Berberine-loaded PLGA nanoparticles alleviate ulcerative colitis by targeting IL-6/IL-6R axis.

AIMS: The present study aims to develop a nano-delivery system that encapsulates berberine (BBR) into PLGA-based nanoparticles (BPL-NPs), to treat ulcerative colitis (UC). Furthermore, the therapeutic efficacy and molecular targeting mechanisms of BPL-NPs in the management of UC are thoroughly examined. METHODS: Emulsion solvent-driven methods were used to self-assemble BBR and PLGA into nanoparticles, resulting in the development of the nano-delivery system (BPL-NPs). The therapeutic effectiveness of BPL-NPs was evaluated using a dextran sulfate sodium (DSS)-induced model of ulcerative colitis in mice and a lipopolysaccharide (LPS)-induced model of inflammation in THP-1 macrophages. The interaction between Mφs and NCM-460 cells was investigated using a co-culture system. The molecular targeting ability of BPL-NPs in the treatment of UC was validated through in vitro as well as in vivo experiments. RESULTS: The BPL-NPs demonstrated a particle size of 184 ± 22.4 nm, enhanced dispersibility in deionized water, and a notable encapsulation efficiency of 31.1 ± 0.2%. The use of BPL-NPs clearly improved the clinical symptoms and pathological changes associated with UC in mice while also ensuring minimal toxicity. In addition, BPL-NPs improved intestinal epithelial cell apoptosis and enhanced the function of the intestinal barrier by inhibiting M1 Mφs infiltration and IL-6 signaling pathway in mice with UC. Furthermore, the BPL-NPs were found to selectively target the IL-6/IL-6R axis during the M1 Mφs-induced apoptosis of NCM460 cells. CONCLUSION: The BPL-NPs were confirmed to harbor anti-inflammatory effects both in vitro and in vivo, along with enhanced water solubility and bioactivity. In addition, the precise targeting of the IL-6/IL-6R axis was confirmed as the mechanism by which the BPL-NPs exerted therapeutic effects in UC, as demonstrated in both in vitro as well as in vivo studies.

Myasthenia gravis complicated with pulmonary infection by Nocardia cyriacigeorgica: a case report and literature review.

Myasthenia gravis (MG) is an autoimmune disease. Patients with MG due to compromised autoimmune regulation, progressive muscle weakness, and prolonged use of immunosuppressants and glucocorticoid, often present with concomitant infections. However, cases of MG complicated by Nocardia infection are rare. In this case, we report MG complicated with pulmonary infection by Nocardia cyriacigeorgica. A 71-year-old male farmer who was admitted for management of MG. After 7 weeks of treatment of MG, the patient reported improvement. However, clinical presentation, inflammatory markers, and imaging findings supported a diagnosis of pulmonary infection. To further elucidate the etiology, Nocardia was identified in sputum smear microscopy and sputum culture, with 16S rRNA gene sequencing confirming N. cyriacigeorgica. The patient was prescribed trimethoprim-sulfamethoxazole. After 1 month of treatment, clinical symptoms of MG and pulmonary nocardiosis showed significant improvement. Additionally, we searched PubMed for case reports of Nocardia cyriacigeorgica pulmonary infection from 2010 to 2024 and conducted a statistical analysis of the case information. This report aims to highlights the increased risk of pulmonary Nocardia infection in MG patients after the use of steroids and immunosuppressants, thereby enhancing clinical awareness.

Denosumab for Management of Hypercalcemia in Primary Hyperparathyroidism.

Denosumab is a completely human monoclonal high-affinity antibody that binds to the nuclear factor kappa-B ligand (RANKL) and is widely used to treat osteoporosis. Furthermore, it can potentially lower serum calcium levels by inhibiting osteoclast activation and preventing bone calcium from being released into the blood. This review aimed to provide evidence of the efficacy and safety of denosumab in treating hypercalcemia in primary hyperparathyroidism (PHPT). PubMed and the Cochrane Library were searched for published studies that described denosumab for hypercalcemia management in PHPT. Data were extracted by two independent investigators and analyzed using SPSS 23. The risk of bias was assessed by NIH Quality Assessment Tool. In total, 161 patients with PHPT from 18 studies were included in this review. The average age was 61 (47-72) years and the highest serum calcium was 3.76 (3.11-4.20) mmol/l. We found that denosumab can effectively reduce the serum calcium level by a median reduction of 0.5 mmol/l within 3 days. Significant reduction was maintained for 14 days. The serum calcium-lowering effect weakened after one month. In conclusion, denosumab has a potential clinical value in treating hypercalcemia in patients with PHPT.

