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Abstract Background Lung cancer brain metastases (LC-BrMs) are frequently associated with dismal mortality rates in patients with lung cancer; however, standard of care therapies for LC-BrMs are still limited in their efficacy. A deep understanding of molecular mechanisms and tumor microenvironment of LC-BrMs will provide us with new insights into developing novel therapeutics for treating patients with LC-BrMs. Methods Here, we performed integrated analyses of genomic, transcriptomic, proteomic, metabolomic, and single-cell RNA sequencing data which were derived from a total number of 154 patients with paired and unpaired primary lung cancer and LC-BrM, spanning four published and two newly generated patient cohorts on both bulk and single cell levels. Results We uncovered that LC-BrMs exhibited a significantly greater intra-tumor heterogeneity. We also observed that mutations in a subset of genes were almost always shared by both primary lung cancers and LC-BrM lesions, including TTN, TP53, MUC16, LRP1B, RYR2, and EGFR. In addition, the genome-wide landscape of somatic copy number alterations was similar between primary lung cancers and LC-BrM lesions. Nevertheless, several regions of focal amplification were significantly enriched in LC-BrMs, including 5p15.33 and 20q13.33. Intriguingly, integrated analyses of transcriptomic, proteomic, and metabolomic data revealed mitochondrial-specific metabolism was activated but tumor immune microenvironment was suppressed in LC-BrMs. Subsequently, we validated our results by conducting real-time quantitative reverse transcription PCR experiments, immunohistochemistry, and multiplexed immunofluorescence staining of patients’ paired tumor specimens. Therapeutically, targeting oxidative phosphorylation with gamitrinib in patient-derived organoids of LC-BrMs induced apoptosis and inhibited cell proliferation. The combination of gamitrinib plus anti-PD-1 immunotherapy significantly improved survival of mice bearing LC-BrMs. Patients with a higher expression of mitochondrial metabolism genes but a lower expression of immune genes in their LC-BrM lesions tended to have a worse survival outcome. Conclusions In conclusion, our findings not only provide comprehensive and integrated perspectives of molecular underpinnings of LC-BrMs but also contribute to the development of a potential, rationale-based combinatorial therapeutic strategy with the goal of translating it into clinical trials for patients with LC-BrMs.

Abstract Magnesium (Mg) metal is a promising anode candidate for high-energy and cost-effective multivalent metal batteries, but suffers from severe surface passivation in conventional electrolytes, especially aqueous solutions. Here, we uncover that MgH2, in addition to the well-known MgO and Mg(OH)2, can be formed during the passivation of Mg by water. The formation mechanism and spatial distribution of MgH2, and its detrimental effect on interfacial dynamics and stability of Mg anode are revealed by comprehensive experimental and theoretical investigations. Furthermore, a graphite-based hydrophobic and Mg2+-permeable water-tolerant interphase is drawn using a pencil on the surface of Mg anodes, allowing them to cycle stably in symmetric (> 900 h) and full cells (> 500 cycles) even after contact with water. The mechanistic understanding of MgH2-involved Mg passivation and the design of pencil-drawn waterproof Mg anodes may inspire the further development of Mg metal batteries with high water resistance.

Rotator cuff repair is a common orthopaedic procedure. Despite advancements in the mechanics of rotator cuff repair, the re-tear rate post repair remains significant. This review assesses the available literature on usage of collagen bio-inductive scaffolds for rotator cuff repairs. Augmentation of biology is a key strategy to improving success of rotator cuff repair. Current evidence suggests that augmentation of rotator cuff repairs with a collagen bio-inductive scaffold improves the thickness of the rotator cuff. There is a favourable safety profile, and its usage may improve re-tear rates. However, there is currently no consensus on whether clinical outcomes are improved by the usage of collagen bio-inductive scaffolds. Further research is necessary to increase our understanding of the clinical effects of using collagen bio-inductive scaffolds and to determine which patient profiles will best benefit from its usage.

Abstract Mahjong, a complex game with hidden information and sparse rewards, poses significant challenges. Existing Mahjong AIs require substantial hardware resources and extensive datasets to enhance AI capabilities. The authors propose a transformer‐based Mahjong AI (Tjong) via hierarchical decision‐making. By utilising self‐attention mechanisms, Tjong effectively captures tile patterns and game dynamics, and it decouples the decision process into two distinct stages: action decision and tile decision. This design reduces decision complexity considerably. Additionally, a fan backward technique is proposed to address the sparse rewards by allocating reversed rewards for actions based on winning hands. Tjong consists of 15M parameters and is trained using approximately 0.5 M data over 7 days of supervised learning on a single server with 2 GPUs. The action decision achieved an accuracy of 94.63%, while the claim decision attained 98.55% and the discard decision reached 81.51%. In a tournament format, Tjong outperformed AIs (CNN, MLP, RNN, ResNet, VIT), achieving scores up to 230% higher than its opponents. Furthermore, after 3 days of reinforcement learning training, it ranked within the top 1% on the leaderboard on the Botzone platform.

Abstract Background The effect of nirmatrelvir/ritonavir on preventing post-COVID condition (PCC) in the BA4, BA5, and XBB Omicron predominant periods is not well understood. The purpose of this study was to assess how nirmatrelvir/ritonavir treatment affected both PCC and health-related quality of life. Methods This retrospective cohort study enrolled 2,524 adults aged 18 years and older who were eligible for nirmatrelvir/ritonavir between July 14 to November 14, 2022. All outcomes were observed from the patient’s first visit to the primary health clinic, 1 week, 1 month, 3 months, and 6 months after testing positive for COVID-19. The primary outcome was the presence of PCC. Secondary outcomes included the effects on health-related quality of life, such as walking, bathing and dressing, activities, cause adverse emotions or signs that prevent individuals from leading normal lives over a 180-day observation period. Results There were no significant differences observed between the nirmatrelvir/ritonavir and those not administered (control group) in terms of PCC symptoms at 3 months (OR 0.71 95% CI 0.31, 1.64) and 6 months (OR 1.30 95% CI 0.76, 2.21). At 3 months, the use of nirmatrelvir/ritonavir was associated with a 26% reduction in symptoms causing negative emotions (OR 0.74 95% CI 0.60, 0.92) and an increased likelihood of symptoms limiting walking (OR 1.58 95% CI 1.10, 2.27). However, there were no significant differences between the nirmatrelvir/ritonavir and the control group in terms of the impact of PCC on health-related quality of life at 6 months. Conclusions Our study indicates that the administration of nirmatrelvir/ritonavir does not significantly reduce PCC after 3 months and 6 months in a population with high vaccination coverage.

Abstract Indoor vertical farming emerges as a sustainable paradigm, enabling crop cultivation in vertically layered ecosystems under precisely controlled environmental parameters. This innovative approach not only bolsters climate resilience but also minimizes the strain on precious arable land and water resources, aligning with sustainable principles. While posited as a transformative solution to global food security challenges and the limitations of traditional agriculture, a pivotal facet within indoor farming necessitates sustainable optimization: the crops cultivated within. Conventional commercial crop varieties utilized in indoor vertical farming lack tailored adaptations to controlled environments, underscoring the imperative to cultivate crops endowed with distinct indoor-farming traits. These include better performance under energy-efficient artificial lighting, high growth rate, and unique flavours. In this review, we highlight recent technological advancements in crop breeding and elaborate these coveted indoor-farming traits. In addition, we illuminate potential genetic workflows essential for breeders to strategically refine crops as a foundation for the long-term sustainability of indoor farming.

