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Abstract N6-methyladenosine (m6A) RNA modification orchestrates cellular epitranscriptome through tuning the homeostasis of transcript stability, translation efficiency, and the transcript affinity toward RNA-binding proteins (RBPs). An aberrant m6A deposition on RNA can lead toward oncogenic expression profile (mRNA), impaired mitochondrial metabolism (mtRNA), and translational suppression (rRNA) of tumor suppressor genes. In addition, non-coding RNAs (ncRNAs), such as X-inactive specific transcript (XIST), miRNAs, and α-ketoglutarate-centric metabolic transcripts are also regulated by the m6A epitranscriptome. Notably, recent studies had uncovered a myriad of m6A-modified transcripts the center of hematopoietic stem cell (HSC) regulation, in which m6A modification act as a context dependent switch to the on and off of hematopoietic stem cell (HSC) maintenance, lineage commitment and terminal differentiation. In this review, we sequentially unfold the m6A mediated epithelial-to-hematopoietic transition in progenitor blood cell production, lymphocytic lineage expansion (T cells, B cells, NK cells, and non-NK ILCs), and the m6A crosstalk with the onco-metabolic prospects of leukemogenesis. Together, an encompassing body of evidence highlighted the emerging m6A significance in the regulation of HSC biology and leukemogenesis.

Abstract Background Metabolic dysfunction-associated steatohepatitis (MASH) is a growing global health concern with no effective pharmacological treatments. SNP-630, a newly developed synthetic molecule with multiple mechanisms of action, and a mixture of two of its active metabolites (SNP-630-MS) inhibit CYP2E1 expression to prevent reactive oxygen species generation, thereby reducing the accumulation of hepatic triglycerides and lowering chemokine levels. This study investigated the SNP-630’s potential to alleviate the liver injury in MASH and its efficacy in both a mouse model and patients with MASH to identify a drug candidate that targets multiple pathways implicated in MASH. Methods SNP-630 and SNP-630-MS were separately administered to the MASH mouse model. The tolerability, safety, and efficacy of SNP-630-MS were also evaluated in 35 patients with MASH. The primary endpoint of the study was assessment of the changes in serum alanine aminotransferase (ALT) levels from baseline to week 12, while the secondary endpoints included the evaluation of liver inflammation, steatosis, and fibrosis parameters and markers. Results SNP-630 treatment in mice improved inflammation, liver steatosis, and fibrosis compared with that in the MASH control group. Both SNP-630 and SNP-630-MS treatments markedly reduced ALT levels, hepatic triglyceride content, and the expression of inflammatory cytokines monocyte chemoattractant protein 1 and fibrotic collagen (i.e., Col1a1, Col3a1, and Timp1) in mice. In the clinical trial, patients treated with SNP-630-MS exhibited significant improvement in ALT levels at week 12 compared with baseline levels, with no reports of severe adverse events. This improvement in ALT levels surpassed that achieved with most other MASH candidates. SNP-630-MS demonstrated potential antifibrotic effects, as evidenced by a significant decrease in the levels of fibrogenesis-related biomarkers such as CCL4, CCL5, and caspase 3. Subgroup analysis using FibroScan measurements further indicated the efficacy of SNP-630-MS in ameliorating liver fibrosis. Conclusions SNP-630 and SNP-630-MS demonstrated favorable results in mice. SNP-630-MS showed excellent tolerability in mice and patients with MASH. Efficacy analyses indicated that SNP-630-MS improved liver steatosis and injury in patients with MASH, suggesting that SNP-630 and 630-MS are promising therapeutic options for MASH. Larger scale clinical trials remain warranted to assess the efficacy and safety of SNP-630 in MASH. Trial registration: ClinicalTrials.gov NCT03868566. Registered 06 March 2019-Retrospectively registered, https://clinicaltrials.gov/study/NCT03868566

