Inhibition of ASGR1 decreases lipid levels by promoting cholesterol excretion.

High cholesterol is a major risk factor for cardiovascular disease1. Currently, no drug lowers cholesterol through directly promoting cholesterol excretion. Human genetic studies have identified that the loss-of-function Asialoglycoprotein receptor 1 (ASGR1) variants associate with low cholesterol and a reduced risk of cardiovascular disease2. ASGR1 is exclusively expressed in liver and mediates internalization and lysosomal degradation of blood asialoglycoproteins3. The mechanism by which ASGR1 affects cholesterol metabolism is unknown. Here, we find that Asgr1 deficiency decreases lipid levels in serum and liver by stabilizing LXRα. LXRα upregulates ABCA1 and ABCG5/G8, which promotes cholesterol transport to high-density lipoprotein and excretion to bile and faeces4, respectively. ASGR1 deficiency blocks endocytosis and lysosomal degradation of glycoproteins, reduces amino-acid levels in lysosomes, and thereby inhibits mTORC1 and activates AMPK. On one hand, AMPK increases LXRα by decreasing its ubiquitin ligases BRCA1/BARD1. On the other hand, AMPK suppresses SREBP1 that controls lipogenesis. Anti-ASGR1 neutralizing antibody lowers lipid levels by increasing cholesterol excretion, and shows synergistic beneficial effects with atorvastatin or ezetimibe, two widely used hypocholesterolaemic drugs. In summary, this study demonstrates that targeting ASGR1 upregulates LXRα, ABCA1 and ABCG5/G8, inhibits SREBP1 and lipogenesis, and therefore promotes cholesterol excretion and decreases lipid levels.

GRAMD1/ASTER-mediated cholesterol transport promotes Smoothened cholesterylation at the endoplasmic reticulum.

Hedgehog (Hh) signaling pathway plays a pivotal role in embryonic development. Hh binding to Patched1 (PTCH1) derepresses Smoothened (SMO), thereby activating the downstream signal transduction. Covalent SMO modification by cholesterol in its cysteine-rich domain (CRD) is essential for SMO function. SMO cholesterylation is a calcium-accelerated autoprocessing reaction, and STIM1-ORAI1-mediated store-operated calcium entry promotes cholesterylation and activation of endosome-localized SMO. However, it is unknown whether the Hh-PTCH1 interplay regulates the activity of the endoplasmic reticulum (ER)-localized SMO. Here, we found that PTCH1 inhibited the COPII-dependent export of SMO from the ER, whereas Hh promoted this process. The RRxWxR amino acid motif in the cytosolic tail of SMO was essential for COPII recognition, ciliary localization, and signal transduction activity. Hh and PTCH1 regulated cholesterol modification of the ER-localized SMO, and SMO cholesterylation accelerated its exit from ER. The GRAMD1/ASTER sterol transport proteins facilitated cholesterol transfer to ER from PM, resulting in increased SMO cholesterylation and enhanced Hh signaling. Collectively, we reveal a regulatory role of GRAMD-mediated cholesterol transport in ER-resident SMO maturation and Hh signaling.

Continuously tunable silicon optical true-time delay lines with a large delay tuning range and a low delay fluctuation.

On-chip switchable optical true-time delay lines (OTTDLs) feature a large group delay tuning range but suffer from a discrete tuning step. OTTDLs with a large delay tuning range and a continuous tuning capability are highly desired. In this paper, we propose and experimentally demonstrate a silicon-based broadband continuously tunable OTTDL comprising a 7-bit delay line and a switch-based continuously tunable delay line. The group delay of the entire OTTDL can be continuously tuned from 0 to 1020.16 ps. A delay error within -1.27 ps to 1.75 ps, and a delay fluctuation of less than 2.69 ps in the frequency range of 2∼25 GHz are obtained. We analyze the causes of the delay fluctuation and its influence on beamforming. Moreover, we also propose a simplified non-invasive calibration method that can significantly reduce the complexity of the delay state calibration and can be easily extended to delay lines with more stages of optical switches. The high performance of our OTTDL chip and the calibration method drive practical applications of integrated OTTDLs.