Abstract Peptide coacervates self‐assembling via liquid‐liquid phase separation are appealing intracellular delivery vehicles of macromolecular therapeutics (proteins, DNA, mRNA) owing to their non‐cytotoxicity, high encapsulation capacity, and efficient cellular uptake. However, the mechanisms by which these viscoelastic droplets cross the cellular membranes remain unknown. Here, using multimodal imaging, data analytics, and biochemical inhibition assays, we identify the key steps by which droplets enter the cell. We find that the uptake follows a non‐canonical pathway and instead integrates essential features of macropinocytosis and phagocytosis, namely active remodeling of the actin cytoskeleton and appearance of filopodia‐like protrusions. Experiments using giant unilamellar vesicles show that the coacervates attach to the bounding membrane in a charge‐ and cholesterol‐dependent manner but do not breach the lipid bilayer barrier. Cell uptake in the presence of small molecule inhibitors – interfering with actin and tubulin polymerization – confirm the active role of cytoskeleton remodeling, most prominently evident in electron microscopy imaging. These findings suggest a peculiar internalization mechanism for viscoelastic, glassy coacervate droplets combining features of non‐specific uptake of fluids by macropinocytosis and particulate uptake of phagocytosis. The broad implications of this study will enable to enhance the efficacy and utility of coacervate‐based strategies for intracellular delivery of macromolecular therapeutics.

Abstract Background Myopia affects 1.4 billion individuals worldwide. Notably, there is increasing evidence that choroidal thickness plays an important role in myopia and risk of developing myopia-related conditions. With the advancements in artificial intelligence (AI), choroidal thickness segmentation can now be automated, offering inherent advantages such as better repeatability, reduced grader variability, and less reliance for manpower. Hence, we aimed to evaluate the agreement between AI-automated and manual segmented measurements of subfoveal choroidal thickness (SFCT) using two swept-source optical coherence tomography (OCT) systems. Methods Subjects aged ≥ 16 years, with myopia of ≥ 0.50 diopters in both eyes, were recruited from the Prospective Myopia Cohort Study in Singapore (PROMYSE). OCT scans were acquired using Triton DRI-OCT and PLEX Elite 9000. OCT images were segmented both automatically with an established SA-Net architecture and manually using a standard technique with adjudication by two independent graders. SFCT was subsequently determined based on the segmentation. The Bland–Altman plot and intraclass correlation coefficient (ICC) were used to evaluate the agreement. Results A total of 229 subjects (456 eyes) with mean [± standard deviation (SD)] age of 34.1 (10.4) years were included. The overall SFCT (mean ± SD) based on manual segmentation was 216.9 ± 82.7 µm with Triton DRI-OCT and 239.3 ± 84.3 µm with PLEX Elite 9000. ICC values demonstrated excellent agreement between AI-automated and manual segmented SFCT measurements (PLEX Elite 9000: ICC = 0.937, 95% CI: 0.922 to 0.949, P

Abstract Background and objectives Nirmatrelvir/ritonavir was administered orally to manage mild to moderate symptoms of COVID-19 in adult patients. The objectives of this study were to (i) evaluate the cost-effectiveness of prescribing nirmatrelvir/ritonavir within 5 days of a COVID-19 illness in order to avert hospitalization within a 30-day period in the Malaysia setting; (ii) determine how variations in pricing and hospitalization rates will affect the cost-effectiveness of nirmatrelvir/ritonavir. Methods The 30-day hospitalization related to COVID-19 was determined using 1 to 1 propensity score-matched real-world data in Malaysia from 14 July 2022 to 14 November 2022. To determine the total per-person costs related to COVID-19, we added the cost of drug (nirmatrelvir/ritonavir or control), clinic visits and inpatient care. Incremental cost-effectiveness ratio (ICER) per hospitalization averted was calculated. Results Our cohort included 31,487 patients. The rate of hospitalization within 30 days was found to be 0.35% for the group treated with nirmatrelvir/ritonavir, and 0.52% for the control group. The nirmatrelvir/ritonavir group cost an additional MYR 1,625.72 (USD 358.88) per patient. This treatment also resulted in a reduction of 0.17% risk for hospitalization, which corresponded to an ICER of MYR 946,801.26 (USD 209,006.90) per hospitalization averted. Conclusion In Malaysia, where vaccination rates were high, nirmatrelvir/ritonavir has been shown to be beneficial in the outpatient treatment of adults with COVID-19 who have risk factors; however, it was only marginally cost effective against hospitalization for healthy adults during the Omicron period.

Abstract Gastric cancer is a highly prevalent disease that poses a serious threat to public health. In clinical practice, gastroscopy is frequently used by medical practitioners to screen for gastric cancer. However, the symptoms of gastric cancer at different stages of advancement vary significantly, particularly in the case of early gastric cancer (EGC). The manifestations of EGC are often indistinct, leading to a detection rate of less than 10%. In recent years, researchers have focused on leveraging deep learning algorithms to assist medical professionals in detecting EGC and thereby improve detection rates. To enhance the ability of deep learning to detect EGC and segment lesions in gastroscopic images, an Improved Mask R-CNN (IMR-CNN) model was proposed. This model incorporates a “Bi-directional feature extraction and fusion module” and a “Purification module for feature channel and space” based on the Mask R-CNN (MR-CNN). Our study includes a dataset of 1120 images of EGC for training and validation of the models. The experimental results indicate that the IMR-CNN model outperforms the original MR-CNN model, with Precision, Recall, Accuracy, Specificity and F1-Score values of 92.9%, 95.3%, 93.9%, 92.5% and 94.1%, respectively. Therefore, our proposed IMR-CNN model has superior detection and lesion segmentation capabilities and can effectively aid doctors in diagnosing EGC from gastroscopic images.

Abstract Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.

Abstract The electrochemical conversion of nitrate to ammonia is a way to eliminate nitrate pollutant in water. Cu-Co synergistic effect was found to produce excellent performance in ammonia generation. However, few studies have focused on this effect in high-entropy oxides. Here, we report the spin-related Cu-Co synergistic effect on electrochemical nitrate-to-ammonia conversion using high-entropy oxide Mg0.2Co0.2Ni0.2Cu0.2Zn0.2O. In contrast, the Li-incorporated MgCoNiCuZnO exhibits inferior performance. By correlating the electronic structure, we found that the Co spin states are crucial for the Cu-Co synergistic effect for ammonia generation. The Cu-Co pair with a high spin Co in Mg0.2Co0.2Ni0.2Cu0.2Zn0.2O can facilitate ammonia generation, while a low spin Co in Li-incorporated MgCoNiCuZnO decreases the Cu-Co synergistic effect on ammonia generation. These findings offer important insights in employing the synergistic effect and spin states inside for selective catalysis. It also indicates the generality of the magnetic effect in ammonia synthesis between electrocatalysis and thermal catalysis.

Epstein–Barr virus (EBV), a member of the gamma herpesvirus, is the first identified human oncovirus and is associated with various malignancies. Understanding the intricate interactions between EBV antigens and cellular pathways is crucial to unraveling the molecular mechanisms in EBV-mediated diseases. However, fully elucidating EBV–host interactions and the associated pathogenesis remains a significant challenge. In this study, we employed large language models (LLMs) to screen 36,105 EBV-relevant scientific publications and summarize the current literature landscape on various EBV-associated diseases like Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), nasopharyngeal carcinoma (NPC), and so on. LLM-generated data indicate that the most-studied EBV-associated pathways are enriched in immune response, apoptosis, cell growth, and replication. The analyses of protein–protein interactions (PPIs) reveal three principal EBV-related protein clusters: TP53-centered apoptotic factors, EBV-associated transcription factors, and immune response elements. Utilizing our dataset and public databases, we demonstrated that BLLF3-targeted TLR2-associated factors are effective diagnostic markers for DLBCL. Next, we confirmed the co-expression of LMP1-targeted calcium pathway factors in BL. Finally, we demonstrated the correlation and co-expression of LMP1-induced PARP1, HIF1A, HK2, and key glycolysis-related factors, further suggesting that LMP1 actively regulates the glycolysis pathway. Therefore, our study presents a comprehensive functional encyclopedia of the interactions between EBV antigens and host signaling pathways across various EBV-associated diseases, providing valuable insights for the development of therapeutic strategies.

