A high reticulocyte count is a risk factor for the onset of metabolic dysfunction-associated steatotic liver disease: Cross-sectional and prospective studies of data of 310,091 individuals from the UK Biobank.

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a considerable health risk. Nevertheless, its risk factors are not thoroughly comprehended, and the association between the reticulocyte count and MASLD remains uncertain. This study aimed to explore the relationship between reticulocyte count and MASLD. Methods: A total of 310,091 individuals from the UK Biobank were included in this cross-sectional study, and 7,316 individuals were included in this prospective study. The cross-sectional analysis categorized reticulocyte count into quartiles, considering the sample distribution. Logistic regression models examined the connection between reticulocyte count and MASLD. In the prospective analysis, Cox analysis was utilized to investigate the association. Results: Our study findings indicate a significant association between higher reticulocyte count and an elevated risk of MASLD in both the cross-sectional and prospective analyses. In the cross-sectional analysis, the adjusted odds ratios (ORs) of MASLD increased stepwise over reticulocyte count quartiles (quartile 2: OR 1.22, 95% CI 1.17-1.28, p < 0.001; quartile 3: OR 1.44; 95% CI 1.38-1.51, p < 0.001; quartile 4: OR 1.66, 95% CI 1.59-1.74, p < 0.001). The results of prospective analyses were similar. Conclusion: Increased reticulocyte count was independently associated with a higher risk of MASLD. This discovery offers new insights into the potential of reticulocytes as biomarkers for MASLD.

Unified Convolutional Sparse Transformer for Disease Diagnosis, Monitoring, Drug Development, and Therapeutic Effect Prediction from EEG Raw Data.

Electroencephalogram (EEG) analysis plays an indispensable role across contemporary medical applications, which encompasses diagnosis, monitoring, drug discovery, and therapeutic assessment. This work puts forth an end-to-end deep learning framework that is uniquely tailored for versatile EEG analysis tasks by directly operating on raw waveform inputs. It aims to address the challenges of manual feature engineering and the neglect of spatial interrelationships in existing methodologies. Specifically, a spatial channel attention module is introduced to emphasize the critical inter-channel dependencies in EEG signals through channel statistics aggregation and multi-layer perceptron operations. Furthermore, a sparse transformer encoder is used to leverage selective sparse attention in order to efficiently process long EEG sequences while reducing computational complexity. Distilling convolutional layers further concatenates the temporal features and retains only the salient patterns. As it was rigorously evaluated on key EEG datasets, our model consistently accomplished a superior performance over the current approaches in detection and classification assignments. By accounting for both spatial and temporal relationships in an end-to-end paradigm, this work facilitates a versatile, automated EEG understanding across diseases, subjects, and objectives through a singular yet customizable architecture. Extensive empirical validation and further architectural refinement may promote broader clinical adoption prospects.

Bioinformatics analysis and identification of potential key genes and pathways in the pathogenesis of nonischemic cardiomyopathy.

Nonischemic cardiomyopathy (NICM) is a major cause of advanced heart failure, and the morbidity and mortality associated with NICM are serious medical problems. However, the etiology of NICM is complex and the related mechanisms involved in its pathogenesis remain unclear. The microarray datasets GSE1869 and GSE9128 retrieved from the Gene Expression Omnibus database were used to identify differentially expressed genes (DEGs) between NICM and normal samples. The co-expressed genes were identified using Venn diagrams. Kyoto Encyclopedia of Genes and Genomes pathway analyses and gene ontology enrichment were used to clarify biological functions and signaling pathways. Analysis of protein-protein interaction networks using Search Tool for the Retrieval of Interacting Genes/Proteins online to define the hub genes associated with NICM pathogenesis. A total of 297 DEGs were identified from GSE1869, 261 of which were upregulated genes and 36 were downregulated genes. A total of 360 DEGs were identified from GSE9128, 243 of which were upregulated genes and 117 were downregulated genes. In the 2 datasets, the screening identified 36 co-expressed DEGs. Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology analysis showed that DEGs were mainly enriched in pantothenate and CoA biosynthesis, beta-alanine metabolism, kinetochore, G-protein beta/gamma-subunit complex, and other related pathways. The PPI network analysis revealed that DUSP6, EGR1, ZEB2, and XPO1 are the 4 hub genes of interest in the 2 datasets. Bioinformatics analysis of hub genes and key signaling pathways is an effective way to elucidate the mechanisms involved in the development of NICM. The results will facilitate further studies on the pathogenesis and therapeutic targets of NICM.