Safety and efficacy of day anterior cervical discectomy and fusion procedure for degenerative cervical spondylosis: a retrospective analysis.

OBJECTIVE: Our study aimed to develop a day anterior cervical discectomy and fusion (ACDF) procedure to treat degenerative cervical spondylosis (DCS). The goal was to analyze its clinical implications, safety, and early effects to provide a better surgical option for eligible DCS patients. METHODS: A retrospective analysis was performed to identify DCS patients who underwent day ACDF from September 2022 to August 2023. The operative time, intraoperative blood loss, postoperative drainage, preoperative and postoperative visual analog scale (VAS) scores, neck disability index (NDI) scores, Japanese Orthopedic Association (JOA) scores, JOA recovery rate (RR), incidence of dysphagia-related symptoms, 30-day hospital readmission rate, and incidence of other complications were recorded to evaluate early clinical outcomes. Radiography was performed to assess the location of the implants, neurological decompression, and cervical physiological curvature. RESULTS: All 33 patients (23 women and 10 men) underwent successful surgery and experienced significant symptomatic and neurological improvements. Among them, 26 patients underwent one-segment ACDF, 5 underwent two-segment ACDF, and 2 underwent three-segment ACDF. The average operative time was 71.1 ± 20.2 min, intraoperative blood loss was 19.1 ± 6.2 mL, and postoperative drainage was 9.6 ± 5.8 mL. The preoperative VAS and NDI scores improved postoperatively (7.1 ± 1.2 vs. 3.1 ± 1.3 and 66.7% ± 4.8% vs. 24.1% ± 2.5%, respectively), with a significant difference (P < 0.01). Moreover, the preoperative JOA scores improved significantly postoperatively (7.7 ± 1.3 vs. 14.2 ± 1.4; P < 0.01) with an RR of 93.9% in good or excellent. Postoperative dysphagia-related symptoms occurred in one patient (3.0%). During the follow-up period, no patient was readmitted within 30 days after discharge; however, an incisional hematoma was reported in one patient on the 6th day after discharge, which was cured by pressure dressing. The postoperative radiographs revealed perfect implant positions and sufficient nerve decompression in all patients. Furthermore, the preoperative cervical physiological curvature improved significantly after the operation (14.5° ± 4.0° vs. 26.3° ± 5.4°; P < 0.01). CONCLUSIONS: Day ACDF has good safety and early clinical efficacy, and it could be an appropriate choice for eligible DCS patients.

Ablation of Plasma Prekallikrein Decreases Low-Density Lipoprotein Cholesterol by Stabilizing Low-Density Lipoprotein Receptor and Protects Against Atherosclerosis.

BACKGROUND: High blood cholesterol accelerates the progression of atherosclerosis, which is an asymptomatic process lasting for decades. Rupture of atherosclerotic plaques induces thrombosis, which results in myocardial infarction or stroke. Lowering cholesterol levels is beneficial for preventing atherosclerotic cardiovascular disease. METHODS: Low-density lipoprotein (LDL) receptor (LDLR) was used as bait to identify its binding proteins in the plasma, and the coagulation factor prekallikrein (PK; encoded by the KLKB1 gene) was revealed. The correlation between serum PK protein content and lipid levels in young Chinese Han people was then analyzed. To investigate the effects of PK ablation on LDLR and lipid levels in vivo, we genetically deleted Klkb1 in hamsters and heterozygous Ldlr knockout mice and knocked down Klkb1 using adeno-associated virus-mediated shRNA in rats. The additive effect of PK and proprotein convertase subtilisin/kexin 9 inhibition also was evaluated. In addition, we applied the anti-PK neutralizing antibody that blocked the PK and LDLR interaction in mice. Mice lacking both PK and apolipoprotein e (Klkb1-/-Apoe-/-) were generated to assess the role of PK in atherosclerosis. RESULTS: PK directly bound LDLR and induced its lysosomal degradation. The serum PK concentrations positively correlated with LDL cholesterol levels in 198 young Chinese Han adults. Genetic depletion of Klkb1 increased hepatic LDLR and decreased circulating cholesterol in multiple rodent models. Inhibition of proprotein convertase subtilisin/kexin 9 with evolocumab further decreased plasma LDL cholesterol levels in Klkb1-deficient hamsters. The anti-PK neutralizing antibody could similarly lower plasma lipids through upregulating hepatic LDLR. Ablation of Klkb1 slowed the progression of atherosclerosis in mice on Apoe-deficient background. CONCLUSIONS: PK regulates circulating cholesterol levels through binding to LDLR and inducing its lysosomal degradation. Ablation of PK stabilizes LDLR, decreases LDL cholesterol, and prevents atherosclerotic plaque development. This study suggests that PK is a promising therapeutic target to treat atherosclerotic cardiovascular disease.

