Synthesis and evaluation of pentacyclic triterpenoids conjugates as novel HBV entry inhibitors targeting NTCP receptor.

Chronic liver diseases caused by hepatitis B virus (HBV) are the accepted main cause leading to liver cirrhosis, hepatic fibrosis, and hepatic carcinoma. Sodium taurocholate cotransporting polypeptide (NTCP), a specific membrane receptor of hepatocytes for triggering HBV infection, is a promising target against HBV entry. In this study, pentacyclic triterpenoids (PTs) including glycyrrhetinic acid (GA), oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) were modified via molecular hybridization with podophyllotoxin respectively, and resulted in thirty-two novel conjugates. The anti-HBV activities of conjugates were evaluated in HepG2.2.15 cells. The results showed that 66% of the conjugates exhibited lower toxicity to the host cells and had significant inhibitory effects on the two HBV antigens, especially HBsAg. Notably, the compounds BA-PPT1, BA-PPT3, BA-PPT4, and UA-PPT3 not only inhibited the secretion of HBsAg but also suppressed HBV DNA replication. A significant difference in the binding of active conjugates to NTCP compared to the HBV PreS1 antigen was observed by SPR assays. The mechanism of action was found to be the competitive binding of these compounds to the NTCP 157-165 epitopes, blocking HBV entry into host cells. Molecular docking results indicated that BA-PPT3 interacted with the amino acid residues of the target protein mainly through π-cation, hydrogen bond and hydrophobic interaction, suggesting its potential as a promising HBV entry inhibitor targeting the NTCP receptor.

Diet and lifestyle behaviours simultaneously act on frailty: it is time to move the threshold of frailty prevention and control forward.

BACKGROUND: To analyse the association among the simultaneous effects of dietary intake, daily life behavioural factors, and frailty outcomes in older Chinese women, we predicted the probability of maintaining physical robustness under a combination of different variables. METHODS: The Fried frailty criterion was used to determine the three groups of "frailty", "pre-frailty", and "robust", and a national epidemiological survey was performed. The three-classification decision tree model was fitted, and the comprehensive performance of the model was evaluated to predict the probability of occurrence of different outcomes. RESULTS: Among the 1,044 participants, 15.9% were frailty and 50.29% were pre-frailty; the overall prevalence first increased and then decreased with age, reaching a peak at 70-74 years of age. Through univariate analysis, filtering, and embedded screening, eight significant variables were identified: staple food, spices, exercise (frequency, intensity, and time), work frequency, self-feeling, and family emotions. In the three-classification decision tree, the values of each evaluation index of Model 3 were relatively average; the accuracy, recall, specificity, precision, and F1 score range were between 75% and 84%, and the AUC was also greater than 0.800, indicating excellent performance and the best interpretability of the results. Model 3 takes exercise time as the root node and contains 6 variables and 10 types, suggesting the impact of the comprehensive effect of these variables on robust and non-robust populations (the predicted probability range is 6.67-93.33%). CONCLUSION: The combined effect of these factors (no exercise or less than 0.5 h of exercise per day, occasional exercise, exercise at low intensity, feeling more tired at work, and eating too many staple foods (> 450 g per day) are more detrimental to maintaining robustness.

[Ligusticum cycloprolactam inhibits IL-1ß-induced apoptosis and inflammation of rat chondrocytes via HMGB1/TLR4/NF-κB signaling pathway].