Free-electron interaction with nonlinear optical states in microresonators.

The short de Broglie wavelength and strong interaction empower free electrons to probe structures and excitations in materials and biomolecules. Recently, electron-photon interactions have enabled new optical manipulation schemes for electron beams. In this work, we demonstrate the interaction of electrons with nonlinear optical states inside a photonic chip-based microresonator. Optical parametric processes give rise to spatiotemporal pattern formation corresponding to coherent or incoherent optical frequency combs. We couple such "microcombs" to electron beams, demonstrate their fingerprints in the electron spectra, and achieve ultrafast temporal gating of the electron beam. Our work demonstrates the ability to access solitons inside an electron microscope and extends the use of microcombs to spatiotemporal control of electrons for imaging and spectroscopy.

Mechanistic Insights into the N-Hydroxylations Catalyzed by the Binuclear Iron Domain of SznF Enzyme: Key Piece in the Synthesis of Streptozotocin.

SznF, a member of the emerging family of heme-oxygenase-like (HO-like) di-iron oxidases and oxygenases, employs two distinct domains to catalyze the conversion of Nω-methyl-L-arginine (L-NMA) into N-nitroso-containing product, which can subsequently be transformed into streptozotocin. Using unrestricted density functional theory (UDFT) with the hybrid functional B3LYP, we have mechanistically investigated the two sequential hydroxylations of L-NMA catalyzed by SznF's binuclear iron central domain. Mechanism B primarily involves the O-O bond dissociation, forming Fe(IV)=O, induced by the H+/e- introduction to the FeA side of µ-1,2-peroxo-Fe2(III/III), the substrate hydrogen abstraction by Fe(IV)=O, and the hydroxyl rebound to the substrate N radical. The stochastic addition of H+/e- to the FeB side (mechanism C) can transition to mechanism B, thereby preventing enzyme deactivation. Two other competing mechanisms, involving the direct O-O bond dissociation (mechanism A) and the addition of H2O as a co-substrate (mechanism D), have been ruled out.

Critical fractions in reclaimed water responsible for membrane fouling: Isolation, fouling characteristics, quantitative and qualitative variations in practical application.

Considering the different fouling characteristics between model foulants and organic components in real reclaimed water, it is of great importance to identify the critical foulants responsible for membrane fouling. This study identified and isolated the fraction with molecular weight (MW) > 100 kDa as the critical foulant in secondary effluent by MW cut-off membrane of 100 kDa with high efficiency. This fraction accounted for 92.2% membrane fouling of raw water, including 28.7%, 29.7% and 33.8% fouling contribution by subfractions with MW between 100-300, 300-500 and > 500 kDa. Specifically, the critical fraction with MW > 100 kDa were mainly distributed in two parts: < 0.22 µm and > 0.45 µm, corresponding to 41.9% and 56.9% fouling contribution of this fraction. Furthermore, both total organic carbon (TOC) and fouling potential of fraction with MW > 100 kDa were monitored, presenting about threefold increase from September to January in next year. Membrane fouling contribution of this critical fraction in raw secondary effluent were mainly distributed in 85∼95% throughout the 5 months, demonstrating its predominant fouling propensity. Moreover, the TOC concentration of fraction with MW > 100 kDa presented distinct positive correlation with the fouling potential of raw secondary effluent (R2 = 0.947), which was promising to be a surrogate for predicting membrane fouling in practical application.

Phosphorylation of 4.1N by CaMKII Regulates the Trafficking of GluA1-containing AMPA Receptors During Long-term Potentiation in Acute Rat Hippocampal Brain Slices.