NOD1 and NOD2 as two representative members of nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family play important roles in antimicrobial immunity. However, transcription mechanism of nod1 and nod2 and their signal circle are less understood in teleost fish. In this study, with the cloning of card9 and ripk2 in Chinese perch, the interaction between NOD1, NOD2, and CARD9 and RIPK2 were revealed through coimmunoprecipitation and immunofluorescence assays. The overexpression of NOD1, NOD2, RIPK2 and CARD9 induced significantly the promoter activity of NF-κB, IFNh and IFNc. Furthermore, it was found that nod1 and nod2 were induced by poly(I:C), type I IFNs, RLR and even NOD1/NOD2 themselves through the ISRE site of their proximal promoters. It is thus indicated that nod1 and nod2 can be classified also as ISGs due to the presence of ISRE in their proximal promoter, and their expression can be mechanistically controlled through PRR pathway as well as through IFN signaling in antiviral immune response.

Abstract Objective To present a study to identify the characteristics of coexisting early gastric cancer (EGC) and benign submucosal lesions, with the aim of reducing the adverse consequences of overdiagnosis and overtreatment. Methods In this retrospective study, we searched the endoscopic databases of three tertiary centers. We screened of patients suspected of early gastric cancer submucosal infiltration by conventional endoscopy and ultimately selected for endoscopic submucosal dissection treatment after endoscopic ultrasonography and magnifying endoscopy with narrow-band imaging examination. Patients with coexisting EGC and benign submucosal lesions in histological sections were included. Clinical data and endoscopic images were reviewed. To evaluate the precision of endoscopists’ diagnoses for this type of lesion, eight endoscopists with different experiences were recruited to judge the infiltration depth of these lesions and analyze the accuracy rate. Results We screened 520 patients and retrospectively identified 18 EGC patients with an invasive cancer-like morphology. The most common lesion site was the cardia (12/18, 66.67%). The coexisting submucosal lesions could be divided into solid (5/18, 27.78%) and cystic (13/18, 72.22%). The most common type of submucosal lesion was gastritis cystica profunda (12/18, 66.67%), whereas leiomyoma was the predominant submucosal solid lesion (3/18, 16.67%). Ten (55.56%) patients

Abstract Background African swine fever virus (ASFV) is one of the most fatal swine etiological agents and has a huge economic impact on the global pork industry. Given that no effective vaccines or anti-ASFV drugs are available, there remains a pressing need for novel anti-ASFV drugs. This study aimed to investigate the anti-African swine fever virus (ASFV) activity of brequinar, a DHODH inhibitor. Methods The anti-ASFV activity of brequinar was investigated using IFA, HAD, HAD50, qRT-PCR, and western blotting assays. The western blotting assay was used to investigate whether brequinar inhibits ASFV replication by killing ASFV particles directly or by acting on cell factors. The confocal microscopy and western blotting assays were used to investigate whether brequinar inhibits ASFV replication by activating ferroptosis. Results In this study, brequinar was found to effectively inhibit ASFV replication ex vivo in porcine alveolar macrophages (PAMs) in a dose-dependent manner. In kinetic studies, brequinar was found to maintain ASFV inhibition from 24 to 72 hpi. Mechanistically, the time-of-addition assay showed that brequinar exerted anti-ASFV activity in all treatment modes, including pre-, co-, and post-treatment rather than directly killing ASFV particles. Notably, FerroOrange, Mito-FerroGreen, and Liperfluo staining experiments showed that brequinar increased the accumulation of intracellular iron, mitochondrial iron, and lipid peroxides, respectively. Furthermore, we also found that ferroptosis agonist cisplatin treatment inhibited ASFV replication in a dose-dependent manner and the inhibitory effect of brequinar on ASFV was partially reversed by the ferroptosis inhibitor ferrostatin-1, suggesting that brequinar activates ferroptosis to inhibit ASFV replication. Interestingly, exogenous uridine supplementation attenuated the anti-ASFV activity of brequinar, indicating that brequinar inhibits ASFV replication by inhibiting DHODH activity and the depletion of intracellular pyrimidine pools; however, the induction of ferroptosis by brequinar treatment was not reversed by exogenous uridine supplementation, suggesting that brequinar activation of ferroptosis is not related to the metabolic function of pyrimidines. Conclusions Our data confirm that brequinar displays potent antiviral activity against ASFV in vitro and reveal the mechanism by which brequinar inhibits ASFV replication by activating ferroptosis, independent of inhibiting pyrimidine synthesis, providing novel targets for the development of anti-ASFV drugs.

Objective: To determine if nirmatrelvir-ritonavir 300mg/100mg treatment for 5 days in high-risk outpatients with mild to moderate COVID-19 symptoms was associated with a reduction in hospitalization, intensive care unit (ICU) admission, and death. Methods: This 1:1 propensity score matched cohort study from 647 public health clinics in Malaysia included all patients with COVID-19 with positive tests aged 18 years and older, who were eligible for nirmatrelvir-ritonavir treatment within 5 days of illness from July 14, 2022, to November 14, 2022. The exposed group was patients with COVID-19 initiated with nirmatrelvir-ritonavir treatment, whereas those not initiated with the drug served as the control group. Data was analyzed from July 14, 2022 to December 31, 2022. Results: A total of 20,966 COVID-19 high-risk outpatients (n = 10,483 for nirmatrelvir-ritonavir group and n = 10,483 for control group) were included in the study. Nirmatrelvir-ritonavir treatment was associated with a 36% reduction (adjusted hazard ratio 0.64 [95% CI 0.43, 0.94]) in hospitalization compared with those not given the drug. There was a single ICU admission for the control group and one death each was reported in the nirmatrelvir-ritonavir and control group, respectively. Conclusions: Nirmatrelvir-ritonavir treatment was associated with reduced hospitalization in high-risk patients with COVID-19 even in highly vaccinated populations.

Cable-driven parallel robots (CDPRs) have been gaining much attention due to their many advantages over traditional parallel robots or serial robots, such as their markedly large workspace and lightweight design. However, one of the main issues that needs to be urgently solved is the tension in the distribution of CDPRs due to two reasons. The first is that a cable can only be stretched but not compressed, and the other is the redundancy of the parallel robot. To address the problem, an optimization method for tension distribution is proposed in the paper. The structural design of the parallel robot is first discussed. The dynamics model of the parallel robot is established by the Newton–Euler method. Based on the minimum variance of cables’ tension, an optimization method of tension distribution is presented for the parallel robot. Furthermore, the tension extreme average term is introduced in the optimization method, and the firefly algorithm is applied to obtain the optimal solution for tension distribution. Finally, the proposed approach is tested in the simulation case where the end-effector of the robot moves in a circular motion. Simulation results demonstrate that the uniformity and continuity of tension are both outstanding for the proposed method. In contrast with traditional solving methods, the efficiency of this method is largely improved.