Chondrocytes are unique resident cells in the articular cartilage, and the pathological changes of them can lead to the occurrence of osteoarthritis(OA). Ligusticum cycloprolactam(LIGc) are derivatives of Z-ligustilide(LIG), a pharmacodynamic marker of Angelica sinensis, which has various biological functions such as anti-inflammation and inhibition of cell apoptosis. However, its protective effect on chondrocytes in the case of OA and the underlying mechanism remain unclear. This study conducted in vitro experiments to explore the molecular mechanism of LIGc in protecting chondrocytes from OA. The inflammation model of rat OA chondrocyte model was established by using interleukin-1ß(IL-1ß) to induce. LIGc alone and combined with glycyrrhizic acid(GA), a blocker of the high mobility group box-1 protein(HMGB1)/Toll-like receptor 4(TLR4)/nuclear factor-kappa B(NF-κB) signaling pathway, were used to intervene in the model, and the therapeutic effects were systematically evaluated. The viability of chondrocytes treated with different concentrations of LIGc was measured by the cell counting kit-8(CCK-8), and the optimal LIGc concentration was screened out. Annexin V-FITC/PI apoptosis detection kit was employed to examine the apoptosis of chondrocytes in each group. The enzyme-linked immunosorbent assay(ELISA) was employed to measure the expression of cyclooxygenase-2(COX-2), prostaglandin-2(PGE2), and tumor necrosis factor-alpha(TNF-α) in the supernatant of chondrocytes in each group. Western blot was employed to determine the protein levels of B-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax), caspase-3, HMGB1, TLR4, and NF-κB p65. The mRNA levels of HMGB1, TLR4, NF-κB p65, and myeloid differentiation factor 88(MyD88) in chondrocytes were determined by real-time fluorescent quantitative PCR(RT-qPCR). The safe concentration range of LIGc on chondrocytes was determined by CCK-8, and then the optimal concentration of LIGc for exerting the effect was clarified. Under the intervention of IL-1ß, the rat chondrocyte model of OA was successfully established. The modeled chondrocytes showed increased apoptosis rate, promoted expression of COX-2, PGE2, and TNF-α, up-regulated protein levels of Bax, caspase-3, HMGB1, TLR4, and NF-κB p65 and mRNA levels of HMGB1, TLR4, NF-κB p65, and MyD88, and down-regulated protein level of Bcl-2. However, LIGc reversed the IL-1ß-induced changes of the above factors. Moreover, LIGc combined with GA showed more significant reversal effect than LIGc alone. These fin-dings indicate that LIGc extracted and derived from the traditional Chinese medicine A. sinensis can inhibit the inflammatory response of chondrocytes and reduce the apoptosis of chondrocytes, and this effect may be related to the HMGB1/TLR4/NF-κB signaling pathway. The pharmacological effect of LIGc on protecting chondrocytes has potential value in delaying the progression of OA and improving the clinical symptoms of patients, and deserves further study.

Association analysis between organophosphorus flame retardants exposure and the risk of depression: Data from NHANES 2017-2018.

BACKGROUND: Organophosphorus flame retardants (OPFRs) can damage the brain and may cause abnormal behaviors. There was no population-based study to reveal the relationship between OPFRs and the occurrence of depression. This study utilized a publicly available database to investigate the correlation between OPFRs exposure and the risk of depression, and the mediation effect of inflammation on the correlation. METHODS: Data in this study was from the database of the National Health and Nutrition Examination Survey. Multifactorial logistic regression was used to estimate the relationship between OPFRs exposure and the risk of depression, and a mediation effect model was constructed to explore the impact of inflammation on the correlation. RESULTS: Data of 1273 participants was included in the study. It was found that individuals with high urinary concentration of bis-(2-chloroethyl) phosphate had an increased risk of developing depression (OR = 1.217, 95 % CI: 1.032-1.435). Combined exposure to OPFRs was significantly associated with the increased risk of depression than single OPFRs exposure. Subgroup analyses based on inflammatory levels in the body revealed that inflammation might exert the mediation effect on the association between OPFRs exposure and the risk of depression, with the contribution proportion of 8.23 %. LIMITATIONS: Cross-sectional data and rapid metabolism of OPFRs lead to uncertainty in revealing long-term exposure in the body. CONCLUSIONS: There was a correlation between OPFRs exposure and the risk of depression, which may be mediated by inflammation in the body to some extent.

Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.

Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 µM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg-1·d-1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.

A Radical-Generating Probe to Release Free Fluorophores and Identify Artemisinin-Sensitive Cancer Cells.