OBJECTIVE: GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) inserted into postsynaptic membranes are key to the process of long-term potentiation (LTP). Some evidence has shown that 4.1N plays a critical role in the membrane trafficking of AMPARs. However, the underlying mechanism behind this is still unclear. We investigated the role of 4.1N-mediated membrane trafficking of AMPARs during theta-burst stimulation long-term potentiation (TBS-LTP), to illustrate the molecular mechanism behind LTP. METHODS: LTP was induced by TBS in rat hippocampal CA1 neuron. Tat-GluA1 (MPR), which disrupts the association of 4.1N-GluA1, and autocamtide-2-inhibitory peptide, myristoylated (Myr-AIP), a CaMKII antagonist, were used to explore the role of 4.1N in the AMPARs trafficking during TBS-induced LTP. Immunoprecipitation (IP) and immunoblotting (IB)were used to detect protein expression, phosphorylation, and the interaction of p-CaMKII-4.1N-GluA1. RESULTS: We found that Myr-AIP attenuated increases of p-CaMKII (T286), p-GluA1 (ser831), and 4.1N phosphorylation after TBS-LTP, and decreased the association of p-CaMKII-4.1N-GluA1, along with the expression of GluA1, at postsynaptic densities during TBS-LTP. We also designed interfering peptides to disrupt the interaction between 4.1N and GluA1, which showed that Tat-GluA1 (MPR) or Myr-AIP inhibited TBS-LTP and attenuated increases of GluA1 at postsynaptic sites, while Tat-GluA1 (MPR) or Myr-AIP had no effects on miniature excitatory postsynaptic currents (mEPSCs) in non-stimulated hippocampal CA1 neurons. CONCLUSION: Active CaMKII enhanced the phosphorylation of 4.1N and facilitated the association of p-CaMKII with 4.1N-GluA1, which in turn resulted in GluA1 trafficking during TBS-LTP. The association of 4.1N-GluA1 is required for LTP, but not for basal synaptic transmission.

Quantitative health risk assessment of microbial hazards from water sources for community and self-supply drinking water systems.

In low and medium income countries (LMIC) drinking water sources (wells and boreholes) often contain a high number of pathogenic microorganisms, that can pose significant human and environmental health risks. In this study, a quantitative microbial risk assessment approach based on existing literature was conducted to evaluate and compare the quantitative health risks associated with different age groups using various drinking water supply systems. Results showed that both community-supply and self-supply modes exhibit similar levels of risk. However, the self-supply water source consistently showed higher risks compared to the community-supply one. Borehole water was found to be a more suitable option than well water, consistently showing between 5 and 8 lower health risks for E. coli and fecal coliform levels, respectively. The sensitivity analysis further showed the importance of prioritizing the reduction of E. coli concentration in well water and fecal coliform concentration in borehole water. This study offers a fresh perception on quantifying the impact of exposure concentration and age groups, shedding light on how they affect environmental health risks. These findings provide valuable insights for stakeholders involved in the management and protection of water sources.

Active sites of atomically dispersed Pt supported on Gd-doped ceria with improved low temperature performance for CO oxidation.

"Single - atom" catalysts (SACs) have been the focus of intense research, due to debates about their reactivity and challenges toward determining and designing "single - atom" (SA) sites. To address the challenge, in this work, we designed Pt SACs supported on Gd-doped ceria (Pt/CGO), which showed improved activity for CO oxidation compared to its counterpart, Pt/ceria. The enhanced activity of Pt/CGO was associated with a new Pt SA site which appeared only in the Pt/CGO catalyst under CO pretreatment at elevated temperatures. Combined X-ray and optical spectroscopies revealed that, at this site, Pt was found to be d-electron rich and bridged with Gd-induced defects via an oxygen vacancy. As explained by density functional theory calculations, this site opened a new path via a dicarbonyl intermediate for CO oxidation with a greatly reduced energy barrier. These results provide guidance for rationally improving the catalytic properties of SA sites for oxidation reactions.

High density lithium niobate photonic integrated circuits.