Histone Demethylation Profiles in Nonalcoholic Fatty Liver Disease and Prognostic Values in Hepatocellular Carcinoma: A Bioinformatic Analysis.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with multifactorial pathogenesis; histone demethylases (HDMs) are emerging as attractive targets. We identified HDM genes (including KDM5C, KDM6B, KDM8, KDM4A, and JMJD7) that were differentially expressed in NAFLD and normal samples by exploring gene expression profiling datasets. There was no significant difference in the expression of genes related to histone demethylation between mild and advanced NAFLD. In vitro and in vivo studies indicated that KDM6B and JMJD7 were upregulated at the mRNA level in NAFLD. We explored the expression levels and prognostic values of the identified HDM genes in hepatocellular carcinoma (HCC). KDM5C and KDM4A were upregulated in HCC compared to normal tissue, while KDM8 showed downregulation. The abnormal expression levels of these HDMs could provide prognostic values. Furthermore, KDM5C and KDM4A were associated with immune cell infiltration in HCC. HDMs were associated with cellular and metabolic processes and may be involved in the regulation of gene expression. Differentially expressed HDM genes identified in NAFLD may provide value to understanding pathogenesis and in the development of epigenetic therapeutic targets. However, on the basis of the inconsistent results of in vitro studies, future in vivo experiments combined with transcriptomic analysis are needed for further validation.

Broadband continuously tunable microwave photonic delay line based on cascaded silicon microrings.

We present a novel broadband continuously tunable microwave photonic delay line consisting of a modulator, a four-stage microring resonator delay line, a tunable optical bandpass filter, and a photodetector. Unlike the traditional microring delay lines working at the on-resonant wavelength, the microring resonators in our chip work at the anti-resonant wavelengths, leading to a large delay bandwidth and a small delay ripple. The experimental results show that relative group delay can be continuously tuned from 0 to 160 ps for microwave frequencies in the range of 0 to 16 GHz. The delay ripple is less than 6.2 ps. These results represent an important step towards the realization of integrated continuously tunable delay lines demanded in broadband microwave phased array antennas.

Machine learning interatomic potential developed for molecular simulations on thermal properties of ß-Ga2O3.

The thermal properties of ß-Ga2O3 can significantly affect the performance and reliability of high-power electronic devices. To date, due to the absence of a reliable interatomic potential, first-principles calculations based on density functional theory (DFT) have been routinely used to probe the thermal properties of ß-Ga2O3. DFT calculations can only tackle small-scale systems due to the huge computational cost, while the thermal transport processes are usually associated with large time and length scales. In this work, we develop a machine learning based Gaussian approximation potential (GAP) for accurately describing the lattice dynamics of perfect crystalline ß-Ga2O3 and accelerating atomic-scale simulations. The GAP model shows excellent convergence, which can faithfully reproduce the DFT potential energy surface at a training data size of 32 000 local atomic environments. The GAP model is then used to predict ground-state lattice parameters, coefficients of thermal expansion, heat capacity, phonon dispersions at 0 K, and anisotropic thermal conductivity of ß-Ga2O3, which are all in excellent agreement with either the DFT results or experiments. The accurate predictions of phonon dispersions and thermal conductivities demonstrate that the GAP model can well describe the harmonic and anharmonic interactions of phonons. Additionally, the successful application of our GAP model to the phonon density of states of a 2500-atom ß-Ga2O3 structure at elevated temperature indicates the strength of machine learning potentials to tackle large-scale atomic systems in long molecular simulations, which would be almost impossible to generate with DFT-based molecular simulations at present.