The smart light-up probes have been extensively developed to image various enzymes and other bioactive molecules. Upon activation, these probes result in light-up fluorophores that exist in a protein-bound or a free form. The difference between these two forms has not yet been reported. Here, we present a pair of smart light-up probes that generate a protein-bound fluorophore and a free fluorophore upon activation by heme. Probe 8 generated a radical-attached fluorophore that predominantly existed in the free form, while probe 10 generated an α,ß-unsaturated ketone-attached fluorophore that showed extensive labeling of proteins. In live-cell imaging, probe 8 showed greater fluorescence intensity than probe 10 when low concentrations (0.1-5 µM) of the probes were used, but probe 8 was less fluorescent than probe 10 when the concentrations of the probes were high (10 µM). Finally, probe 8 was used to reflect the activation level of the endoperoxide bond in cancer cells and to effectively distinguish ART-sensitive cancer cells from ART-insensitive ones.

Effect of care bundles for acute kidney injury: A systematic review and meta-analysis.

PURPOSE: Acute kidney injury (AKI) is frequent among in-hospital patients with high incidence and mortality. Implementing a series of evidence-based AKI care bundles may improve patient outcomes by reducing changeable standards of care. The aim of this meta-analysis was therefore to appraise the influences of AKI care bundles on patient outcomes. MATERIALS AND METHODS: We explored three international databases (PubMed, Embase, and Cochrane Central Register of Controlled Trials) and two Chinese databases (Wanfang Data and China National Knowledge Infrastructure) for studies from databases inception until November 30, 2022, comparing the impact of different AKI care bundles with usual standards of care in patients with or at risk for AKI. The study quality of non-randomized controlled trials and randomized controlled trials was evaluated by the NIH Study Quality Assessment Tool and the Cochrane risk of bias tool. Heterogeneity between studies was appraised by Cochran's Q test and I2 statistics. The possible origins of heterogeneity between studies were assessed adopting Meta-regression and subgroup analyses. Funnel plot asymmetry and Egger regression and Begg correlation tests were performed to discover potential publication bias. Data analysis was completed by software (RevMan 5.3 and Stata 15.0). The primary outcome was short- or long-term mortality. The secondary outcomes involved the incidence and severity of AKI. RESULTS: Sixteen studies containing 25,690 patients and 25,903 AKI episodes were included. In high-risk AKI patients determined by novel biomarkers, electronic alert or risk prediction score, the application of AKI care bundles significantly reduced the AKI incidence (OR, 0.71; 95% CI, 0.53-0.96; p = 0.02; I2 = 84%) and AKI severity (OR, 0.59; 95% CI, 0.39-0.89; p = 0.01; I2 = 65%). No strong evidence is available to prove that care bundles can significantly reduce mortality (OR, 1.16; 95% CI, 0.58-2.30; p = 0.68; I2 = 97%). CONCLUSIONS: The introduction of AKI care bundles in routine clinical practice can effectively improve the outcomes of patients with or at-risk of AKI. However, the accumulated evidence is limited and not strong enough to make definite conclusions.

Organ donation after brain death from autoimmune glial fibrillary acidic protein astrocytopathy: A case report.

Background: No reports of organ donation have been documented in patients suffering from severe autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy. Case presentation: A 27-year-old male patient developed a fever and headache, followed a week later by weakness and unsteadiness in his limbs. He attended his local hospital, but no cause was found. Thirteen days later, he became unconscious and was promptly moved to the intensive care unit for symptomatic support treatment, with no improvement. He was then transferred to our hospital, where he suffered a cardiac arrest on the same day. The family abandoned treatment and opted for organ donation, for financial reasons. Cell-based assays demonstrated GFAP antibodies in the cerebrospinal fluid. Two kidney recipients and one liver recipient showed no abnormal reactions 15 months after receiving organ transplants. Conclusions: We report a case of organ donation following brain death in a patient diagnosed with GFAP astrocytopathy, highlighting the need for vigilance regarding the potential occurrence of cardiac arrest in patients with this condition. Considering the potential of GFAP astrocytopathy is crucial when observing deteriorating symptoms, seizures, and consciousness disturbances subsequent to a suspected viral infection. Successful organ donation from patients with GFAP astrocytopathy may be feasible given the exclusion of systemic infection and the absence of peripheral organ involvement.