Photonic integrated circuits have the potential to pervade into multiple applications traditionally limited to bulk optics. Of particular interest for new applications are ferroelectrics such as Lithium Niobate, which exhibit a large Pockels effect, but are difficult to process via dry etching. Here we demonstrate that diamond-like carbon (DLC) is a superior material for the manufacturing of photonic integrated circuits based on ferroelectrics, specifically LiNbO3. Using DLC as a hard mask, we demonstrate the fabrication of deeply etched, tightly confining, low loss waveguides with losses as low as 4 dB/m. In contrast to widely employed ridge waveguides, this approach benefits from a more than one order of magnitude higher area integration density while maintaining efficient electro-optical modulation, low loss, and offering a route for efficient optical fiber interfaces. As a proof of concept, we demonstrate a III-V/LiNbO3 based laser with sub-kHz intrinsic linewidth and tuning rate of 0.7 PHz/s with excellent linearity and CMOS-compatible driving voltage. We also demonstrated a MZM modulator with a 1.73 cm length and a halfwave voltage of 1.94 V.

Metronomic capecitabine inhibits liver transplant rejection in rats by triggering recipients' T cell ferroptosis.

BACKGROUND: Capecitabine (CAP) is a classic antimetabolic drug and has shown potential antirejection effects after liver transplantation (LT) in clinical studies. Our previous study showed that metronomic CAP can cause the programmed death of T cells by inducing oxidative stress in healthy mice. Ferroptosis, a newly defined non-apoptotic cell death that occurs in response to iron overload and lethal levels of lipid peroxidation, is an important mechanism by which CAP induces cell death. Therefore, ferroptosis may also play an important role in CAP-induced T cell death and play an immunosuppressive role in acute rejection after trans-plantation. AIM: To investigate the functions and underlying mechanisms of antirejection effects of metronomic CAP. METHODS: A rat LT model of acute rejection was established, and the effect of metronomic CAP on splenic hematopoietic function and acute graft rejection was evaluated 7 d after LT. In vitro, primary CD3+ T cells were sorted from rat spleens and human peripheral blood, and co-cultured with or without 5-fluorouracil (5-FU) (active agent of CAP). The levels of ferroptosis-related proteins, ferrous ion concentration, and oxidative stress-related indicators were observed. The changes in mito-chondrial structure were observed using electron microscopy. RESULTS: With no significant myelotoxicity, metronomic CAP alleviated graft injury (Banff score 9 vs 7.333, P < 0.001), prolonged the survival time of the recipient rats (11.5 d vs 16 d, P < 0.01), and reduced the infiltration rate of CD3+ T cells in peripheral blood (6.859 vs 3.735, P < 0.001), liver graft (7.459 vs 3.432, P < 0.001), and spleen (26.92 vs 12.9, P < 0.001), thereby inhibiting acute rejection after LT. In vitro, 5-FU, an end product of CAP metabolism, induced the degradation of the ferritin heavy chain by upregulating nuclear receptor coactivator 4, which caused the accumulation of ferrous ions. It also inhibited nuclear erythroid 2 p45-related factor 2, heme oxygenase-1, and glutathione peroxidase 4, eventually leading to oxidative damage and ferroptosis of T cells. CONCLUSION: Metronomic CAP can suppress acute allograft rejection in rats by triggering CD3+ T cell ferroptosis, which makes it an effective immunosuppressive agent after LT.

Efficacy and safety of different PD-1 inhibitors in combination with lenvatinib in the treatment of unresectable primary liver cancer: a multicentre retrospective study.

Immune checkpoint inhibitors (ICIs) are safe and efficacious treatments for advanced primary liver cancer (PLC). The efficacy of different ICIs in the treatment of liver cancer remains unclear. The purpose of this study was to explore whether there is a difference in the efficacy and safety of various programmed cell death protein 1 (PD-1) inhibitors in combination with lenvatinib in the treatment of unresectable PLC. Patients with PLC treated with lenvatinib in combination with PD-1 inhibitors (camrelizumab, tislelizumab, sintilimab, or pembrolizumab) between January 2018 and December 2021 were retrospectively enrolled. Tumor response, adverse events, and grades were evaluated. Kaplan-Meier analysis and log-rank test were used to compare the overall survival and progression-free survival of patients treated with different PD-1 inhibitors. Cox regression analysis was used for univariate and multivariate analyses to identify clinical variables related to treatment efficacy. This study included a total of 176 patients who received a combination of lenvatinib and PD-1 inhibitors. Of these, 103 patients received camrelizumab, 44 received tislelizumab, 20 received sintilimab, and 9 received pembrolizumab. There was no significant difference in the pairwise comparison of camrelizumab, tislelizumab, sintilimab, and pembrolizumab using Kaplan-Meier survival analysis. Adverse events occurred in 40 (22.7%) patients (grade ≥ 3, 2.3%). The incidence of grade 3 adverse events among the four PD-1 inhibitor groups was below 5%. Camrelizumab, tislelizumab, sintilimab, and pembrolizumab are viable options for patients with unresectable PLC. These PD-1 inhibitors in combination with lenvatinib showed good safety profiles. The results guide selecting treatment for patients with unresectable PLC.