Activatable Near-Infrared Fluorescence Probe for Hypochlorous Acid Detection in Early Diagnosis of Keloids.

Keloids represent pathologic conditions characterized by the presence of hyalinized collagen bundles and chronic inflammatory reactions. Recently, increased ROS production and disrupted apoptosis mechanisms in keloids have been reported, although the detailed mechanisms remain unclear. Herein, we developed a specific fluorescence probe, Pro-NBS, to investigate ClO- levels in keloids. The probe demonstrated high specificity for ClO- over other ROS and exhibited a strong linear detection relationship. Based on its performance, we focused on the TGF-ß pathway in the development of keloids. ROS upregulation was observed in keloid-derived fibroblasts. Using ClO- as an intrinsic overexpression marker, our probe effectively distinguished between normal fibroblasts and keloid-derived fibroblasts both in vitro and in vivo. Furthermore, Pro-NBS showed potential for monitoring the progression and evaluating the systematic therapy of abnormal scarring or keloids.

Application of Dynamic [18F]FDG PET/CT Multiparametric Imaging Leads to an Improved Differentiation of Benign and Malignant Lung Lesions.

PURPOSE: To evaluate the potential of whole-body dynamic (WBD) 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) multiparametric imaging in the differential diagnosis between benign and malignant lung lesions. PROCEDURES: We retrospectively analyzed WBD PET/CT scans from patients with lung lesions performed between April 2020 and March 2023. Multiparametric images including standardized uptake value (SUV), metabolic rate (MRFDG) and distribution volume (DVFDG) were visually interpreted and compared. We adopted SUVmax, metabolic tumor volume (MTV) and total lesion glycolysis (TLG) for semi-quantitative analysis, MRmax and DVmax values for quantitative analysis. We also collected the patients' clinical characteristics. The variables above with P-value < 0.05 in the univariate analysis were entered into a multivariate logistic regression. The statistically significant metrics were plotted on receiver-operating characteristic (ROC) curves. RESULTS: A total of 60 patients were included for data evaluation. We found that most malignant lesions showed high uptake on MRFDG and SUV images, and low or absent uptake on DVFDG images, while benign lesions showed low uptake on MRFDG images and high uptake on DVFDG images. Most malignant lesions showed a characteristic pattern of gradually increasing FDG uptake, whereas benign lesions presented an initial rise with rapid fall, then kept stable at a low level. The AUC values of MRmax and SUVmax are 0.874 (95% CI: 0.763-0.946) and 0.792 (95% CI: 0.667-0.886), respectively. DeLong's test showed the difference between the areas is statistically significant (P < 0.001). CONCLUSIONS: Our study demonstrated that dynamic [18F]FDG PET/CT imaging based on the Patlak analysis was a more accurate method of distinguishing malignancies from benign lesions than conventional static PET/CT scans.

Functionalized flattened bamboo board: In-situ immersion assembly of flame-retardant, waterproof and anti-mold composite coatings.

The flattened bamboo board (FB) represents a promising innovation in the bamboo industry. To address the challenges of flammability and hygroscopicity, composite coatings consisting of melamine (MEL), phytic acid (PA), cerium ions (Ce3+), and sodium laurate (La) are assembled on the FB surface through an in-situ impregnation strategy. The resulting MEL/PA-Ce3+@La FB exhibits exceptional flame retardancy. It achieves a V-0 rating in the vertical burning test (UL-94) and boasts a high limiting oxygen index (LOI) value of 38.5 %. The coated FB exhibits superhydrophobicity, evidenced by a water contact angle of 156.5°, which can be attributed to the in-situ growth of PA-Ce3+ complexes (for constructing micro/nanoscale coarse structures) and the modification with La (for reducing surface energy).This superhydrophobic surface imparts both self-cleaning and anti-mold properties to the coated FB. Moreover, the coated FB exhibits excellent mechanical stability, withstanding 36 cycles of sandpaper abrasion and tape peeling without losing its hydrophobicity. In summary, this work provides an innovative strategy for the bamboo processing industry to produce flattened bamboo boards with combined flame retardancy, superhydrophobic and anti-mold properties. Such versatility holds significant potential to facilitate the utilization of flattened bamboo boards in the construction and decorative materials industries.