Swine pseudorabies virus attenuated vaccine reprograms the kidney cancer tumor microenvironment and synergizes with PD-1 blockade.

The global incidence rate of kidney cancer (KC) has been steadily increasing over the past 30 years. With the aging global population, kidney cancer has become an escalating concern that necessitates vigilant surveillance. Nowadays, surgical intervention remains the optimal therapeutic approach for kidney cancer, while the availability of efficacious treatments for advanced tumors remains limited. Oncolytic viruses, an emerging form of immunotherapy, have demonstrated encouraging anti-neoplastic properties and are progressively garnering public acceptance. However, research on oncolytic viruses in kidney cancer is relatively limited. Furthermore, given the high complexity and heterogeneity of kidney cancer, it is crucial to identify an optimal oncolytic virus agent that is better suited for its treatment. The present study investigates the oncolytic activity of the Pseudorabies virus live attenuated vaccine (PRV-LAV) against KC. The findings clearly demonstrate that PRV-LAV exhibits robust oncolytic activity targeting KC cell lines. Furthermore, the therapeutic efficacy of PRV-LAV was confirmed in both a subcutaneous tumor-bearing nude mouse model and a syngeneic mouse model of KC. Combined RNA-seq analysis and flow cytometry revealed that PRV-LAV treatment substantially enhances the infiltration of a diverse range of lymphocytes, including T cells, B cells, macrophages, and NK cells. Additionally, PRV-LAV treatment enhances T cell activation and exerts antitumor effects. Importantly, the combination of PRV-LAV with anti-PD-1 antibodies, an approved drug for KC treatment, synergistically enhances the efficacy against KC. Overall, the discovery of PRV-LAV as an effective oncolytic virus holds significant importance for improving the treatment efficacy and survival rates of KC patients.

Coupling of nanostraws with diverse physicochemical perforation strategies for intracellular DNA delivery.

Effective intracellular DNA transfection is imperative for cell-based therapy and gene therapy. Conventional gene transfection methods, including biochemical carriers, physical electroporation and microinjection, face challenges such as cell type dependency, low efficiency, safety concerns, and technical complexity. Nanoneedle arrays have emerged as a promising avenue for improving cellular nucleic acid delivery through direct penetration of the cell membrane, bypassing endocytosis and endosome escape processes. Nanostraws (NS), characterized by their hollow tubular structure, offer the advantage of flexible solution delivery compared to solid nanoneedles. However, NS struggle to stably self-penetrate the cell membrane, resulting in limited delivery efficiency. Coupling with extra physiochemical perforation strategies is a viable approach to improve their performance. This study systematically compared the efficiency of NS coupled with polyethylenimine (PEI) chemical modification, mechanical force, photothermal effect, and electric field on cell membrane perforation and DNA transfection. The results indicate that coupling NS with PEI modification, mechanical force, photothermal effects provide limited enhancement effects. In contrast, NS-electric field coupling significantly improves intracellular DNA transfection efficiency. This work demonstrates that NS serve as a versatile platform capable of integrating various physicochemical strategies, while electric field coupling stands out as a form worthy of primary consideration for efficient DNA transfection.

Hemophagocytic lymphohistiocytosis during treatment of intracranial multifocal germinoma: a case report and literature review.

Hemophagocytic lymphohistiocytosis (HLH), also known as hemophagocytic syndrome (HPS), is a benign histiocytosis with hyperreactive proliferation of the mononuclear phagocyte system caused by immune function abnormalities, which often occurs under the background of genetic mutations, inflammation, infection or tumors. Because the research on malignancy-associated HLH (M-HLH) is focused on hematological malignancies, reports on HLH secondary to solid tumors are rare. In this case, we report a 14-year-old girl who developed HLH during treatment for intracranial multifocal germinoma, and the disease was controlled after hormone combined with etoposide(VP-16) and other related treatments. To our knowledge, there have been no documented cases of HLH caused by intracranial multifocal germinoma.

