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.

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.

A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.

The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.

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.

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.

Dietary and lifestyle oxidative balance scores are independently and jointly associated with nonalcoholic fatty liver disease: a 20 years nationally representative cross-sectional study.

Background: Oxidative stress is an important contributor to the progression of nonalcoholic fatty liver disease (NAFLD), but whether dietary and lifestyle pro- and antioxidants may have combined or independent effects on NAFLD, and advanced liver fibrosis (AHF) remains unclear. We aimed to elucidate the relationship between a well-established oxidative balance score (OBS) and NAFLD/AHF. Methods: This was a cross-sectional study. We included adult participants with complete data from the National Health and Nutrition Examination Survey 1999-2018. Survey-weighted adjusted multivariate regression analyses were used to examine the association of all OBS with NAFLD/AHF. A combination of restricted cubic splines, mediation analysis, stratified analysis, and sensitivity analysis were used to further elucidate these associations. Results: We included 6,341 eligible adult participants with prevalence of NAFLD and AHF of 30.2 and 13.9%, respectively. In the fully adjusted model, the highest quartile of OBS, dietary OBS, and lifestyle OBS were associated with 65, 55, and 77% reduced risk of NAFLD, respectively, compared with the reference population, respectively. However, all OBS were not associated with the risk of AHF. All OBS were nonlinearly associated with risk of NAFLD and had a more pronounced reduced risk for OBS, dietary OBS, and lifestyle OBS after exceeding 26, 21, and 5 points, respectively. OBS may exert a protective effect indirectly through inflammation, oxidative stress, and glycolipid metabolism markers. Stratification and sensitivity analyses demonstrate the robustness of our findings. Conclusion: All OBS were nonlinearly and negatively associated with NAFLD risk. These effects may exert indirectly through inflammation, oxidative stress, and glycolipid metabolism markers.

Emerging role of α-Klotho in energy metabolism and cardiometabolic diseases.

BACKGROUND AND AIM: Klotho was first identified as a gene associated with aging and longevity in 1997. α-Klotho is an anti-aging protein and its role in energy metabolism, various cardiovascular diseases (CVDs), and metabolic disorders is increasingly being recognized. In this review, we aimed to outline the potential protective role and therapeutic prospects of α-Klotho in energy metabolism and cardiometabolic diseases (CMDs). METHODS: We comprehensively reviewed the relevant literature in PubMed using the keywords 'Klotho', 'metabolism', 'cardiovascular', 'diabetes', 'obesity', 'metabolic syndrome', and 'nonalcoholic fatty liver disease'. RESULTS: α-Klotho can be divided into membrane-bound Klotho, secreted Klotho, and the most studied circulating soluble Klotho that can act as a hormone. Klotho gene polymorphisms have been implicated in energy metabolism and CMDs. α-Klotho can inhibit insulin/insulin growth factor-1 signaling and its overexpression can lead to a 'healthy insulin resistance' and may exert beneficial effects on the regulation of glycolipid metabolism and central energy homeostasis. α-Klotho, mainly serum Klotho, has been revealed to be protective against CVDs, diabetes and its complications, obesity, and nonalcoholic fatty liver disease. Human recombinant Klotho protein/Klotho gene delivery, multiple drugs, or natural products, and exercise can increase α-Klotho expression. CONCLUSION: Overall, α-Klotho has demonstrated its potential as a promising target for modulating energy metabolism and CMDs, and further research is needed to explore its utilization in clinical practice in the future.

Three-Layered Thin Films for Simultaneous Infrared Camouflage and Radiative Cooling.

With the rapid advancements in aerospace technology and infrared detection technology, there are increasing needs for materials with simultaneous infrared camouflage and radiative cooling capabilities. In this study, a three-layered Ge/Ag/Si thin film structure on a titanium alloy TC4 substrate (a widely used skin material for spacecraft) is designed and optimized to achieve such spectral compatibility by combining the transfer matrix method and the genetic algorithm. The structure exhibits a low average emissivity of 0.11 in the atmospheric windows of 3-5 µm and 8-14 µm for infrared camouflage and a high average emissivity of 0.69 in 5-8 µm for radiative cooling. Furthermore, the designed metasurface shows a high degree of robustness regarding the polarization and incidence angle of the incoming electromagnetic wave. The underlying mechanisms allowing for the spectral compatibility of the metasurface can be elucidated as follows: the top Ge layer selectively transmits electromagnetic waves ranging from 5-8 µm while it reflects those in the ranges of 3-5 µm and 8-14 µm. The transmitted electromagnetic waves from the Ge layer are first absorbed by the Ag layer and then localized in the Fabry-Perot resonance cavity formed by Ag layer, Si layer and TC4 substrate. Ag and TC4 make further intrinsic absorptions during the multiple reflections of the localized electromagnetic waves.