Phytoremediation of metals in oil sands process affected water by native wetland species.

Process affected water and other industrial wastewaters are a major environmental concern. During oil sands mining, large amounts of oil sands process affected water (OSPW) are generated and stored in ponds until reclaimed and ready for surface water discharge. While much research has focused on organics in process waters, trace metals at high concentrations may also pose environmental risks. Phytoremediation is a cost effective and sustainable approach that employs plants to extract and reduce contaminants in water. The research was undertaken in mesocosm scale constructed wetlands with plants exposed to OSPW for 60 days. The objective was to screen seven native emergent wetland species for their ability to tolerate high metal concentrations (arsenic, cadmium, copper, chromium, copper, nickel, selenium, zinc), and then to evaluate the best performing species for OSPW phytoremediation. All native plant species, except Glyceria grandis, tolerated and grew in OSPW. Carex aquatilis (water sedge), Juncus balticus (baltic rush), and Typha latifolia (cattail) had highest survival and growth, and had high metal removal efficiencies for arsenic (81-87 %), chromium (78-86 %), and cadmium (74-84 %), relative to other metals; and greater than 91 % of the dissolved portions were removed. The native plant species were efficient accumulators of all metals, as demonstrated by high root and shoot bioaccumulation factors; root accumulation was greater than shoot accumulation. Translocation factor values were greater than one for Juncus balticus (chromium, zinc) and Carex aquatilis (cadmium, chromium, cobalt, nickel). The results demonstrate the potential suitability of these species for phytoremediation of a number of metals of concern and could provide an effective and environmentally sound remediation approach for wastewaters.

Semi-supervised Double Deep Learning Temporal Risk Prediction (SeDDLeR) with Electronic Health Records.

BACKGROUND: Risk prediction plays a crucial role in planning for prevention, monitoring, and treatment. Electronic Health Records (EHRs) offer an expansive repository of temporal medical data encompassing both risk factors and outcome indicators essential for effective risk prediction. However, challenges emerge due to the lack of readily available gold-standard outcomes and the complex effects of various risk factors. Compounding these challenges are the false positives in diagnosis codes, and formidable task of pinpointing the onset timing in annotations. OBJECTIVE: We develop a Semi-supervised Double Deep Learning Temporal Risk Prediction (SeDDLeR) algorithm based on extensive unlabeled longitudinal Electronic Health Records (EHR) data augmented by a limited set of gold standard labels on the binary status information indicating whether the clinical event of interest occurred during the follow-up period. METHODS: The SeDDLeR algorithm calculates an individualized risk of developing future clinical events over time using each patient's baseline EHR features via the following steps: (1) construction of an initial EHR-derived surrogate as a proxy for the onset status; (2) deep learning calibration of the surrogate along gold-standard onset status; and (3) semi-supervised deep learning for risk prediction combining calibrated surrogates and gold-standard onset status. To account for missing onset time and heterogeneous follow-up, we introduce temporal kernel weighting. We devise a Gated Recurrent Units (GRUs) module to capture temporal characteristics. We subsequently assess our proposed SeDDLeR method in simulation studies and apply the method to the Massachusetts General Brigham (MGB) Biobank to predict type 2 diabetes (T2D) risk. RESULTS: SeDDLeR outperforms benchmark risk prediction methods, including Semi-parametric Transformation Model (STM) and DeepHit, with consistently best accuracy across experiments. SeDDLeR achieved the best C-statistics ( 0.815, SE 0.023; vs STM +.084, SE 0.030, P-value .004; vs DeepHit +.055, SE 0.027, P-value .024) and best average time-specific AUC (0.778, SE 0.022; vs STM + 0.059, SE 0.039, P-value .067; vs DeepHit + 0.168, SE 0.032, P-value <0.001) in the MGB T2D study. CONCLUSION: SeDDLeR can train robust risk prediction models in both real-world EHR and synthetic datasets with minimal requirements of labeling event times. It holds the potential to be incorporated for future clinical trial recruitment or clinical decision-making.