Abstract African swine fever (ASF), caused by ASF virus (ASFV) infection, poses a huge threat to the pork industry owing to ineffective preventive and control measures. Hence, there is an urgent need to develop strategies, including antiviral drugs targeting ASFV, for preventing ASFV spread. This study aimed to identify novel compounds with anti-ASFV activity. To this end, we screened a small chemical library of 102 compounds, among which the natural flavonoid dihydromyricetin (DHM) exhibited the most potent anti-ASFV activity. DHM treatment inhibited ASFV replication in a dose- and time-dependent manner. Furthermore, it inhibited porcine reproductive and respiratory syndrome virus and swine influenza virus replication, which suggested that DHM exerts broad-spectrum antiviral effects. Mechanistically, DHM treatment inhibited ASFV replication in various ways in the time-to-addition assay, including pre-, co-, and post-treatment. Moreover, DHM treatment reduced the levels of ASFV-induced inflammatory mediators by regulating the TLR4/MyD88/MAPK/NF-κB signaling pathway. Meanwhile, DHM treatment reduced the ASFV-induced accumulation of reactive oxygen species, further minimizing pyroptosis by inhibiting the ASFV-induced NLRP3 inflammasome activation. Interestingly, the effects of DHM on ASFV were partly reversed by treatment with polyphyllin VI (a pyroptosis agonist) and RS 09 TFA (a TLR4 agonist), suggesting that DHM inhibits pyroptosis by regulating TLR4 signaling. Furthermore, targeting TLR4 with resatorvid (a specific inhibitor of TLR4) and small interfering RNA against TLR4 impaired ASFV replication. Taken together, these results reveal the anti-ASFV activity of DHM and the underlying mechanism of action, providing a potential compound for developing antiviral drugs targeting ASFV.

Amomum villosum Lour. (A. villosum), known as Sharen in China, is widely used for culinary and medicinal purposes due to containing a diverse set of bioactive compounds. In this study, the optimum ethanol extraction process was optimized and the composition and biological activities (antioxidant and antitumor) of five different fractions (dichloromethane, petroleum ether, ethyl acetate, n-butanol and H2O) extracted from the ethanol extract of A. villosum were investigated. The results showed that the optimal extraction conditions were extraction temperature 80°C, extraction time 120 min, ethanol concentration 40% and solid–liquid ratio 1:25 g/mL. Moreover, 35 bioactive compounds were successfully identified by UPLC-ESI-QTOF-MS/MS from five factions for the first time, including 12 phenolic acids and derivatives, 2 organic acids, 12 flavonoids and derivatives, 2 oxylipins and 7 proanthocyanidins. Among them, ethyl acetate fraction (Fr-EtOAc) exhibited the highest content of total phenolic (374.01 mg GAE/g DW) and flavonoid (93.11 mg RE/g DW), where vanillic acid, catechin, epicatechin and protocatechuic acid were the predominant phenolic compounds that accounting for 81.65% of the quantified bioactive compounds. In addition, Fr-EtOAc demonstrated excellent total antioxidant activity (IC50 of DPPH and ABTS assays were 0.23, 0.08 mg/mL, respectively, and FRAP assay was 322.91 mg VCE/100 g DW) and antitumor activity (1,000 μg/mL, 79.04% inhibition rate). The results could provide guidance for the industrial production and application of A. villosum.

The yield of wheat in wheat–rice rotation cropping systems in the Yangtze River Plain, China, is adversely impacted by waterlogging. A raised bed planting (RBP) pattern may reduce waterlogging and increase the wheat yield after rice cultivation by improving the grain number per spike. However, the physiological basis for grain formation under RBP conditions remains poorly understood. The present study was performed over two growing seasons (2018/2019 and 2019/2020) to examine the effects of the planting pattern (i.e., RBP and flat planting (FP)) on the floret and grain formation features and leaf photosynthetic source characteristics of wheat. The results indicated that implementation of the RBP pattern improved the soil–plant nitrogen (N) supply during floret development, which facilitated balanced floret development, resulting in a 9.5% increase in the number of fertile florets per spike. Moreover, the RBP pattern delayed wheat leaf senescence and increased the photosynthetic source capacity by 13.9%, which produced more assimilates for grain filling. Delayed leaf senescence was attributed to the resultant high leaf N content and enhanced antioxidant metabolism. Correspondingly, under RBP conditions, 7.6–8.6% more grains per spike were recorded, and the grain yield was ultimately enhanced by 10.4–12.7%. These results demonstrate that the improvement of the spike differentiation process and the enhancement of the leaf photosynthetic capacity were the main reasons for the increased grain number per spike of wheat under the RBP pattern, and additional improvements in this technique should be achievable through further investigation.

Abstract In this study, we aim to investigate the therapeutic effect and safety of ALK inhibitor in ALK-positive lung cancer patients. 59 patients with ALK-positive lung cancer from August 2013 to August 2022 were retrospectively recruited. The basic information, pathological type, clinical stage and treatment strategy were collected. These patients were divided into two groups, including 29 patients of conventional adjuvant chemotherapy, and 30 cases of targeted therapy. The patients in the targeted therapy group underwent adjuvant targeted therapy with crizotinib for 2 years. The observation indicators include curative effects and adverse events. The disease-free survival (DFS) and overall survival (OS) were also analyzed. We analyzed the pathological stages after adjuvant chemotherapy and targeted therapy in lung cancer, no significant difference in the p stage N and T was found between the two therapeutic groups. However, the DFS events, DFS median time and OS median time showed significant improvement in the targeted therapy group when compared with adjuvant chemotherapy (all P

In this work, the designed bioactive glass utilized waste is expected to improve mechanical properties while maintaining the bioactivity performance during the in-vitro assessment. Herein, the novel bioactive glasses were prepared using the melt-quenching approach. Phosphate buffer saline was used as an immersion medium during the in-vitro bioactivity and biodegradability evaluation to ascertain the glass's bioactivity characteristics. The XRD results indicated the carbonate apatite phase for sample 0F and the fluorapatite and calcite phase for sample 3F, supported by the FTIR spectra. Further, the pH increased from (7.437 ± 0.004) to (9.699 ± 0.058) for 0F and (9.635 ± 0.014) for 3F, indicating the samples' bioactivity in response to the immersion medium. In addition, 3F exhibited a higher hardness (3.29 ± 0.07 GPa) and toughness (2.4 ± 0.08 MPa m1/2), supported by the weight gained in the biodegradability analysis. This work offers a promising technique to fabricate the bioactive glass incorporating waste, adding fluoride content into the glass for potential dental application.

The COVID-19 pandemic has raised the standard regarding the current vaccine development pace, as several messenger RNA (mRNA)-lipid nanoparticle (LNP) vaccines have proved their ability to induce strong immunogenicity and protective efficacy. We developed 1-methylpseudouridine-containing mRNA-LNP vaccines, expressing either the more conserved SARS-CoV-2 nucleoprotein (mRNA-N) or spike protein (mRNA-S), both based on the prototypic viral sequences. When combining both mRNA-S and mRNA-N together (mRNA-S+N), the vaccine showed high immunogenicity and broad protection against different SARS-CoV-2 variants, including wildtype, Delta, BA.1, BA.5, and BQ.1. To better understand the mechanisms behind this broad protection obtained by mRNA-S+N, we analyzed innate and adaptive immune parameters following vaccination in mice. Compared to either mRNA-S or mRNA-N alone, mice vaccinated with mRNA-S+N exhibited an increase in the innate immune response, as depicted by the higher cytokine (IL-6 and chemokine (MCP-1) levels. In addition, lymph node immunophenotyping showed the maturation and activation of dendritic cells and natural killer cells, respectively. To understand the adaptive immune response, RNA-Seq analyses of the lung and spleen samples of the vaccinated mice were performed in parallel and revealed a stronger immune gene-expression profile in the lung than that in the spleen. Compared to mRNA-S alone, mRNA-S+N vaccination elicited higher levels of expression for genes involved in multiple immune pathways, including T cells, cytokine signaling, antigen presentation, B cells, and innate immunity. Together, our studies provide immunological insights into the mechanisms of broad protection conferred by dual mRNA vaccination against SARS-CoV-2 variants.