A heterogeneously integrated lithium niobate-on-silicon nitride photonic platform.

The availability of thin-film lithium niobate on insulator (LNOI) and advances in processing have led to the emergence of fully integrated LiNbO3 electro-optic devices. Yet to date, LiNbO3 photonic integrated circuits have mostly been fabricated using non-standard etching techniques and partially etched waveguides, that lack the reproducibility achieved in silicon photonics. Widespread application of thin-film LiNbO3 requires a reliable solution with precise lithographic control. Here we demonstrate a heterogeneously integrated LiNbO3 photonic platform employing wafer-scale bonding of thin-film LiNbO3 to silicon nitride (Si3N4) photonic integrated circuits. The platform maintains the low propagation loss (<0.1 dB/cm) and efficient fiber-to-chip coupling (<2.5 dB per facet) of the Si3N4 waveguides and provides a link between passive Si3N4 circuits and electro-optic components with adiabatic mode converters experiencing insertion losses below 0.1 dB. Using this approach we demonstrate several key applications, thus providing a scalable, foundry-ready solution to complex LiNbO3 integrated photonic circuits.

Activation and Conversion of Methane to Syngas over ZrO2/Cu(111) Catalysts near Room Temperature.

Enzymatic systems achieve the catalytic conversion of methane at room temperature under mild conditions. In this study, varying thermodynamic and kinetic parameters, we show that the reforming of methane by water (MWR, CH4 + H2O → CO + 3H2) and the water-gas shift reaction (WGS, CO + H2O → H2 + CO2), two essential processes to integrate fossil fuels toward a H2 energy loop, can be achieved on ZrO2/Cu(111) catalysts near room temperature. Measurements of ambient-pressure X-ray photoelectron spectroscopy and mass spectrometry, combined with density functional calculations and kinetic Monte Carlo simulations, were used to study the behavior of the inverse oxide/metal catalysts. The superior performance is associated with a unique zirconia-copper interface, where multifunctional sites involving zirconium, oxygen, and copper work coordinatively to dissociate methane and water at 300 K and move forward the MWR and WGS processes.

Ultrafast tunable lasers using lithium niobate integrated photonics.

Early works1 and recent advances in thin-film lithium niobate (LiNbO3) on insulator have enabled low-loss photonic integrated circuits2,3, modulators with improved half-wave voltage4,5, electro-optic frequency combs6 and on-chip electro-optic devices, with applications ranging from microwave photonics to microwave-to-optical quantum interfaces7. Although recent advances have demonstrated tunable integrated lasers based on LiNbO3 (refs. 8,9), the full potential of this platform to demonstrate frequency-agile, narrow-linewidth integrated lasers has not been achieved. Here we report such a laser with a fast tuning rate based on a hybrid silicon nitride (Si3N4)-LiNbO3 photonic platform and demonstrate its use for coherent laser ranging. Our platform is based on heterogeneous integration of ultralow-loss Si3N4 photonic integrated circuits with thin-film LiNbO3 through direct bonding at the wafer level, in contrast to previously demonstrated chiplet-level integration10, featuring low propagation loss of 8.5 decibels per metre, enabling narrow-linewidth lasing (intrinsic linewidth of 3 kilohertz) by self-injection locking to a laser diode. The hybrid mode of the resonator allows electro-optic laser frequency tuning at a speed of 12 × 1015 hertz per second with high linearity and low hysteresis while retaining the narrow linewidth. Using a hybrid integrated laser, we perform a proof-of-concept coherent optical ranging (FMCW LiDAR) experiment. Endowing Si3N4 photonic integrated circuits with LiNbO3 creates a platform that combines the individual advantages of thin-film LiNbO3 with those of Si3N4, which show precise lithographic control, mature manufacturing and ultralow loss11,12.