The Effects of High-Salt Gastric Intake on the Composition of the Intestinal Microbiota in Wistar Rats.

BACKGROUND A high-salt diet may result in chronic disease and changes in the intestinal microbiota. This pilot study aimed to investigate the microbial composition of the intestine in Wistar rats given intragastric high-salt infusions for four weeks. MATERIAL AND METHODS Six 4-week-old male Wistar rats were fed standard chow and divided into the high-salt group (n=3) and the control study group (n=3). Rats in the high-salt group were given 1 ml of 10% NaCl solution intragastrically three times per week for four weeks. The fecal pellets were collected, and the microbiota was characterized using 16S rRNA gene sequencing that targeted the V4 region. The relative abundance of microbial populations was compared using linear discriminant analysis effect size (LEfSe) statistical analysis for the identification of biomarkers between two or more groups, principal component analysis (PCA), and linear discriminant analysis (LDA). Microbial genome prediction was performed using the phylogenetic investigation of communities by reconstructing the unobserved states (PICRUSt) bioinformatics software. RESULTS There was no significant difference in the alpha diversity of the fecal microbiota between the high-salt group and the control group. However, PCA showed structural segregation between the two groups. Further analysis using LEfSe showed that the intestinal contents in the high-salt group had significantly reduced populations of Lactobacillus and Prevotella NK3B31, and a significant increase in Alloprevotella and Prevotella 9, without physiological or pathological changes. CONCLUSIONS A pilot study in Wistar rats showed that high-salt intake was associated with a change in the composition of the intestinal microbiota.

Extracting optical constants of solid materials with micro-rough surfaces from ellipsometry without using effective medium approximation.

The effective medium approximation (EMA) model may cause a large deviation in the data analysis of spectroscopic ellipsometry (SE) for solid materials with randomly micro-rough surfaces since it ignores the influence of the lateral irregularities of the rough surfaces on the electromagnetic scattering. In this work, a novel inversion framework is developed to extract optical constants from the SE parameters for solid materials with randomly micro-rough surfaces. Our approach enables the integration of the Levenberg-Marquardt optimization algorithm and the first-principles calculations of electromagnetic scattering. In each iterative step, the electromagnetic interactions with rough surfaces are accurately obtained from first-principles calculations without using the EMA model for rough estimation, which significantly guarantees the precision and wide applicability of our method for actual surfaces without a perfectly Gaussian height distribution. Furthermore, a superior advantage of our approach is that its error can be feasibly evaluated from the instrumental errors of the surface morphology detectors and the SE.

Clinical Features of Patients with Bronchiectasis with Comorbid Chronic Obstructive Pulmonary Disease in China.

BACKGROUND The prevalence of bronchiectasis with comorbid chronic obstructive pulmonary disease (COPD) is rising, which causes extremely high risk of exacerbation and mortality. We aimed to evaluate the differences in clinicopathological manifestations, immune function, and inflammation in bronchiectasis patients with comorbid COPD vs. patients who only have COPD. MATERIAL AND METHODS Clinicopathological characteristics, including common potentially pathogenic microorganisms, lung function, immune function, and inflammation were assessed in bronchiectasis patients with comorbid COPD and in patients who only had COPD. RESULTS Compared to patients who only had COPD, patients with bronchiectasis with comorbid COPD had a higher positive rate of sputum bacteria (45.27% vs. 28.03%, P<0.01). Among them, Pseudomonas aeruginosa (P. aeruginosa) accounted for 25.19% in COPD (4.37%) (P<0.01). Likewise, patients with bronchiectasis with comorbid COPD had worse lung function, worse COPD assessment test scores, and worse Modified Medical Research Council scores. Moreover, compared with COPD only cases, patients with bronchiectasis with comorbid COPD had higher levels of white blood cells (WBC), neutrophils, C-reactive protein (CRP), and procalcitonin (PCT) (all P<0.05). Interestingly, the expression levels of Treg in patients with bronchiectasis with comorbid COPD were lower than in patients with COPD only (P<0.05). Th17 and Th17/Treg levels were higher (P<0.05). Furthermore, remarkable increased level of IL17 and IL-6 and decreased level of IL-10 and TGF-ß were observed in the bronchiectasis combined COPD than in pure COPD (All P<0.05). CONCLUSIONS Our findings suggest that P. aeruginosa is the main pathogen of bacterial infection in bronchiectasis patients with comorbid COPD. These patients have more serious clinical manifestations and immune imbalance, which should be considered when providing clinical treatment.