Purpose: To examine the 6-year incidence of visual impairment (VI) and identify risk factors associated with VI in a multiethnic Asian population. Design: Prospective, population-based, cohort study. Participants: Adults aged ≥ 40 years were recruited from the Singapore Epidemiology of Eye Diseases cohort study at baseline. Eligible subjects were re-examined after 6 years. Subjects included in the final analysis had a mean age of 56.1 ± 8.9 years, and 2801 (50.5%) were female. Methods: All participants underwent standardized examination and interviewer-administered questionnaire at baseline. Incidences were standardized to the Singapore Population Census 2010. A Poisson binomial regression model was used to evaluate the associations between baseline factors and incident presenting VI. Main Outcome Measures: Incident presenting VI was assessed at the 6-year follow-up visit. Visual impairment (presenting visual acuity < 20/40), low vision (presenting visual acuity < 20/40 but ≥ 20/200), and blindness (presenting visual acuity < 20/200) were defined based on United States definition. Results: A total of 5551 subjects (2188 Chinese, 1837 Indians, and 1526 Malays) were evaluated, of whom 514 developed incident presenting VI over 6 years. Malays had a higher incidence of low vision and blindness (13.0%; 0.6%) than Indians (7.0%; 0.1%) and Chinese (7.7%; 0.2%). Among Malay individuals with VI at baseline, 52.8% remained visually impaired after 6 years, which was considerably higher than Chinese (32.4%) and Indians (37.2%). Older age (per decade; relative risk [RR] = 1.59), a history of cardiovascular disease (RR = 1.38), current smoking (RR = 1.31), smaller housing type (1- to 2-room public flat; RR = 2.01), and no formal education (RR = 1.63) at baseline were associated with a higher risk of incident VI (all P ≤ 0.027). Older age (> 60 years) contributed the highest population attributable risk to incident VI (27.1%), followed by lower monthly income (Singapore dollar < $2000; 26.4%) and smaller housing type (24.7%). Overall, undercorrected refractive error (49.1%) and cataract (82.6%) were leading causes for low vision and blindness, respectively. This was consistently observed across the 3 ethnicities. Conclusions: In this multiethnic Asian population, Malays had a higher VI incidence compared to Indians and Chinese. Leading causes of VI are mostly treatable, suggesting that more efforts are needed to further mitigate preventable visual loss. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.

African swine fever (ASF) is a virulent infectious diseases of pigs caused by the African swine fever virus (ASFV) that can spread widely and cause high fatality rates. Currently, there is no effective way to treat the disease, and there is no effective vaccine to prevent it. Rhein, an anthraquinone compound extracted from many traditional Chinese medicines, exhibits anti-inflammatory, anti-tumor, and anti-viral activities. However, the anti-viral effects of rhein on ASFV remain unclear. Therefore, this study aimed to investigate the anti-ASFV activity of rhein in porcine alveolar macrophages (PAMs) and the underlying mechanisms. In this study, we confirmed that rhein inhibits ASFV replication significantly in a dose-dependent manner in vitro. Moreover, rhein could alter the susceptibility of PAMs to ASFV and promoted the production of superoxide in the mitochondria, which induced the loss of mitochondrial membrane potential, leading to the activation of caspase-9, caspase-3, and apoptosis. Mito-TEMPO, a mitochondria-targeted antioxidant, blocked rhein-induced mitochondrial superoxide generation and loss of mitochondrial membrane potential, prevented caspase-9 and caspase-3 activation, alleviated apoptosis, and suppressed the anti-ASFV activity of rhein. Altogether, our results suggested that rhein could play an anti-ASFV role by inducing apoptosis through the activation of the caspase-dependent mitochondrial apoptotic pathway and may provide a novel compound for developing anti-ASFV drugs.

Eu3+ incorporated zinc-borosilicate glass was synthesized using melt-quenching method. XRD and FTIR verified the amorphous nature of the samples. The absorption spectra indicate the Eu3+ ions in the UV-visible region at ∼394 nm. The direct and indirect band gap decrease from 5.152 eV to 5.082 eV and 4.133 eV to 3.837 eV, respectively. Meanwhile, the refractive index decrease from 2.145 to 2.202, while the Urbach energy ranges from 0.682 eV to 0.733 eV. All the samples have a good transmission percentage at 70–75%. Under the excitation of 400 nm, the intensity of the PL spectra increased when the Eu3+ dopant increased. The optimum content for Eu3+ incorporated ZnO–B2O3–GB glass is 3 wt.% among the other Eu3+ content (0, 1, and 2 wt.%) in this work. The reddish-orange emission at 612 nm (5D0 → 7F2) indicates the most intense emission and the CIE chromaticity coordinates imply in the reddish-orange region.

AbstractBackground Helicobacter pylori (H. pylori) is recognized as a type I carcinogen in gastric cancer (GC). However, GC still occurs after H. pylori eradication, and its diagnosis is more complicated. This study aimed to summarize the characteristics of early GC (EGC) after H. pylori eradication to help accurately identify EGC and avoid missed diagnosis and misdiagnosis.Methods A total of 81 patients of EGC after H. pylori eradication (Hp-eradicated group), resected by endoscopic submucosal dissection (ESD), and 105 cases of H. pylori infection-related EGC (control group) were assessed. After propensity-score matching, the clinical characteristics, endoscopic manifestations, and histopathological features of the 62 matched patients in each group were analyzed. We also conducted specific analyses in combination with endoscopic and histopathological images.Results There were more patients in the Hp-eradicated group who received proton pump inhibitor (PPI) for >1 year compared to the control group (p 1 year (p = 0.005), mucosal map-like redness (p

Summary: In light of growing interest in using emerging large language models (LLMs) for self-diagnosis, we systematically assessed the performance of ChatGPT-3.5, ChatGPT-4.0, and Google Bard in delivering proficient responses to 37 common inquiries regarding ocular symptoms. Responses were masked, randomly shuffled, and then graded by three consultant-level ophthalmologists for accuracy (poor, borderline, good) and comprehensiveness. Additionally, we evaluated the self-awareness capabilities (ability to self-check and self-correct) of the LLM-Chatbots. 89.2% of ChatGPT-4.0 responses were ‘good’-rated, outperforming ChatGPT-3.5 (59.5%) and Google Bard (40.5%) significantly (all p

IntroductionOur study aimed to examine the relationship between cardiovascular diseases (CVD) with peripapillary retinal fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thickness profiles in a large multi-ethnic Asian population study.Methods6,024 Asian subjects were analyzed in this study. All participants underwent standardized examinations, including spectral domain OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec). In total, 9,188 eyes were included for peripapillary RNFL analysis (2,417 Malays; 3,240 Indians; 3,531 Chinese), and 9,270 eyes (2,449 Malays, 3,271 Indians, 3,550 Chinese) for GCIPL analysis. History of CVD was defined as a self-reported clinical history of stroke, myocardial infarction, or angina. Multivariable linear regression models with generalized estimating equations were performed, adjusting for age, gender, ethnicity, diabetes, hypertension, hyperlipidaemia, chronic kidney disease, body mass index, current smoking status, and intraocular pressure.ResultsWe observed a significant association between CVD history and thinner average RNFL (β = −1.63; 95% CI, −2.70 to −0.56; p = 0.003). This association was consistent for superior (β = −1.79, 95% CI, −3.48 to −0.10; p = 0.038) and inferior RNFL quadrant (β = −2.14, 95% CI, −3.96 to −0.32; p = 0.021). Of the CVD types, myocardial infarction particularly showed significant association with average (β = −1.75, 95% CI, −3.08 to −0.42; p = 0.010), superior (β = −2.22, 95% CI, −4.36 to −0.09; p = 0.041) and inferior (β = −2.42, 95% CI, −4.64 to −0.20; p = 0.033) RNFL thinning. Among ethnic groups, the association between CVD and average RNFL was particularly prominent in Indian eyes (β = −1.92, 95% CI, −3.52 to −0.33; p = 0.018). CVD was not significantly associated with average GCIPL thickness, albeit a consistent negative direction of association was observed (β = −0.22, 95% CI, −1.15 to 0.71; p = 0.641).DiscussionIn this large multi-ethnic Asian population study, we observed significant association between CVD history and RNFL thinning. This finding further validates the impact of impaired systemic circulation on RNFL thickness.