The single value fluctuation of impact work occurs frequently in high strength steel, especially for medium or super thick plates. With respect to the single value fluctuation of impact work in 700 MPa low alloy thin tempered plate, the present study carried out a comprehensive and comparative analysis through metallographic microstructure, second-phase precipitated particle and inclusion distribution. The results show that the microstructure type, grain boundary ratio of HAGBs/LAGBs, grain size and orientation of the specimens with 37 J and 7 J impact work are basically the same. The two specimens show excellent process-microstructure consistency, which fully indicate that the temperature fields of the two specimens are consistent. Since the temperature field is basically the same, the (Ti, Nb, Mo)C compound precipitated particles in the two specimens maintain a good Baker-Nutting relationship with the matrix, and the interface between the precipitated particles and the matrix maintain a stable coherent/semi-coherent relationship. The main reason for the decrease of impact work of tempered plate is related to the distribution of inclusions. There are more spherical and square large size inclusion particles and microcracks in the specimen with lower impact work. Among them, the large square inclusion particles dominate mostly. And with the increase of the plastic deformation degree of the metal matrix, the large square inclusion has an obvious evolution by separation from the matrix to forming microcracks, and then to fracture.

Abstract Purpose This research evaluates the effect of balloon pulmonary angioplasty (BPA) on cardiac electrophysiological changes in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Methods Involving a retrospective analysis of 39 CTEPH patients (average age 61 ± 11), who had at least two BPAs and paired ECGs pre- and post-surgery, we examined changes in ECG indicators of right ventricular hypertrophy and their correlation with hemodynamic results. Results BPA yielded marked improvements in cardiac function and hemodynamics. ECG parameters, specifically the Lewis criteria and Butler-Leggett score, correlated strongly with hemodynamics and were predictive of a mean pulmonary arterial pressure (mPAP) ≥ 35mmHg. Notably, QRS complex axis normalization was observed in 25 patients, with 14 fully normalizing (range − 30° to + 90°). The qR pattern in V1 vanished in 9 cases, and 75% of the patients in qR pattern in V1 group had QRS complex electrical axis completely returned to normal range. The qR V1 group had higher mPAP and pulmonary vascular resistance (PVR), and lower cardiac output and index compared to the non-qR V1 group, alongside a higher Butler-Leggett score. Conclusions BPA enhances cardiac function and hemodynamics in CTEPH patients, with certain ECG measures such as Lewis criteria and Butler-Leggett score reflecting the severity of hemodynamic impairment. The reversal of QRS axis deviation and the disappearance of the qR pattern in lead V1 may serve as valuable indicators for assessing post-BPA satisfaction in CTEPH patients.

Abstract Purpose Previous research shows conflicting views on the relationship between obesity and osteoporosis, partly due to variations in obesity classification and the nonlinear nature of these relationships. This study investigated the association between adiposity indices and osteoporosis, diagnosed using dual-energy X-ray absorptiometry (DXA), employing nonlinear models and offering optimal thresholds to prevent further bone mineral density decline. Methods In 2019, a prospective study enrolled males over 50 years and postmenopausal women. Anthropometric measurements, blood biochemistry, and osteoporosis measured by DXA were collected. Associations between adiposity indices and osteoporosis were analyzed using a generalized additive model and segmented regression model. Results The study included 872 women and 1321 men. Indices such as abdominal volume index (AVI), visceral adiposity index (VAI), waist circumference (WC), hip circumference, body mass index (BMI), waist-to-hip ratio, and waist-to-height ratio (WHtR) were inversely associated with osteoporosis. In women, the relationship between the risk of osteoporosis and the adiposity indices was U-shaped, with thresholds of WC = 94 cm, AVI = 17.67 cm2, BMI = 25.74 kg/m2, VAI = 4.29, and WHtR = 0.61, considering changes in bone mineral density. Conversely, men exhibited a linear patterns for the inverse association. Conclusion The impact of obesity and adiposity on osteoporosis varies significantly between women and men. In postmenopausal women, the relationship is nonlinear (U-shaped), with both very low and very high adiposity linked to higher osteoporosis risk. In men over 50, the relationship is linear, with higher adiposity associated with lower osteoporosis risk. The study suggests that maintaining specific levels of adiposity could help prevent osteoporosis in postmenopausal women.

To alleviate social problems in agriculture such as aging and labor force shortages, automatic growth monitoring based on image measurement has been introduced to tomato cultivation in greenhouses. The overlap of leaves and fruits makes precise observations challenging. In this study, we applied context recognition to tomato growth monitoring by using a Bayesian network. The proposed method combines image recognition using convolutional networks and context recognition using Bayesian networks. It enables not only the recognition of individual tomatoes but also the evaluation of tomato plants. An accurate number of tomatoes and the condition of the stocks can be estimated based on the number of ripe and unripened tomatoes in addition to their density information. The verification experiments clarified that a more accurate number of tomatoes could be estimated than with simple tomato detection, and the stock states could also be evaluated correctly. Compared to conventional methods, the method used in this study has improved tomato decision accuracy by 23%.