Applicability of the effective medium approximation in the ellipsometry of randomly micro-rough solid surfaces.

The effective medium approximation (EMA) has been widely applied to model the effect of a solid sample with surface roughness in spectroscopic ellipsometry (SE). There are two specific cases to utilize the EMA model. One is utilizing the EMA model to perform the inversion of the optical constants of solid samples from the SE measurements. Another is utilizing the EMA model to estimate the thickness of the rough layer at solid surface from the SE measurements under the condition in which the optical constants of samples are known. For the first case, the thickness of the rough layer is usually assumed to be the root mean square (rms) roughness as measured by atomic force microscopy (AFM). We theoretically investigate the error of the EMA model to estimate optical constants for different surface morphologies and materials. Because the EMA model only accounts for the height irregularities of rough surfaces but neglects the effect of the lateral irregularities on electromagnetic scattering from rough surfaces, it is difficult to obtain high-precision results for optical constants. Moreover, the inversion error of optical constants by using the EMA model is difficult to evaluate. In the second case, the thickness of the rough layer is estimated by using the EMA model from the SE measurements, called the EMA model roughness. We show that the EMA model roughness generally has a deviation from the rms roughness as measured by AFM. Some correlated relationships are established between the EMA model roughness and the morphological parameters of rough surfaces. It is found that these relationships have similar forms but not identical coefficients for different materials. The results from this work may facilitate a better understanding and utilization for the EMA model in SE.

General design method of ultra-broadband perfect absorbers based on magnetic polaritons.

Starting from one-dimensional gratings and the theory of magnetic polaritons (MPs), we propose a general design method of ultra-broadband perfect absorbers. Based on the proposed design method, the obtained absorber can keep the spectrum-average absorptance over 99% at normal incidence in a wide range of wavelengths; this work simultaneously reveals the robustness of the absorber to incident angles and polarization angles of incident light. Furthermore, this work shows that the spectral band of perfect absorption can be flexibly extended to near the infrared regime by adjusting the structure dimension. The findings of this work may facilitate the active design of ultra-broadband absorbers based on plasmonic nanostructures.

A Novel Technique to Detect EGFR Mutations in Lung Cancer.

Epidermal growth factor receptor (EGFR) gene mutations occur in multiple human cancers; therefore, the detection of EGFR mutations could lead to early cancer diagnosis. This study describes a novel EGFR mutation detection technique. Compared to direct DNA sequencing detection methods, this method is based on allele-specific amplification (ASA), recombinase polymerase amplification (RPA), peptide nucleic acid (PNA), and SYBR Green I (SYBR), referred to as the AS-RPA-PNA-SYBR (ARPS) system. The principle of this technique is based on three continuous steps: ASA or ASA combined with PNA to prevent non-target sequence amplification (even single nucleotide polymorphisms, SNPs), the rapid amplification advantage of RPA, and appropriate SYBR Green I detection (the samples harboring EGFR mutations show a green signal). Using this method, the EGFR 19Del(2) mutation was detected in 5 min, while the EGFR L858R mutation was detected in 10 min. In this study, the detection of EGFR mutations in clinical samples using the ARPS system was compatible with that determined by polymerase chain reaction (PCR) and DNA sequencing methods. Thus, this newly developed methodology that uses the ARPS system with appropriate primer sets is a rapid, reliable, and practical way to assess EGFR mutations in clinical samples.

[Characteristics of refractive status of mutant Lumican transgenic mice].