Abstract Background Reactivation of Epstein Barr virus (EBV) leads to modulation of the viral and cellular epitranscriptome. N6-methyladenosine (m6A) modification is a type of RNA modification that regulates metabolism of mRNAs. Previous reports demonstrated that m6A modification affects the stability and metabolism of EBV encoded mRNAs. However, the effect of reactivation on reprograming of the cellular mRNAs, and how this contributes to successful induction of lytic reactivation is not known. Methods Methylated RNA immunoprecipitation sequencing (MeRIP-seq), transcriptomic RNA sequencing (RNA-seq) and RNA pull-down PCR were used to screen and validate differentially methylated targets. Western blotting, quantitative real-time PCR (RT-qPCR) and immunocytochemistry were used to investigate the expression and localization of different proteins. RNA stability and polysome analysis assays were used to detect the half-lives and translation efficiencies of downstream genes. Insertion of point mutation to disrupt the m6A methylation sites was used to verify the effect of m6A methylation on its stability and expression levels. Results We report that during EBV reactivation the m6A eraser ALKBH5 is significantly downregulated leading to enhanced methylation of the cellular transcripts DTX4 and TYK2, that results in degradation of TYK2 mRNAs and higher efficiency of translation of DTX4 mRNAs. This resulted in attenuation of IFN signaling that promoted progression of viral lytic replication. Furthermore, inhibition of m6A methylation of these transcripts led to increased production of IFN, and a substantial reduction in viral copy number, which suggests abrogation of lytic viral replication. Conclusion Our findings illuminate the significance of m6A modification in overcoming the innate immune response during EBV reactivation. We now report that during lytic reactivation EBV targets the RNA methylation system of the host to attenuate the innate immune response by suppressing the interferon signaling which facilitates successful lytic replication of the virus.

Abstract Refuse storage and collection systems are potential sources of food and harbourage areas for rodents which transmit pathogens. We examined the factors associated with rodent activity in public housing municipal waste collection premises in a highly urbanized city-state. We analysed data from April 2019 to March 2020 in mixed-effects logistic regression models to examine the independent factors associated with rodent activity in central refuse chute rooms (CRCs), individual refuse chute (IRC) bin chambers and bin centres. We accounted for within-year patterns, repeated measures and nested effects. We observed a heterogeneous spatial distribution of rodent activity. Rodent droppings were strongly associated with rodent activity in CRCs (aOR: 6.20, 95% CI: 4.20–9.15), bin centres (aOR: 3.61, 95% CI: 1.70–7.64) and IRC bin chambers (aOR: 90.84, 95% CI: 70.13–117.67). Gnaw marks were positively associated with rodent activity in CRCs (aOR: 5.61, 95% CI: 3.55–8.97) and IRC bin chambers (aOR: 2.05, 95% CI: 1.43–2.95), as were rub marks in CRCs (aOR: 5.04, 95% CI: 3.44–7.37) and IRC bin chambers (aOR: 3.07, 95% CI: 1.74–5.42). Each burrow increased the odds of rodent sightings in bin centres (aOR: 1.03, 95% CI: 1.00–1.06). The odds of rodent sightings in an IRC bin chamber increased with every additional bin chute chamber within the same block (aOR: 1.04, 95% CI: 1.01–1.07). We identified several factors that well predicted rodent activity in waste collection premises. Municipal estate managers with limited resources can adopt a risk-based approach in tailoring the focus of their rodent control interventions.

Highlights A unique electrolyte combination for rechargeable aluminum battery was fabricated using aluminum trifluoromethanesulfonate as the main salt and tetrabutylammonium chloride as an additive. The presence of additive activates the Al-anode surface toward plating/stripping and aids in the formation of a protective solid electrolyte interphase layer on the anode, resulting in a substantially suppressed anodic overpotential for 1300 cycles. The cheap, high flash point and non-corrosive nature of the electrolyte makes it commercially promising.

Single-cell multimodal sequencing technologies are developed to simultaneously profile different modalities of data in the same cell. Here the authors develops a multimodal deep clustering method for the analysis of single-cell multi-omics data that supports clustering different types of multi-omics data and multi-batch data, as well as downstream differential expression analysis.

Summary: Background: Large language models (LLMs) are garnering wide interest due to their human-like and contextually relevant responses. However, LLMs’ accuracy across specific medical domains has yet been thoroughly evaluated. Myopia is a frequent topic which patients and parents commonly seek information online. Our study evaluated the performance of three LLMs namely ChatGPT-3.5, ChatGPT-4.0, and Google Bard, in delivering accurate responses to common myopia-related queries. Methods: We curated thirty-one commonly asked myopia care-related questions, which were categorised into six domains—pathogenesis, risk factors, clinical presentation, diagnosis, treatment and prevention, and prognosis. Each question was posed to the LLMs, and their responses were independently graded by three consultant-level paediatric ophthalmologists on a three-point accuracy scale (poor, borderline, good). A majority consensus approach was used to determine the final rating for each response. ‘Good’ rated responses were further evaluated for comprehensiveness on a five-point scale. Conversely, ‘poor’ rated responses were further prompted for self-correction and then re-evaluated for accuracy. Findings: ChatGPT-4.0 demonstrated superior accuracy, with 80.6% of responses rated as ‘good’, compared to 61.3% in ChatGPT-3.5 and 54.8% in Google Bard (Pearson's chi-squared test, all p ≤ 0.009). All three LLM-Chatbots showed high mean comprehensiveness scores (Google Bard: 4.35; ChatGPT-4.0: 4.23; ChatGPT-3.5: 4.11, out of a maximum score of 5). All LLM-Chatbots also demonstrated substantial self-correction capabilities: 66.7% (2 in 3) of ChatGPT-4.0's, 40% (2 in 5) of ChatGPT-3.5's, and 60% (3 in 5) of Google Bard's responses improved after self-correction. The LLM-Chatbots performed consistently across domains, except for ‘treatment and prevention’. However, ChatGPT-4.0 still performed superiorly in this domain, receiving 70% ‘good’ ratings, compared to 40% in ChatGPT-3.5 and 45% in Google Bard (Pearson's chi-squared test, all p ≤ 0.001). Interpretation: Our findings underscore the potential of LLMs, particularly ChatGPT-4.0, for delivering accurate and comprehensive responses to myopia-related queries. Continuous strategies and evaluations to improve LLMs’ accuracy remain crucial. Funding: Dr Yih-Chung Tham was supported by the National Medical Research Council of Singapore (NMRC/MOH/HCSAINV21nov-0001).