Critical minority fractions causing membrane fouling in reclaimed water: Fouling characteristics, mechanisms and control strategies.

In regard to membrane-based technologies of wastewater reclamation, the reported key foulants were faced with dilemma that they could not be effectively separated and extracted from reclaimed water for thorough investigation. In this study, the crucial foulants were proposed as "critical minority fraction (FCM)", representing the fraction with molecular weight (MW) > 100 kDa which could be easily separated by physical filtration using MW cut-off membrane of 100 kDa with fairly high recovery ratio. FCM with low dissolved organic carbon (DOC) concentration (∼1 mg/L) accounted for less than 20% of the total DOC in reclaimed water, while contributed to more than 90% of the membrane fouling, and thus FCM could be considered as a "perfect criminal" causing membrane fouling. Furthermore, pivotal fouling mechanism was attributed to the significant attractive force between FCM and membranes, which led to severe fouling development due to the aggregation of FCM on membrane surface. Fluorescent chromophores of FCM were concentrated in regions of proteins and soluble microbial products, with proteins and polysaccharides accounted for 45.2% and 25.1% of the total DOC, specifically. FCM was further fractionated into six fractions, among which hydrophobic acids and hydrophobic neutrals were the dominant components in terms of DOC content (∼80%) as well as fouling contribution. Regarding to these pronounced properties of FCM, targeted fouling control strategies including ozonation and coagulation were applied and proved to achieve remarkable fouling control effect. High-performance size-exclusion chromatography results suggested that ozonation achieved distinct transformation of FCM into low MW fractions, while coagulation removed FCM directly, thus leading to effective fouling alleviation. Therefore, the investigation of the critical foulants was expected to help glean valuable insight into the fouling mechanism and develop targeted fouling control technologies in practical applications.

Efficacy of acupuncture for endometriosis-associated pain: a multicenter randomized single-blind placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of acupuncture in the treatment of endometriosis-associated pain. DESIGN: A multicenter, randomized, single-blind, placebo-controlled trial. INSTITUTIONS: Four tertiary hospitals in Jiangxi and Hainan Provinces. SUBJECTS: Women with endometriosis-associated pain aged between 20 and 40 years. INTERVENTION: Subjects were assigned randomly to receive either acupuncture or sham acupuncture treatment for 12 weeks, starting one week before each expected menstruation and administered as a 30-minute session once per day, 3 times a week. During the menstruation period, acupuncture was administered daily when pelvic pain associated with endometriosis occurred. After acupuncture or sham acupuncture treatment, the subjects were followed for another 12 weeks. MAIN OUTCOME MEASURES: Changes in maximum pain as assessed with the visual analog scale (VAS) for various pelvic pain, duration of dysmenorrhea, and scores on the Multidimensional Pain Inventory, Beck Depression Inventory, Profile of Mood States, and Endometriosis Health Profile from baseline to week 12 and week 24. RESULTS: A total of 106 women were assigned randomly to the acupuncture and sham groups. In the acupuncture group, the reduction in the dysmenorrhea VAS score was significantly greater after treatment, but not at the end of the trial, compared to the sham group. The duration of pain was significantly shorter in the acupuncture group. All test scores were improved to a significantly greater extent in the acupuncture group than in the sham group at week 12 but not at week 24. Changes in nonmenstrual pelvic pain and dyspareunia VAS scores were not different between the groups. No severe adverse events or differences in adverse events were recorded. CONCLUSION: Acupuncture is an effective and safe method of relieving dysmenorrhea, shortening the pain duration, and improving wellbeing and quality of life in women with endometriosis-associated pain, although its efficacy fades after treatment is discontinued. CLINICAL TRIAL REGISTRATION NUMBER: NCT03125304.