Rapid heating is a promising technique for achieving excellent mechanical properties. This study innovatively applies rapid heating to a novel Ti–Mo martensite steel through in-situ observation experiments. By comparing the microstructure evolutions at heating rates of 1 and 30 °C/s, the relationship between microstructure and property evolution was elucidated. The results indicate that the refined austenite grains resulting from rapid heating stem from enhanced grain nucleation, accumulated dislocations, and the increased formation of new carbides under the large superheat. Furthermore, carbide maturation predominates during the slow heating process, while rapid heating accelerates new carbide precipitation with limited carbide maturation. Moreover, during rapid heating, both coherent and non-coherent relationships were observed between the (Ti, Mo, Fe)C particles and the martensite matrix, demonstrating a remarkable pinning effect on grain boundary migration. Nevertheless, during slow heating, large-sized (Ti, Mo)C carbides were formed, presenting a non-coherent relationship with the martensite matrix. Additionally, the primary differences in strength caused by rapid heating compared to slow heating include grain refinement, dislocation, and precipitation strengthenings, with dislocation strengthening playing the dominant role.

Indirect matrix converters (IMC) feature an AC-AC configuration without an intermediate DC link and wide application prospects in wind power generation, AC transmission, and various other fields, known for their sinusoidal input/output, high power density, and superior operating efficiency. However, these converters inevitably generate common-mode voltages during modulation operations, causing motor damage and affecting the reliable functioning of the systems. This paper aims to enhance the operational reliability of IMCs by suppressing common-mode voltage output, and focuses on five classical modulation methods for suppressing common-mode voltage peaks by 42.3% in IMCs, including the modulation method for synthesizing reference output voltage vectors using adjacent four effective voltage vectors at the inverter stage, that for synthesizing reference output voltage vectors using adjacent three effective voltage vectors at the inverter stage, that for synthesizing reference current vectors using adjacent three effective current vectors at the rectifier stage, that for synthesizing reference current vectors using two adjacent 120° effective current vectors plus a zero-current vector at the rectifier stage, and that for synthesizing reference current vectors using weighted three effective current vectors at the rectifier stage. By modeling the effective value (root mean square, rms) of output common-mode voltages, which incorporates the influence of voltage transfer ratios on these values, a quantitative analysis was conducted to explore the variation patterns of the rms value of common-mode voltages. Following this, an evaluation was performed on the suppression capability of different modulation methods on common-mode voltages. The comparative analysis results indicated that the space vector modulation method of synthesizing reference voltage using adjacent four effective voltage vectors at the inverter stage exhibited the best suppression effect on the rms value of common-mode voltages in IMCs. Additionally, the correctness of the theoretical analysis results was verified through simulations and experiments.

Objective This study aims to overcome challenges in lumbar spine imaging, particularly lumbar spinal stenosis, by developing an automated segmentation model using advanced techniques. Traditional manual measurement and lesion detection methods are limited by subjectivity and inefficiency. The objective is to create an accurate and automated segmentation model that identifies anatomical structures in lumbar spine magnetic resonance imaging scans. Methods Leveraging a dataset of 539 lumbar spinal stenosis patients, the study utilizes the residual U-Net for semantic segmentation in sagittal and axial lumbar spine magnetic resonance images. The model, trained to recognize specific tissue categories, employs a geometry algorithm for anatomical structure quantification. Validation metrics, like Intersection over Union (IOU) and Dice coefficients, validate the residual U-Net’s segmentation accuracy. A novel rotation matrix approach is introduced for detecting bulging discs, assessing dural sac compression, and measuring yellow ligament thickness. Results The residual U-Net achieves high precision in segmenting lumbar spine structures, with mean IOU values ranging from 0.82 to 0.93 across various tissue categories and views. The automated quantification system provides measurements for intervertebral disc dimensions, dural sac diameter, yellow ligament thickness, and disc hydration. Consistency between training and testing datasets assures the robustness of automated measurements. Conclusion Automated lumbar spine segmentation with residual U-Net and deep learning exhibits high precision in identifying anatomical structures, facilitating efficient quantification in lumbar spinal stenosis cases. The introduction of a rotation matrix enhances lesion detection, promising improved diagnostic accuracy, and supporting treatment decisions for lumbar spinal stenosis patients.