African swine fever virus (ASFV) is the etiological agent of African swine fever (ASF), which is one of the most harmful swine diseases in the pig industry because of its nearly 100% mortality rate in domestic pigs and results in incalculable economic loss. Ever since ASF was initially reported, scientists have worked to develop anti-ASF vaccines; however, currently no clinically effective vaccine for ASF is available. Therefore, the development of novel measures to prevent ASFV infection and transmission is essential. In this study, we aimed to investigate the anti-ASF activity of theaflavin (TF), a natural compound mainly isolated from black tea. We found that TF potently inhibited ASFV replication at non-cytotoxic concentrations ex vivo in primary porcine alveolar macrophages (PAMs). Mechanistically, we found that TF inhibited ASFV replication by acting on cells rather than interacting directly with ASFV to inhibit viral replication. Further, we found that TF upregulated the AMPK (5′-AMP-activated protein kinase) signaling pathway in ASFV-infected and uninfected cells, and treatment with the AMPK agonist MK8722 upregulated the AMPK signaling pathway and inhibited ASFV proliferation in a dose-dependent manner. Notably, the effects of TF on AMPK activation and ASFV inhibition were partially reversed by the AMPK inhibitor dorsomorphin. In addition, we found that TF down-regulated the expression of genes related to lipid synthesis and decreased the intracellular accumulation of total cholesterol and total triglycerides in ASFV-infected cells, suggesting that TF may inhibit ASFV replication by disrupting lipid metabolism. In summary, our results demonstrated that TF is an ASFV infection inhibitor and revealed the mechanism by which ASFV replication is inhibited, providing a novel mechanism and potential lead compound for the development of anti-ASFV drugs.

In recent years, higher requirements have been placed on the response characteristics of X-ray detectors in the field of medical diagnostic imaging. Due to this, high sensitivity, high attenuation coefficient and low cost detection materials need to be developed. In this paper, the geometric model of a detector was established by Geant4 code. The absorption efficiency and mass attenuation coefficient of MAPbBr3 crystals were calculated in the energy range of 30 keV to 100 keV. Compared with the mass attenuation coefficient of the NIST database, the deviation was within 1.39%. The signal charge number and detection sensitivity of the X-ray interaction with the MAPbBr3 crystal ware calculated. Compared with the CdTe crystal and α-Se, the MAPbBr3 crystal still had a larger detection sensitivity under a smaller applied electric field, which was approximately 9 times higher than that of α-Se. This result indicated that the detection sensitivity could be greatly improved by using a high atomic number and high charge mobility-lifetime product. Based on the simulation results, the 2 mm thick MAPbBr3 crystal exhibited the highest detection sensitivity at 60 keV X-rays, which was in agreement with the experimental results.

Summary: Nitrogen oxides (NOx) emissions carry pernicious consequences on air quality and human health, prompting an upsurge of interest in eliminating them from the atmosphere. The electrochemical NOx reduction reaction (NOxRR) is among the promising techniques for NOx removal and potential conversion into valuable chemical feedstock with high conversion efficiency while benefiting energy conservation. However, developing efficient and stable electrocatalysts for NOxRR remains an arduous challenge. This review provides a comprehensive survey of recent advancements in NOxRR, encompassing the underlying fundamentals of the reaction mechanism and rationale behind the design of electrocatalysts using computational modeling and experimental efforts. The potential utilization of NOxRR in a Zn-NOx battery is also explored as a proof of concept for concurrent NOx abatement, NH3 synthesis, and decarbonizing energy generation. Despite significant strides in this domain, several hurdles still need to be resolved in developing efficient and long-lasting electrocatalysts for NOx reduction. These possible means are necessary to augment the catalytic activity and electrocatalyst selectivity and surmount the challenges of catalyst deactivation and corrosion. Furthermore, sustained research and development of NOxRR could offer a promising solution to the urgent issue of NOx pollution, culminating in a cleaner and healthier environment.

The mechanism of urea's action in protein denaturation remains largely unknown. To provide an experimental basis for molecular dynamics (MD) simulations on urea-protein interactions, we investigated the effect of urea on human intestinal fatty acid binding protein (hIFABP) by nuclear magnetic resonance (NMR). Hydrogen-deuterium exchange (HDX) rates at ≤ 2 M urea indicate that urea affects hIFABP in a residue-specific manner via direct urea-protein interactions and preferentially weakens hydrogen bonds between highly protected amides. Residue-specific effects of urea on NMR peak intensities and chemical shifts further support the presence of direct urea-protein interactions. Two-dimensional (2D) water-rotating frame Overhauser enhancement (ROE) data shows one protein-bound water molecule in contact with Val66 and Trp82, one putative bound water molecule in interaction with Thr76 and E-F loop, and that urea at low concentrations cannot displace these protein-bound water molecules. Our urea-nuclear Overhauser effect (NOE) experiments using 15N-urea further show no tightly protein-bound urea molecules. Our results thus suggest specific, but weak or transient, urea-protein interactions, supporting the direct interaction model of urea denaturation.

Abstract Bone age assessment (BAA) evaluates individual skeletal maturity by comparing the characteristics of skeletal development to the standard in a specific population. The X-ray image examination for bone age is tedious and subjective, and it requires high professional skills. Therefore, AI techniques are desired to innovate and improve BAA methods. Most of the BAA method use the whole X-ray image in an end-to-end model directly. Such whole-image-based approaches fail to characterize local changes and provide limited aid for diagnosis and understanding disease progress. To address these issues, we collected and curated a dataset of 2129 cases for the study of BAA with fine-grained skeletal maturity level labels of the 13 ROIs in hand bone based on the expert knowledge from TW method. We designed a four-stage automatic BAA model based on recursive feature pyramid network. Firstly, the palm region was segmented using U-Net, followed by the extraction of multi-target ROIs of hand bone using a recursive feature pyramid network. Given the extracted ROIs, we employed a transfer learning model with attention mechanism to predict the skeletal maturity level of each ROI. Finally, the bone age is assessed based on the percentile curve of bone maturity. The proposed BAA model can automate the BAA. In addition, it provides the detection result of the 13 ROIs and their ROI-level skeletal maturity. The MAE can reach 0.61 years on the dataset with the labeling precision of one year. All the data and annotations used in this paper are released publicly.

Non-syndromic tooth agenesis (NSTA) is one of the most common dental developmental malformations affected by genetic factors predominantly. Among all 36 candidate genes reported in NSTA individuals, EDA, EDAR, and EDARADD play essential roles in ectodermal organ development. As members of the EDA/EDAR/NF-κB signaling pathway, mutations in these genes have been implicated in the pathogenesis of NSTA, as well as hypohidrotic ectodermal dysplasia (HED), a rare genetic disorder that affects multiple ectodermal structures, including teeth. This review provides an overview of the current knowledge on the genetic basis of NSTA, with a focus on the pathogenic effects of the EDA/EDAR/NF-κB signaling pathway and the role of EDA, EDAR, and EDARADD mutations in developmental tooth defects. We also discuss the phenotypic overlap and genetic differences between NSTA and HED. Ultimately, this review highlights the importance of genetic analysis in diagnosing and managing NSTA and related ectodermal disorders, and the need for ongoing research to improve our understanding of these conditions.