Benchmarking multi-omics integration algorithms across single-cell RNA and ATAC data.

Recent advancements in single-cell sequencing technologies have generated extensive omics data in various modalities and revolutionized cell research, especially in the single-cell RNA and ATAC data. The joint analysis across scRNA-seq data and scATAC-seq data has paved the way to comprehending the cellular heterogeneity and complex cellular regulatory networks. Multi-omics integration is gaining attention as an important step in joint analysis, and the number of computational tools in this field is growing rapidly. In this paper, we benchmarked 12 multi-omics integration methods on three integration tasks via qualitative visualization and quantitative metrics, considering six main aspects that matter in multi-omics data analysis. Overall, we found that different methods have their own advantages on different aspects, while some methods outperformed other methods in most aspects. We therefore provided guidelines for selecting appropriate methods for specific scenarios and tasks to help obtain meaningful insights from multi-omics data integration.

Genomic basis of the distinct biosynthesis of ß-glucogallin, a biochemical marker for hydrolyzable tannin production, in three oak species.

Hydrolyzable tannins (HTs), predominant polyphenols in oaks, are widely used in grape wine aging, feed additives, and human healthcare. However, the limited availability of a high-quality reference genome of oaks greatly hampered the recognition of the mechanism of HT biosynthesis. Here, high-quality reference genomes of three Asian oak species (Quercus variabilis, Quercus aliena, and Quercus dentata) that have different HT contents were generated. Multi-omics studies were carried out to identify key genes regulating HT biosynthesis. In vitro enzyme activity assay was also conducted. Dual-luciferase and yeast one-hybrid assays were used to reveal the transcriptional regulation. Our results revealed that ß-glucogallin was a biochemical marker for HT production in the cupules of the three Asian oaks. UGT84A13 was confirmed as the key enzyme for ß-glucogallin biosynthesis. The differential expression of UGT84A13, rather than enzyme activity, was the main reason for different ß-glucogallin and HT accumulation. Notably, sequence variations in UGT84A13 promoters led to different trans-activating activities of WRKY32/59, explaining the different expression patterns of UGT84A13 among the three species. Our findings provide three high-quality new reference genomes for oak trees and give new insights into different transcriptional regulation for understanding ß-glucogallin and HT biosynthesis in closely related oak species.

Bioinspired Stimuli-Responsive Materials for Soft Actuators.

Biological species can walk, swim, fly, jump, and climb with fast response speeds and motion complexity. These remarkable functions are accomplished by means of soft actuation organisms, which are commonly composed of muscle tissue systems. To achieve the creation of their biomimetic artificial counterparts, various biomimetic stimuli-responsive materials have been synthesized and developed in recent decades. They can respond to various external stimuli in the form of structural or morphological transformations by actively or passively converting input energy into mechanical energy. They are the core element of soft actuators for typical smart devices like soft robots, artificial muscles, intelligent sensors and nanogenerators. Significant progress has been made in the development of bioinspired stimuli-responsive materials. However, these materials have not been comprehensively summarized with specific actuation mechanisms in the literature. In this review, we will discuss recent advances in biomimetic stimuli-responsive materials that are instrumental for soft actuators. Firstly, different stimuli-responsive principles for soft actuators are discussed, including fluidic, electrical, thermal, magnetic, light, and chemical stimuli. We further summarize the state-of-the-art stimuli-responsive materials for soft actuators and explore the advantages and disadvantages of using electroactive polymers, magnetic soft composites, photo-thermal responsive polymers, shape memory alloys and other responsive soft materials. Finally, we provide a critical outlook on the field of stimuli-responsive soft actuators and emphasize the challenges in the process of their implementation to various industries.

Two New Sesquiterpenoids and a New Shikimic Acid Metabolite from Mangrove Sediment-Derived Fungus Roussoella sp. SCSIO 41427.