OBJECTIVE: To investigate the change of refractive status in transgenic mice with mutant Lumican (bright proteoglycan) gene at different ages. METHODS: Experimental Study. Fifty-four 3-week-old with mutant Lumican gene (cDNA 596T > C) mice (27 male and 27 female) were randomly divided into 9 groups (n = 6, half male and half female) by random number table. One group (3-week-old) was randomly chosen and measured the refractive status by retinoscopy after mydriasis. Measurement of other groups were repeated the method above respectively in the fourth, fifth, sixth, eighth, tenth, twelfth, sixteenth, and twentieth week. Differences of diopter between right and left eye and between male and female were compared within each group by paired t test. The differences of mice's diopters in different age were compared by Kruskal-Wallis H test. Pairwise comparisons were acquired by Mann-Whitney U test. RESULTS: There were no statistic difference of diopters between binoculus: The mice's diopters of right and left eyes were respective measured in the twentieth week (1.50 ± 0.45) D and (1.25 ± 0.42) D (t = -0.889, P > 0.05), The mice's diopters of right and left eyes were respective measured in the third week (-2.50 ± 2.59) D and (-2.50 ± 4.32) D (t = 0.000, P > 0.05); There were no statistic difference of diopters between different genders: The mice's diopters of female and male were respective measured in the third week (-0.5 ± 3.83) D and (-4.17 ± 1.94) D, (t = 2.079, P > 0.05), The mice's diopters of female and male were respective measured in the twelfth week (1.50 ± 0.84) D and (1.50 ± 1.87) D (t = 0.000, P > 0.05); Analysis of binocular diopters revealed significant differences among nine groups (H = 20.910, P < 0.05). Diopters measured in the third week (-2.50 ± 3.40D) and the sixth week (+3.25 ± 2.67) D had statistical difference (Z = -3.259, P < 0.001). There were no statistical significance between other groups (P > 0.001). CONCLUSIONS: Characteristics of diopters gathered from mice with Lumican gene mutation at different weeks are summarized as follows: Myopia could be observed in the third week. And this situation of myopia was gradually transformed into hyperopia with aging. The maximum hyperopic diopter was observed at 6th-week-old mice. From the eighth to twentieth week, the degree of hyperopic diopter gradually decreased and stabilized.

Graph attention neural networks for mapping materials and molecules beyond short-range interatomic correlations.

Bringing advances in machine learning to chemical science is leading to a revolutionary change in the way of accelerating materials discovery and atomic-scale simulations. Currently, most successful machine learning schemes can be largely traced to the use of localized atomic environments in the structural representation of materials and molecules. However, this may undermine the reliability of machine learning models for mapping complex systems and describing long-range physical effects because of the lack of non-local correlations between atoms. To overcome such limitations, here we report a graph attention neural network as a unified framework to map materials and molecules into a generalizable and interpretable representation that combines local and non-local information of atomic environments from multiple scales. As an exemplary study, our model is applied to predict the electronic structure properties of metal-organic frameworks (MOFs) which have notable diversity in compositions and structures. The results show that our model achieves the state-of-the-art performance. The clustering analysis further demonstrates that our model enables high-level identification of MOFs with spatial and chemical resolution, which would facilitate the rational design of promising reticular materials. Furthermore, the application of our model in predicting the heat capacity of complex nanoporous materials, a critical property in a carbon capture process, showcases its versatility and accuracy in handling diverse physical properties beyond electronic structures.

Parallel wavelength-division-multiplexed signal transmission and dispersion compensation enabled by soliton microcombs and microrings.

The proliferation of computation-intensive technologies has led to a significant rise in the number of datacenters, posing challenges for high-speed and power-efficient datacenter interconnects (DCIs). Although inter-DCIs based on intensity modulation and direct detection (IM-DD) along with wavelength-division multiplexing technologies exhibit power-efficient and large-capacity properties, the requirement of multiple laser sources leads to high costs and limited scalability, and the chromatic dispersion (CD) restricts the transmission length of optical signals. Here we propose a scalable on-chip parallel IM-DD data transmission system enabled by a single-soliton Kerr microcomb and a reconfigurable microring resonator-based CD compensator. We experimentally demonstrate an aggregate line rate of 1.68 Tbit/s over a 20-km-long SMF. The extrapolated energy consumption for CD compensation of 40-km-SMFs is ~0.3 pJ/bit, which is calculated as being around 6 times less than that of the commercial 400G-ZR coherent transceivers. Our approach holds significant promise for achieving data rates exceeding 10 terabits.