Abstract Background Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are common age-related neurodegenerative diseases comprising Lewy body spectrum disorders associated with cortical and subcortical Lewy body pathology. Over 30% of PD patients develop PD dementia (PDD), which describes dementia arising in the context of established idiopathic PD. Furthermore, Lewy bodies frequently accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer’s disease (AD), where they are observed in the amygdala of approximately 60% of sporadic and familial AD. While PDD and DLB share similar pathological substrates, they differ in the temporal onset of motor and cognitive symptoms; however, protein markers to distinguish them are still lacking. Methods Here, we systematically studied a series of AD and PD pathogenesis markers, as well as mitochondria, mitophagy, and neuroinflammation-related indicators, in the substantia nigra (SN), temporal cortex (TC), and caudate and putamen (CP) regions of human post-mortem brain samples from individuals with PDD and DLB and condition-matched controls. Results We found that p-APPT668 (TC), α-synuclein (CP), and LC3II (CP) are all increased while the tyrosine hydroxylase (TH) (CP) is decreased in both PDD and DLB compared to control. Also, the levels of Aβ42 and DD2R, IBA1, and p-LRRK2S935 are all elevated in PDD compared to control. Interestingly, protein levels of p-TauS199/202 in CP and DD2R, DRP1, and VPS35 in TC are all increased in PDD compared to DLB. Conclusions Together, our comprehensive and systematic study identified a set of signature proteins that will help to understand the pathology and etiology of PDD and DLB at the molecular level.

Abstract A Li/KNO3 composite (LKNO), with KNO3 uniformly implanted in bulk metallic Li, is fabricated for battery anode via a facile mechanical kneading approach, which exhibits high Coulombic efficiency and prolonged cycle life. The mechanism behind the enhanced electrochemical performance of the “salt‐in‐metal” composite is investigated, where KNO3 in metallic Li composite electrode would be sustainably released into the electrolyte. The presence of NO3– stabilizes the solid electrolyte interphase by producing functional Li3N, LiNxOy, and Li2O species. K+ from KNO3 also helps to form an electrostatic shield after its adsorption on the electrode protrusions, which suppresses the dendritic growth of metallic Li. With the above advantages, uniform Li plating with dense and planar structure is realized for the LKNO electrode. These findings reveal a deep understanding of the effect of the “salt‐in‐metal” anode and provide new insights into the use of nitrate additives for high‐energy‐density Li metal batteries.

IntroductionType 1 diabetes, a disorder caused by autoimmune destruction of pancreatic insulin-producing cells, is more difficult to manage when it presents at a younger age. We sought to identify genetic correlates of the age of onset by conducting the first genome-wide association study (GWAS) treating the age of first diagnosis as a quantitative trait.MethodsWe performed GWAS with a discovery cohort of 4,014 cases and a replication cohort of 493 independent cases. Genome-wide significant SNPs were mapped to a causal variant by Bayesian conditional analysis and gel shift assay. The causal protein-coding gene was identified and characterized by RNA interference treatment of primary human pan-CD4+ T cells with RNA-seq of the transcriptome. The candidate gene was evaluated functionally in primary cells by CD69 staining and proliferation assays.ResultsOur GWAS replicated the known association of the age of diagnosis with the human leukocyte antigen complex (HLA-DQB1). The second signal identified was in an intron of the NELL1 gene on chromosome 11 and fine-mapped to variant rs10833518 (P < 1.54 × 10−9). Homozygosity for the risk allele leads to average age of onset one year earlier. Knock-down of HIV TAT-interacting protein 2 (HTATIP2), but not other genes in the locus, resulted in alterations to gene expression in signal transduction pathways including MAP kinases and PI3-kinase. Higher levels of HTATIP2 expression are associated with increased viability, proliferation, and activation of T cells in the presence of signals from antigen and cytokine receptors.DiscussionThis study implicates HTATIP2 as a new type 1 diabetes gene acting via T cell regulation. Larger population sample sizes are expected to reveal additional loci.

Gene signatures that predict response to immune checkpoint blockade (ICB) therapies in melanoma have been based on preclinical models and pre-treatment samples. Here the authors develop pathway-based signatures to predict ICB response in melanoma using on-treatment samples, leading to improved performance.

The data in this article are associated with the research paper “GigaAssay – an adaptable high-throughput saturation mutagenesis assay” [1]. The raw data are sequence reads of HIV-1 Tat cDNA amplified from cellular genomic DNA in a new single-pot saturation mutagenesis assay designated the “GigaAssay”. A bioinformatic pipeline and parameters used to analyze the data. Raw, processed, analyzed, and filtered data are reported. The data is processed to calculate the Tat-driven transcription activity for cells with each possible single amino acid substitution in Tat. This data can be reused to interpret Tat intermolecular interactions and HIV latency. This is one of the largest and most complete datasets regarding the impact of amino acid substitutions within a single protein on a molecular function.

Hydrogels composed from biomolecules have gained great interests as biomaterials for tissue engineering. However, their poor mechanical properties limit their application potential. Here, we synthesized a series of tough composite hydrogels from poly (vinyl alcohol) (PVA) and pectin for bone tissue engineering. With a balance of scaffold stiffness and pore size, PVA-Pec-10 hydrogel enhanced adhesion and proliferation of osteoblasts. The hydrogel significantly promoted osteogenesis in vitro by improving the alkaline phosphates (ALP) activity and calcium biomineralization, as well as upregulating the expressions of osteoblastic genes. The composite hydrogel also accelerated the bone healing process in vivo after transplantation into the femoral defect. Additionally, our study demonstrated that pectin and its Ca2+ crosslinking network play a crucial role of inducing osteogenesis through regulating the Ca2+/CaMKII and BMP-SMAD1/5 signaling. The optimized structure composition and multifunctional properties make PVA-Pec hydrogel highly promising to serve as a candidate for bone tissue regeneration.

PurposeThis study aims to compare the outcomes of extravesical (EVUR) and intravesical (IVUR) ureteric reimplantation for primary vesicoureteral reflux (VUR) via systematic review and meta-analysis.MethodsLiterature review from Medline, Embase, and Cochrane since inception to March 2022 was performed. Meta-analysis was conducted on eligible randomized controlled trials (RCT) and observational cohort studies (OCS) comparing outcomes between EVUR and IVUR.ResultsTwelve studies were included, comprising 577 patients (778 ureters) operated by EVUR and 395 patients (635 ureters) by IVUR. Pre-operative VUR grade, postoperative VUR persistence and hydronephrosis was not statistically significant. EVUR had shorter operative time [mean differences (MD) −22.91 min; 95% confidence interval (CI), −44.53 to −1.30, P = 0.04] and hospital stay (MD −2.09 days; 95% CI, −2.82 to −1.36, P < 0.00001) compared to IVUR. Bilateral EVUR had higher risk of postoperative acute urinary retention (ARU) (8.1%) compared to bilateral IVUR (1.7%) (OR = 4.40; 95% CI, 1.33–14.58, P = 0.02). No patient undergoing unilateral EVUR or IVUR experienced ARU.ConclusionBoth EVUR and IVUR are equally effective in correcting primary VUR. Operative time and hospital stay are shorter after EVUR compared to IVUR. However, bilateral EVUR is associated with higher risk of postoperative ARU.

Abstract Alterations to the natural microbiome are linked to different diseases, and the presence or absence of specific microbes is directly related to disease outcomes. We performed a comprehensive analysis with unique cohorts of the four subtypes of breast cancer (BC) characterized by their microbial signatures, using a pan-pathogen microarray strategy. The signature (includes viruses, bacteria, fungi, and parasites) of each tumor subtype was correlated with clinical data to identify microbes with prognostic potential. The subtypes of BC had specific viromes and microbiomes, with ER+ and TN tumors showing the most and least diverse microbiome, respectively. The specific microbial signatures allowed discrimination between different BC subtypes. Furthermore, we demonstrated correlations between the presence and absence of specific microbes in BC subtypes with the clinical outcomes. This study provides a comprehensive map of the oncobiome of BC subtypes, with insights into disease prognosis that can be critical for precision therapeutic intervention strategies.