Synergetic sludge conditioning by US enhanced Fe2+ activated sodium persulfate: Physicochemical properties and mechanisms.

Efficient dewatering of sewage sludge is an energy- and carbon-saving procedure for sludge treatment in wastewater treatment facilities. The ultrasound-coupled divalent iron ion activated persulfate process can effectively promote sludge dewatering and improve organic substance content. Under the action of ultrasound (US 50 w/L), divalent iron ions (Fe2+) 200 mg/g (TS), and persulfate (PDS) 200 mg/g (TS) for 60 min, the capillary suction time (CST) was reduced by 79.74%, and the moisture content of the dewatered sludge cake reached 56.51 wt%. The organic carbon content of treated sludge was also four times higher than the original sludge and types were richer in short-chain volatile species in US/Fe2+/PDS. Moreover, the correlation analysis found that the relationship of between CST and SV30, Zeta and lactate dehydrogenase (LDH) were positive correlation, and the relationship of SCOD and TC were positively correlated with the PN (SB-EPS). Mechanistic studies showed that the US/Fe2+/PDS system could produce oxygen activators by US coupling Fe2+ to strengthen the effect of activated PDS strongly, while the sulfate radicals (SO4·-) radical was a dominant role. The cracking mechanism is divided into two pathways effectively degraded the macromolecule EPS into a small-molecule acid and further reduced the water-holding interfacial affinity as follow: (1) the radical path dominated by hydroxyl radicals (·OH), SO4·-, and superoxide radical (O2·-); (2) the non-radicals dominated by monoclinic oxygen (1O2). Afterwards, the electrostatic force and interfacial free energy were reduced, resulting in enhanced self-flocculation and mobility to enhanced dewaterability. These findings demonstrated the US/Fe2+/PDS system had significant advantages in sludge cracking and provided theoretical support for its practical application.

A novel robust hydrogel-assisted paper-based sensor based on fluorescence UiO-66-NH2@ZIF-8 for the dual-channel detection of captopril.

Captopril (CP) is commonly used as an active enzyme inhibitor for the treatment of coronary heart disease, hypertension and angina pectoris. The development of sensitive and efficient method for CP analysis is of great importance in biomedical research. Herein, we fabricated a sensitive and robust hydrogel-assisted paper-based sensor based on fluorescence UiO-66-NH2@ZIF-8 and Co, N-doped carbon nanozymes with oxidase-mimicking activity for accurate monitoring of captopril. The hydrogel-assisted paper-based sensor appeared a visible pink signal due to the catalytic oxidation of colorless N,N-diethyl-p-phenylenediamine (DPD) to oxDPD by Co, N-doped carbon-based nanozymes, and resulted in the fluorescence quenching of UiO-66-NH2@ZIF-8. In the presence of captopril, the oxidation of chromogenic substrate DPD by Co, N-doped nanozymes in the hydrogel-assisted paper-based sensor was hindered and accompanied by a change in the visible color, leading to recovery of the fluorescence of UiO-66-NH2@ZIF-8, and the change in the fluorescence color could also be observed. Therefore, the quantitative detection of captopril is achieved by taking a smartphone photograph and converting the image parameters into data information using ImageJ software. The portable hydrogel-assisted paper sensor provided sensitive detection of captopril in two modes based on visible color change as well as fluorescence color change with limits of detection of 0.45 µM and 0.47 µM, respectively. This hydrogel-assisted paper-based sensor has been successfully applied to the accurate monitoring of captopril in human serum, providing a potential avenue for in situ detection of captopril.

A case of alveolar soft tissue sarcoma detected by ultrasound examination.

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Potential of biochar and humic substances for phytoremediation of trace metals in oil sands process affected water.