Abstract Introduction Bacterial vaginitis (BV) is a common vaginal disease. Vitamin E has been shown to reduce BV by enhancing immune function, but no studies have analyzed the relationship between vitamin E and BV at different BMIs and ages. Method This study used 2242 participants from four cycles of NHANES 1999–2006 in American. Participants' vitamin E levels were divided into four groups, and analyses such as study population description, stratified analysis, multiple logistic regression analysis, and curve fitting were performed. To perform data processing, the researchers used the statistical package R (The R Foundation; http://www.r-project.org ; version 3.6.3) and Empower Stats software ( www.empowerstats.net , X&Y solutions, Inc. Boston, Massachusetts). Result The concentrations of serum vitamin E were negatively correlated with the risk of BV, especially when vitamin E were at 1198-5459ug/dL with (OR = -0.443, 95%CI = 0.447–0.923, P = 0.032) or without (OR = -0.521, 95%CI = 0.421–0.837, P = 0.006) adjustment for variables. At the same time, at lower levels, there was no significant association. Vitamin E supplementation may significantly reduce the risk of BV (p

Background: The Iconographical Falls Efficacy Scale (Icon-FES) uses short phrases and images to depict activities. This study culturally adapted and validated the Taiwan Chinese version of the 30- and 10-item Icon-FESs (Icon-FESs [TW]) in community-dwelling older individuals. Methods: The Icon-FES (TW) was developed using forward–backward translation. A total of 120 community-dwelling older individuals were recruited. They completed the Taiwan Chinese version of the Falls Efficacy Scale-International (FES-I [TC]), the Icon-FES (TW), the Mini-Mental State Examination, and the World Health Organization Quality of Life Questionnaire Brief Version (WHOQOL-BREF) and were assessed using the Berg Balance Scale and the Short Physical Performance Battery (SPPB). The Icon-FES (TW) was recompleted 1 week later. Confirmatory factor analysis was used to evaluate the overall structure and measurement properties. Results: Cronbach’s alpha values of 0.97 and 0.91 indicated that the 30- and 10-item Icon-FESs (TW) had high internal consistency. The 30- and 10-item Icon-FESs (TW) exhibited significantly high correlation with the FES-I (r = 0.88 and 0.84, respectively). Both versions of the Icon-FES (TW) exhibited mild correlation with the physical domain of the WHOQOL-BREF. The 30- and 10-item Icon-FESs (TW) discriminated by intensity of concern and SPPB score. Their test–retest reliability was high (intraclass correlation coefficient = 0.79 and 0.80 for the 30- and 10-item Icon-FESs (TW), respectively). Neither floor nor ceiling effects were observed. Conclusion: The Icon-FES (TW) is a reliable and valid questionnaire useful for assessing the levels of concern regarding falling among older adults in clinical practice and research.

Objective To evaluate the effectiveness of retrograde tibial intramedullary nail (RTN) in addressing nonunion in the distal one-fourth of the tibia. Methods This retrospective study included consecutive patients who were treated with RTN for nonunion in the distal one-fourth of the tibia between December 2020 and August 2023. Data regarding age, sex, injury mechanism, fracture type, initial fixation method, nonunion duration and type, risk factors, surgical duration, hospital stay, time to bone union, ankle function at final follow-up, and any complications were extracted from hospital records and analysed. Results Five patients in total were included, with previous treatments comprising locking plates and/or external fixation. The mean duration of RTN surgery was 94.0 ± 13.7 min, and mean duration of hospital stay was 9.8 ± 1.9 days. Patients were monitored for 10–18 months post RTN, achieving complete bone healing within a mean of 4.8 months. At the latest follow-up, the mean American Orthopedic Foot and Ankle Society (AOFAS) score was 84.4 ± 6.8 (range, 77–95). No complications, such as infection, reoperation, implant issues, rotational deformity, or shortening were reported. Conclusion RTN emerges as a dependable, minimally invasive, and safe treatment modality for managing nonunion in the distal one-fourth of the tibia.