Two new sesquiterpenoid derivatives, elgonenes M (1) and N (2), and a new shikimic acid metabolite, methyl 5-O-acetyl-5-epi-shikimate (3), were isolated from the mangrove sediment-derived fungus Roussoella sp. SCSIO 41427 together with fourteen known compounds (4-17). The planar structures were elucidated through nuclear magnetic resonance (NMR) and mass spectroscopic (MS) analyses. The relative configurations of 1-3 were ascertained by NOESY experiments, while their absolute configurations were determined by electronic circular dichroism (ECD) calculation. Elgonene M (1) exhibited inhibition of interleukin-1ß (IL-1ß) mRNA, a pro-inflammatory cytokine, at a concentration of 5 µM, with an inhibitory ratio of 31.14%. On the other hand, elgonene N (2) demonstrated inhibition at a concentration of 20 µM, with inhibitory ratios of 27.57%.

The immune cell infiltration-associated molecular subtypes and gene signature predict prognosis for osteosarcoma patients.

Host immune dysregulation involves in the initiation and development of osteosarcoma (OS). However, the exact role of immune cells in OS remains unknown. We aimed to distinguish the molecular subtypes and establish a prognostic model in OS patients based on immunocyte infiltration. The gene expression profile and corresponding clinical feature of OS patients were obtained from TARGET and GSE21257 datasets. MCP-counter and univariate Cox regression analyses were applied to identify immune cell infiltration-related molecular subgroups. Functional enrichment analysis and immunocyte infiltration analysis were performed between two subgroups. Furthermore, Cox regression and LASSO analyses were performed to establish the prognostic model for the prediction of prognosis and metastasis in OS patients. The subgroup with low infiltration of monocytic lineage (ML) was related to bad prognosis in OS patients. 435 DEGs were screened between the two subgroups. Functional enrichment analysis revealed these DEGs were involved in immune- and inflammation-related pathways. Three important genes (including TERT, CCDC26, and IL2RA) were identified to establish the prognostic model. The risk model had good prognostic performance for the prediction of metastasis and overall survival in OS patients. A novel stratification system was established based on ML-related signature. The risk model could predict the metastasis and prognosis in OS patients. Our findings offered a novel sight for the prognosis and development of OS.

Computerised modified paramedian approach technique versus conventional midline approach technique of lumbar puncture: a randomised control trial protocol.

INTRODUCTION: The lumbar puncture (LP) technique is widely used for diagnostic and therapeutic purposes. In recent years, the paramedian approach technique (PAT) has gained increasing interest due to its advantages over the conventional midline approach technique (MAT) that has been traditionally employed in clinical practice for LP. However, there have been inconsistent discussions regarding the efficacy of different LP techniques. Based on digital virtual human and computer simulation techniques, a new approach called computerised modified PAT (CMPAT) was proposed. Therefore, the aim of this study is to discuss a randomised controlled trial (RCT) protocol to investigate and compare the effects of CMPAT and MAT in patients undergoing LP. METHODS AND ANALYSIS: We will conduct a prospective, multicentre RCT. The study will recruit 84 patients aged 18-99 years who require LP. Participants will be randomly assigned to either the CMPAT treatment group (group A) or the MAT treatment group (group B). The primary outcome measure will be the number of needle insertion attempts required for a successful LP. Secondary outcomes will include the puncture success rate, pain assessment in the back, head, and legs, and the occurrence of complications. The measurement of these secondary outcomes will be taken during the procedure, as well as at specific time points: 30 min, 6 hours, 1 day, 3 days, 7 days, 2 weeks and 4 weeks after the procedure. Pain levels will be assessed using a Numerical Rating Scale. ETHICS AND DISSEMINATION: Ethical approval (2022YF052-01) has been obtained from the Ethics Committee of Fujian Medical University Union Hospital, Fuzhou, China. The research findings will be published in an international peer-reviewed scientific journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: ChiCTR2300067937.

Multi-view representation learning for tabular data integration using inter-feature relationships.