Oil sands process affected water (OSPW) is produced during bitumen extraction and typically contains high concentrations of trace metals. Constructed wetlands have emerged as a cost effective and green technology for the treatment of metals in wastewaters. Whether the addition of amendments to constructed wetlands can improve metal removal efficiency is unknown. We investigated the synergistic effects of carbon based amendments and wetland plant species in removal of arsenic, cadmium, cobalt, chromium, copper, nickel, and selenium from OSPW. Three native wetland species (Carex aquatilis, Juncus balticus, Scirpus validus) and two amendments (canola straw biochar, nano humus) were investigated in constructed wetland mesocosms over 60 days. Amendment effect on metal removal efficiency was not significant, while plant species effect was. Phytoremediation resulted in removal efficiencies of 78.61-96.31 % for arsenic, cadmium, and cobalt. Carex aquatilis had the highest removal efficiencies for all metals. Amendments alone performed well in removing some metals and were comparable to phytoremediation for cadmium, cobalt, copper, and nickel. Metals were primarily distributed in roots with negligible translocation to shoots. Our work provides insights into the role of plants and amendments during metal remediation and their complex interactions in constructed treatment wetlands.

Prognostic value of postoperative anti-thyroglobulin antibody in patients with differentiated thyroid cancer.

Purpose: Postoperative thyroglobulin (Tg) generally serves as a biomarker to monitor the recurrence or persistence of differentiated thyroid cancer (DTC), whereas it constrains to interference from anti-thyroglobulin antibody (TgAb). This study aimed to determine the value of postoperative TgAb as a surrogate for monitoring tumor status in DTCs with positive TgAb after successful radioactive iodine (RAI) remnant ablation. Methods: We retrospectively enrolled DTC patients with positive (≥40 IU/mL, Roche) postoperative TgAb measurements. An index of TgAb change (ΔTgAb) was defined to describe the TgAb decrease rate. DTC status was defined as either no evidence of disease (NED) or persistent/recurrent disease (PRD). Univariate and multivariate binary logistic analyses were used to identify the independent risk factors of PRD. Receiver operating characteristic (ROC) curves were performed to determine the optimal cutoff values of each risk factor, and DeLong's test was conducted to compare their predictive powers. Kaplan-Meier curves were used to assess the impact of different TgAb trends in the first year on progression-free survival. Results: Of the 232 patients enrolled, the median diagnosis age was 34 years (range, 18-62 years), with a male-to-female ratio of 1:4.66 (41/191). Among them, after a median follow-up of 44 months (range, 4-128 months),183 (78.87%) patients were evaluated as NED, while the other 49 (21.12%) had either persistent (n = 25) or recurrent disease (n = 24). Multivariate regression showed that ΔTgAb (P < 0.001) and lymph node metastasis (LNM) rate (P = 0.009) were independently relevant to the presence of PRD, with optimal cutoff values of 47.0% and 35.1%, respectively. It is important to note that there is a high negative predictive value (96.93%) of ΔTgAb with the cutoff of 47.0%. DeLong's test showed that ΔTgAb alone and the combination of ΔTgAb and LNM rate were significantly greater than the isolated LNM rate (both P < 0.001) in predicting NED, while there was no statistical difference of the predictive power between ΔTgAb and the combination (P = 0.203). Additionally, patients with ΔTgAb >47.0% had longer progression-free survival than those with ΔTgAb ≤47.0% (not reached vs. 50 months, P < 0.001), and those with ΔTgAb >47.0% or negative conversion within the first year after RAI ablation had longer progression-free survival. Conclusion: Our study suggested that ΔTgAb could serve as a valuable indicator of disease status in DTC patients with positive TgAb. A ΔTgAb of >47.0% is conducive to identify those with NED and may help to obviate their overtreatment. The decrease rate and negative conversion of TgAb in the first year were good predictors of disease-free survival in patients.

Synergistic effects of coal waste derived humic substances and inorganic fertilizer as soil amendments for barley in sandy soil.