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.

Histone Methylation Regulation as a Potential Target for Non-alcoholic Fatty Liver Disease.

Epigenetic modulations are currently emerging as promising targets in metabolic diseases, including non-alcoholic fatty liver disease (NAFLD), for their roles in pathogenesis and therapeutic potential. The molecular mechanisms and modulation potential of histone methylation as a histone post-transcriptional modification in NAFLD have been recently addressed. However, a detailed overview of the histone methylation regulation in NAFLD is lacking. In this review, we comprehensively summarize the mechanisms of histone methylation regulation in NAFLD. We conducted a comprehensive database search in the PubMed database with the keywords 'histone', 'histone methylation', 'NAFLD', and 'metabolism' without time restriction. Reference lists of key documents were also reviewed to include potentially omitted articles. It has been reported that these enzymes can interact with other transcription factors or receptors under pro-NAFLD conditions, such as nutritional stress, which lead to recruitment to the promoters or transcriptional regions of key genes involved in glycolipid metabolism, ultimately regulating gene transcriptional activity to influence the expression. Histone methylation regulation has been implicated in mediating metabolic crosstalk between tissues or organs in NAFLD and serves a critical role in NAFLD development and progression. Some dietary interventions or agents targeting histone methylation have been suggested to improve NAFLD; however, there is still a lack of additional research and clinical translational relevance. In conclusion, histone methylation/demethylation has demonstrated an important regulatory role in NAFLD by mediating the expression of key glycolipid metabolism-related genes, and more research is needed in the future to explore its potential as a therapeutic target.

Unraveling Thermal Transport Correlated with Atomistic Structures in Amorphous Gallium Oxide via Machine Learning Combined with Experiments.

Thermal transport properties of amorphous materials are crucial for their emerging applications in energy and electronic devices. However, understanding and controlling thermal transport in disordered materials remains an outstanding challenge, owing to the intrinsic limitations of computational techniques and the lack of physically intuitive descriptors for complex atomistic structures. Here, it is shown how combining machine-learning-based models and experimental observations can help to accurately describe realistic structures, thermal transport properties, and structure-property maps for disordered materials, which is illustrated by a practical application on gallium oxide. First, the experimental evidence is reported to demonstrate that machine-learning interatomic potentials, generated in a self-guided fashion with minimum quantum-mechanical computations, enable the accurate modeling of amorphous gallium oxide and its thermal transport properties. The atomistic simulations then reveal the microscopic changes in the short-range and medium-range order with density and elucidate how these changes can reduce localization modes and enhance coherences' contribution to heat transport. Finally, a physics-inspired structural descriptor for disordered phases is proposed, with which the underlying relationship between structures and thermal conductivities is predicted in a linear form. This work may shed light on the future accelerated exploration of thermal transport properties and mechanisms in disordered functional materials.

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.

Epidemiology of liver cirrhosis and associated complications: Current knowledge and future directions.

Cirrhosis causes a heavy global burden. In this review, we summarized up-to-date epidemiological features of cirrhosis and its complications. Recent epidemiological studies reported an increase in the prevalence of cirrhosis in 2017 compared to in 1990 in both men and women, with 5.2 million cases of cirrhosis and chronic liver disease occurring in 2017. Cirrhosis caused 1.48 million deaths in 2019, an increase of 8.1% compared to 2017. Disability-adjusted life-years due to cirrhosis ranked 16th among all diseases and 7th in people aged 50-74 years in 2019. The global burden of hepatitis B virus and hepatitis C virus-associated cirrhosis is decreasing, while the burden of cirrhosis due to alcohol and nonalcoholic fatty liver disease (NAFLD) is increasing rapidly. We described the current epidemiology of the major complications of cirrhosis, including ascites, variceal bleeding, hepatic encephalopathy, renal disorders, and infections. We also summarized the epidemiology of hepatocellular carcinoma in patients with cirrhosis. In the future, NAFLD-related cirrhosis will likely become more common due to the prevalence of metabolic diseases such as obesity and diabetes, and the prevalence of alcohol-induced cirrhosis is increasing. This altered epidemiology should be clinically noted, and relevant interventions should be undertaken.

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.