OBJECTIVE: An applied problem facing all areas of data science is harmonizing data sources. Joining data from multiple origins with unmapped and only partially overlapping features is a prerequisite to developing and testing robust, generalizable algorithms, especially in healthcare. This integrating is usually resolved using meta-data such as feature names, which may be unavailable or ambiguous. Our goal is to design methods that create a mapping between structured tabular datasets derived from electronic health records independent of meta-data. METHODS: We evaluate methods in the challenging case of numeric features without reliable and distinctive univariate summaries, such as nearly Gaussian and binary features. We assume that a small set of features are a priori mapped between two datasets, which share unknown identical features and possibly many unrelated features. Inter-feature relationships are the main source of identification which we expect. We compare the performance of contrastive learning methods for feature representations, novel partial auto-encoders, mutual-information graph optimizers, and simple statistical baselines on simulated data, public datasets, the MIMIC-III medical-record changeover, and perioperative records from before and after a medical-record system change. Performance was evaluated using both mapping of identical features and reconstruction accuracy of examples in the format of the other dataset. RESULTS: Contrastive learning-based methods overall performed the best, often substantially beating the literature baseline in matching and reconstruction, especially in the more challenging real data experiments. Partial auto-encoder methods showed on-par matching with contrastive methods in all synthetic and some real datasets, along with good reconstruction. However, the statistical method we created performed reasonably well in many cases, with much less dependence on hyperparameter tuning. When validating feature match output in the EHR dataset we found that some mistakes were actually a surrogate or related feature as reviewed by two subject matter experts. CONCLUSION: In simulation studies and real-world examples, we find that inter-feature relationships are effective at identifying matching or closely related features across tabular datasets when meta-data is not available. Decoder architectures are also reasonably effective at imputing features without an exact match.

Discovery of Enzyme Inhibitors from Mangrove Sediment Derived Fungus Trichoderma harzianum SCSIO 41051.

One new fatty acid derivative, (2E,4E)-6,7-dihydroxy-2-methylocta-2,4-dienoic acid (1), and 16 known compounds (2-17) were isolated from the mangrove sediment derived fungus Trichoderma harzianum SCSIO 41051. Their structures were established by spectroscopic methods, computational ECD, and Mo2(OAc)4-induced ECD experiment. All the compounds were evaluated for their acetylcholinesterase (AChE) and pancreatic lipase (PL) inhibition. Compounds 9 and 14 exhibited moderate AChE inhibitory activities with IC50 values of 2.49 and 2.92 µM, respectively, which compounds 8 and 9 displayed moderate inhibition on PL with IC50 value of 2.30 and 2.34 µM, respectively.

A Dual-domain Engineered Antibody for Efficient HBV Suppression and Immune Responses Restoration.

Chronic hepatitis B (CHB) remains a major public health concern because of the inefficiency of currently approved therapies in clearing the hepatitis B surface antigen (HBsAg). Antibody-based regimens have demonstrated potency regarding virus neutralization and HBsAg clearance. However, high dosages or frequent dosing are required for virologic control. In this study, a dual-domain-engineered anti-hepatitis B virus (HBV) therapeutic antibody 73-DY is developed that exhibits significantly improved efficacy regarding both serum and intrahepatic viral clearance. In HBV-tolerant mice, administration of a single dose of 73-DY at 2 mg kg-1 is sufficient to reduce serum HBsAg by over 3 log10 IU mL-1 and suppress HBsAg to < 100 IU mL-1 for two weeks, demonstrating a dose-lowering advantage of at least tenfold. Furthermore, 10 mg kg-1 of 73-DY sustainably suppressed serum viral levels to undetectable levels for ≈ 2 weeks. Molecular analyses indicate that the improved efficacy exhibited by 73-DY is attributable to the synergy between fragment antigen binding (Fab) and fragment crystallizable (Fc) engineering, which conferred sustained viral suppression and robust viral eradication, respectively. Long-term immunotherapy with reverse chimeric 73-DY facilitated the restoration of anti-HBV immune responses. This study provides a foundation for the development of next-generation antibody-based CHB therapies.