Increasing pressures on land resources requires increased land use efficiency. Over 900 million ha of sandy soils throughout the world are extensively used for agricultural crop production, most requiring nutrient inputs. Although use of humic substances together with inorganic fertilizer as soil amendments has been introduced, their synergistic effects on plant growth in sandy soils are not well addressed. We assessed the efficacy of a lignite waste derived humic substance on barley (Hordeum vulgare L.) growth, with and without inorganic fertilizer. Ten treatments were applied to sandy soils, comprising sole application of the humic product at four rates (NH1, NH2, NH3, NH4), sole application of fertilizer (F), and their combinations (F + NH1, F + NH2, F + NH3, F + NH4). Synergistic effects of nano humus and fertilizer were more notable than the corresponding sole application, particularly on plant biomass and seed production. Combined application with inorganic fertilizer increased root biomass by 92 % (0.1 g per plant), shoot biomass by 80 % (0.5 g per plant), root length by 24 % (3.6 cm), and seed production by 38 % (5 seeds per head) averagely relative to the untreated control, suggesting a strong synergistic effect. The increased seed production was particularly important from an agricultural perspective. Four application rates of nano humus all showed beneficial effects on barley growth with no significant differences. The most distinct positive effect of the humic product as a sole application was on root growth. Our study confirmed that a lignite waste derived humic product, nano humus, together with fertilizer may be an effective soil amendment to enhance agricultural plant growth in sandy soil regions.

N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer.

BACKGROUND: Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m6A)-binding protein involved in a variety of cancers. However, whether m6A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance. METHODS: The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry. RESULTS: Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m6A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/ß-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders. CONCLUSION: Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/ß-catenin pathway and exacerbate chemoresistance in GC.

In situ retention of lignin-rich bamboo green effectively improves the surface properties of flattened bamboo.

Bamboo has tremendous carbon sequestration potential, and bamboo green is underutilized. This work devised a green-keeping technique in bamboo flattening that preserved natural bamboo green in-situ. The impacts of flattening and green-keeping on bamboo morphology, chemical composition, physical qualities, and composite applications were examined. Bamboo cells were wrinkled after flattening, while bamboo green exhibited a more homogenous surface. Bamboo cellulose crystallinity increased after flattening, hemicellulose deteriorated little, and relative lignin content increased. The hydrophobicity and mildew resistance of the surface of G-FB (green-kept flattened bamboo board) were improved. Compared to untreated bamboo, FB and G-FB had 61.1 % and 49.5 % higher tensile strength and 8.0 % and 33.2 % higher MOR. G-FB-made flooring exhibited a MOR of 134.7 MPa and upgraded surface properties. Bamboo green preservation boosted utilization of materials and improved flattened bamboo's exterior surface without affecting lamination bonding. Simple bamboo green preservation multifunctionalizes flattened bamboo composites.

LATTE: Label-efficient incident phenotyping from longitudinal electronic health records.

Electronic health record (EHR) data are increasingly used to support real-world evidence studies but are limited by the lack of precise timings of clinical events. Here, we propose a label-efficient incident phenotyping (LATTE) algorithm to accurately annotate the timing of clinical events from longitudinal EHR data. By leveraging the pre-trained semantic embeddings, LATTE selects predictive features and compresses their information into longitudinal visit embeddings through visit attention learning. LATTE models the sequential dependency between the target event and visit embeddings to derive the timings. To improve label efficiency, LATTE constructs longitudinal silver-standard labels from unlabeled patients to perform semi-supervised training. LATTE is evaluated on the onset of type 2 diabetes, heart failure, and relapses of multiple sclerosis. LATTE consistently achieves substantial improvements over benchmark methods while providing high prediction interpretability. The event timings are shown to help discover risk factors of heart failure among patients with rheumatoid arthritis.

Berberine regulates intestinal microbiome and metabolism homeostasis to treat ulcerative colitis.

