was shown to efficiently inhibit Omicron BA.1, also shows potent neutralization activities against Omicron BA.2. In addition, both BA.1 and BA.2 spike trimers are able to bind to mouse ACE2 with high potency. In contrast, the WT spike trimer binds well to cat ACE2 but not to mouse ACE2. The structures of both BA.1 and BA.2 spike trimer bound to mouse ACE2 reveal the basis for their high affinity interactions. Together, these results suggest a possible evolution pathway for Omicron BA.1 and BA.2 variants via a human-cat-mouse-human circle, which could have important implications in establishing an effective strategy for combating SARS-CoV-2 viral infections.

Stable and Solution-Processable Cumulenic sp-Carbon Wires: A New Paradigm for Organic Electronics.

Solution-processed, large-area, and flexible electronics largely relies on the excellent electronic properties of sp2 -hybridized carbon molecules, either in the form of π-conjugated small molecules and polymers or graphene and carbon nanotubes. Carbon with sp-hybridization, the foundation of the elusive allotrope carbyne, offers vast opportunities for functionalized molecules in the form of linear carbon atomic wires (CAWs), with intriguing and even superior predicted electronic properties. While CAWs represent a vibrant field of research, to date, they have only been applied sparingly to molecular devices. The recent observation of the field-effect in microcrystalline cumulenes suggests their potential applications in solution-processed thin-film transistors but concerns surrounding the stability and electronic performance have precluded developments in this direction. In the present study, ideal field-effect characteristics are demonstrated for solution-processed thin films of tetraphenyl[3]cumulene, the shortest semiconducting CAW. Films are deposited through a scalable, large-area, meniscus-coating technique, providing transistors with hole mobilities in excess of 0.1 cm2  V-1  s-1 , as well as promising operational stability under dark conditions. These results offer a solid foundation for the exploitation of a vast class of molecular semiconductors for organic electronics based on sp-hybridized carbon systems and create a previously unexplored paradigm.

Clinical Characteristics of Coronavirus Disease 2019 (COVID-19): A Comparison Between Laboratory-Confirmed and Clinically Suspected Patients.

To investigate the characteristic findings between laboratory-confirmed and clinically suspected patients with COVID-19. In this retrospective study, we included patients admitted to the Xiangya Hospital from Jan 24 to Feb 10, 2020. Two researchers separately collected and sorted out the patients' epidemiological, demographic, clinical, laboratory, and radiologic findings. SPSS was performed to analyze the collected data. 241 patients were admitted, including 28 (45.5; IQR, 34.0-52.5) confirmed and 213 (42.0; IQR, 30.0-57.0) suspected patients. The prevalence of COVID-19 disease in males was significantly higher than in females (64.3% vs. 35.7%, P = 0.033). Before admission of the confirmed and suspected undiagnosed cases, the onset of symptoms is often manifested as respiratory symptoms such as fever (35.7% vs. 27.7%) and cough (30.7% vs. 32.1%). Twenty patients (71.4%) had an exposure history to high-risk areas, and 14 patients (50.0%) traveled or lived in a high-risk area in the confirmed group, which was significantly different from the suspected group. The pulmonary imaging of the patients in the confirmed group was primarily manifested as ground-glass opacity (89.3%). A total of 499 nucleic acid testing (NAT) was performed to determine the 28 COVID-19 positive throat swabs among the 241 patients. Whether there is a history of high-risk area exposure in the epidemiological investigation is essential in distinguishing the suspected patients from the confirmed patients. Multiple nucleic acid tests were used as the basis for the diagnosis of COVID-19, and during CT examination, ground-glass opacity was used as a COVID-19 indicator. Trail registration Trail registration number. 202012195, Date of registration: 2020.12.22 "retrospectively registered".

A Sequential Three-Phase Pathway Constitutes Tracheary Element Connection in the Arabidopsis/Nicotiana Interfamilial Grafts.

Scion-rootstock union formation is a critical step toward the functional assemblage of heterogeneous plants. Interfamilial scion-rootstock interaction often results in graft incompatibility during the assemblage process, and the underlying mechanisms are largely unknown. In this study, we reported that tracheary element (TE) remodeling, including TE segmentation and deformation, rather than de novo formation from callus or adjacent tissues, took place at the early stage of grafting interface between Arabidopsis thaliana and Nicotiana benthamiana (At/Nb). Following cellular deposits, the short TEs from both partners were overlapping, dependent on the homogeneity of contacting TEs, with each other. Without overlapping, the TEs at the interface would grow laterally, and the TEs above and below the interface would undergo self-fusion to form insulating spiraling bundles. Finally, the overlapping TEs constituted a continuous network through alignment. Our results provide a definitive framework for the critical process of TE behavior in the At/Nb distant grafts, including (1) segmentation and/or deformation, (2) matching, overlapping, and cellular deposits, and (3) aligning or spiraling. These insights might guide us in the future into constructing more compatible distant grafts from the perspective of TE homogeneity.