To examine flavor variations in Xuanwei ham due to different cooking methods, we selected one-year cured Xuanwei ham and applied four techniques: dry frying (DF), baking (BA), steaming (ST), and boiling (BO). Organoleptic evaluation revealed ST received the highest overall sensory score. High-performance liquid chromatography (HPLC) revealed that the total nucleotide content was significantly different (P 1). This study aimed to support comprehensive research on the flavor characteristics of cooked Xuanwei ham and guide the selection of appropriate processing methods.

Abstract Background and Aims Small‐for‐gestational‐age (SGA) newborns have a higher risk of morbidity and mortality. Recognizing the risk factors for SGA helps raise early awareness of the issue and provides valuable insights for both healthcare providers and pregnant women. We aimed to identify determinants of SGA using population‐based databases in Taiwan. Methods Data were retrieved from the National Health Insurance, Birth Reporting, and Maternal and Child Health databases for this nationwide case‐control study. Live births between 20 and 44 weeks of gestation from 2005 to 2014 were enrolled and linked to their mothers to determine maternal conditions during pregnancy. For every SGA newborn, four controls matched by gestational age and birth year were randomly selected. Multivariable logistic regression was used to identify risk factors for SGA, with adjusted odds ratios (aORs) and 95% confidence intervals (CIs) accounting for potential confounders and interaction terms. Results A total of 158,405 live SGA births were identified, with 623,584 controls randomly selected. Independent risk factors for SGA included maternal age

Ratiometric DNA biosensors, which utilize DNA as the recognition element and integrate dual signals from diverse sensing platforms including fluorescence, electrochemistry, and surface-enhanced Raman scattering (SERS), have demonstrated remarkable proficiency in detecting a wide range of targets. In this review, we showcase the significant progress achieved by ratiometric biosensors. Firstly, ratiometric biosensors have made notable advancements in analyzing real samples. These include the analysis of pH values near cancer cells, quantification of miRNA in human cell lysates, detection of human telomerase RNA in cell extracts, and performing DNA logic-gated in situ bioimaging on cell membranes. Secondly, excellent sensitivity has been attained through the utilization of effective amplification methods such as RCA, HCR, and CHA, among others. Thirdly, the construction of stable reference signals has resulted in significantly improved precision for ratiometric biosensors. This breakthrough has overcome matrix effects, enabling reliable detection in real samples with high selectivity. This review provides a comprehensive overview of recent advancements in strategies employed by ratiometric DNA biosensors. We present three types of biosensors based on distinct sensing platforms: fluorescent, electrochemical, and SERS biosensors. Additionally, we discuss future directions and primary challenges in the development of ratiometric DNA biosensors.

Abstract Dietary trans 10, cis 12-conjugated linoleic acid (t10c12-CLA) is a potential candidate in anti-obesity trials. A transgenic mouse was previously successfully established to determine the anti-obesity properties of t10c12-CLA in male mice that could produce endogenous t10c12-CLA. To test whether there is a different impact of t10c12-CLA on lipid metabolism in both sexes, this study investigated the adiposity and metabolic profiles of female Pai mice that exhibited a dose-dependent expression of foreign Pai gene and a shift of t10c12-CLA content in tested tissues. Compared to their gender-match wild-type littermates, Pai mice had no fat reduction but exhibited enhanced lipolysis and thermogenesis by phosphorylated hormone-sensitive lipase and up-regulating uncoupling proteins in brown adipose tissue. Simultaneously, Pai mice showed hepatic steatosis and hypertriglyceridemia by decreasing gene expression involved in lipid and glucose metabolism. Further investigations revealed that t10c10-CLA induced excessive prostaglandin E2, adrenaline, corticosterone, glucagon and inflammatory factors in a dose-dependent manner, resulting in less heat release and oxygen consumption in Pai mice. Moreover, fibroblast growth factor 21 overproduction only in monoallelic Pai/wt mice indicates that it was sensitive to low doses of t10c12-CLA. These results suggest that chronic t10c12-CLA has system-wide effects on female health via synergistic actions of various hormones.