AIMS: This study aims to investigate the effects of berberine (BBR) on the intestinal microbiome (IM) and serum metabolome in ulcerative colitis (UC). Furthermore, the underlying molecular mechanisms of BBR in treating UC also will be explored systematically. MATERIALS AND METHODS: A multi-omics approach that integrates the 16s rDNA, serum metabolome, transcriptomics and bioinformatics was profiled to investigate the potential effects of BBR on the IM, serum metabolites and metabolic pathways, and gene expression. In addition, BBR-induced fecal microbiota transplantation (BBR_FMT) was conducted in pseudo germ-free mice combined with the UC model to explore the effects of the IM on metabolic pathways and gene expression. The results of the transcriptomics and metabolic pathway-related genes were further examined by real-time PCR and western blot. KEY FINDINGS: BBR ameliorated the community of IM and significantly promoted the abundance of f__Muribaculaceae, Bacteroides, Dubosiella, Allobaculum and Akkermansia. The metabolic profiles in UC mice were significantly modulated by BBR treatment. Furthermore, the inflammation-related metabolites and metabolic pathways in serum were negatively correlated with the abundance of Bacteroides and Akkermansia, which were induced by BBR treatment. BBR_FMT significantly inhibited the arachidonic acid (AA) metabolism pathway and its multiple markers with the mediation of the IM. SIGNIFICANCE: BBR ameliorated serum metabolic homeostasis by regulating the IM. The inhibition of the AA metabolism pathway and its multiple markers was one of the mechanisms of BBR in the treatment of UC.

Stem cells from human exfoliated deciduous teeth rejuvenate the liver in naturally aged mice by improving ribosomal and mitochondrial proteins.

BACKGROUND AIMS: Aging is accompanied by a decline in cellular proteome homeostasis, mitochondrial, and metabolic function. Mesenchymal stromal cell (MSC) therapies have been reported to extend lifespan and delay some age-related pathologies, yet the anti-aging rate and mechanisms remain unclear. Here, we investigated the effects and mechanism by transplantation of stem cells from human exfoliated deciduous teeth (SHED) into the naturally aged mice model. METHODS: SHED were cultured in vitro and injected into mice by caudal vein. The in vivo imaging uncovered that SHED labeled by DiR dye mainly migrated to the liver, spleen, and lung organs of wild-type mice. As the main metabolic organ and SHED homing place, the liver was selected for proteomics and aging clock algorithm (LiverClock) analysis, which was constructed to estimate the proteomic pattern related to liver age state. RESULTS: After 6 months of continuous SHED injections, the liver proteomic pattern was reversed from senescent (∼30 months) to a youthful state (∼3 months), accompanied with upregulation of hepatocytes marker genes, anti-aging protein Klotho, a global improvement of liver functional pathways proteins, and a dramatic regulation of ribosomal and mitochondrial proteins, including upregulation of translation elongation and ribosome-sparing proteins Rpsa and Rplp0; elongation factors Eif4a1, Eef1b2, Eif5a; protein-folding chaperones Hsp90aa and Hspe1; ATP synthesis proteins Atp5b, Atp5o, Atp5j; and downregulation of most ribosomal proteins, suggesting that the proteome homeostasis destruction and mitochondria dysfunction in the aged mice liver might be relieved after SHED treatment. CONCLUSIONS: SHED treatment could dramatically relieve the senescent state of the aged liver, affect ribosome component proteins and upregulate the ribosomal biogenesis proteins in the aged mice liver. These results may help understand the improvements and mechanisms of SHED treatment in anti-aging.

Core-Shell Reactor Partitioning Enzyme and Prodrug by ZIF-8 for NADPH-Sensitive In Situ Prodrug Activation.

Enzyme-prodrug therapies have shown unique advantages in efficiency, selectivity, and specificity of in vivo prodrug activation. However, precise spatiotemporal control of both the enzyme and its substrate at the target site, preservation of enzyme activity, and in situ substrate depletion due to low prodrug delivery efficiency continue to be great challenges. Here, we propose a novel core-shell reactor partitioning enzyme and prodrug by ZIF-8, which integrates an enzyme with its substrate and increases the drug loading capacity (DLC) using a prodrug as the building ligand to form a Zn-prodrug shell. Cytochrome P450 (CYP450) is immobilized in ZIF-8, and the antitumor drug dacarbazine (DTIC) is coordinated and deposited in its outer layer with a high DLC of 43.6±0.8 %. With this configuration, a much higher prodrug conversion efficiency of CYP450 (36.5±1.5 %) and lower IC50 value (26.3±2.6 µg/mL) are measured for B16-F10 cells with a higher NADPH concentration than those of L02 cells and HUVECs. With the tumor targeting ability of hyaluronic acid, this core-shell enzyme reactor shows a high tumor suppression rate of 96.6±1.9 % and provides a simple and versatile strategy for enabling in vivo biocatalysis to be more efficient, selective, and safer.