Abstract Biosynthesis of paclitaxel (Taxol™) is a hot topic with extensive and durable interests for decades. However, it is severely hindered due to the very low titers of intermediates. In this study, Escherichia coli was employed to de novo synthesize a key intermediate of paclitaxel, taxadien-5α-yl-acetate (T5OAc). Plasmid-based pathway reconstruction and optimization were conducted for T5OAc production. The endogenous methylerythritol phosphate pathway was enhanced to increase the precursor supply. Three taxadien-5α-ol O-acetyltransferases were tested to obtain the best enzyme for the acetylation step. Metabolic burden was relieved to restore cell growth and promote production through optimizing the plasmid production system. In order to achieve metabolic balance, the biosynthesis pathway was regulated precisely by multivariate-modular metabolic engineering. Finally, in a 5-L bioreactor, the T5OAc titer was enhanced to reach 10.9 mg/L. This represents an approximately 272-fold increase in production compared to the original strain, marking the highest yield of T5OAc ever documented in E. coli, which is believed to be helpful for promoting the progress of paclitaxel biosynthesis.

Abstract Background Although indicator condition (IC)-guided HIV testing (IC-HIVT) is effective at facilitating timely HIV diagnosis, research on IC categories and the related HIV risk in Taiwan is limited. To improve the adoption and spread of IC-HIVT in Taiwan, this study compared the IC categories of people living with HIV (PLWH) and non-HIV controls and investigated delays in the diagnosis of HIV infection. Methods This nationwide, retrospective, 1:10-matched case–control study analyzed data from the Notifiable Diseases Surveillance System and National Health Insurance Research Database to evaluate 42 ICs for the 5-year period preceding a matched HIV diagnostic date from 2009 to 2015. The ICs were divided into category 1 ICs (AIDS-defining opportunistic illnesses [AOIs]), category 2 ICs (diseases associated with impaired immunity or malignancy but not AOIs), category 3 ICs (ICs associated with sexual behaviors), and category 4 ICs (mononucleosis or mononucleosis-like syndrome). Logistic regression was used to evaluate the HIV risk associated with each IC category (at the overall and annual levels) before the index date. Wilcoxon rank-sum test was performed to assess changes in diagnostic delays following an incident IC category by HIV transmission routes. Results Fourteen thousand three hundred forty-seven PLWH were matched with 143,470 non-HIV controls. The prevalence results for all ICs and category 1–4 ICs were, respectively, 42.59%, 11.16%, 15.68%, 26.48%, and 0.97% among PLWH and 8.73%, 1.05%, 4.53%, 3.69%, and 0.02% among non-HIV controls (all P

Background/purpose: An increasing body of evidence indicates correlations between the symptoms of temporomandibular disorder and those of eating disorder (ED). However, further investigation is required to elucidate the temporal and causal relationships between the aforementioned disorders. Materials and methods: This retrospective cohort study was conducted using data from the Taiwan National Health Insurance Research Database. Temporomandibular joint disorder (TMJD) was analyzed both as the cause and consequence of ED. We collected the data (from January 1, 1998, to December 31, 2011) of patients with antecedent TMJD (N = 15,059) or ED (N = 1219) and their respective controls (1:10), matched by age, sex, income level, residential location, and comorbidities. This study included patients who had received a new diagnosis of an ED or a TMJD between January 1, 1998, and December 31, 2013. Cox regression models were used to assess the risk of ED or TMJD development in patients with antecedent TMJD or ED. Results: TMJD patients had an approximately 3.70-fold (95 % confidence interval [CI]: 1.93–7.10) risk of ED development. Similarly, patients with ED had an approximately 4.78-fold (95 % CI: 2.52–9.09) risk of TMJD development. Subgroup analyses based on ED subtypes indicated antecedent TMJD and bulimia nervosa as the predictors of increased bulimia nervosa and TMJD risks (hazard ratios: 6.41 [95 % CI: 2.91 to 14.11] and 5.84 [95 % CI: 2.75 to 12.41]), respectively. Conclusion: Previous TMJD and ED are associated with increased risks of subsequent ED and TMJD; these findings suggest the presence of a bidirectional temporal association between TMJD and ED.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play a role in this process. Pathogens could interfere with transepithelial Cl− transport via impairment of the cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function, Cl− transport and the robust inflammatory response remain to be elucidated. Here, we have demonstrated that E protein down-regulated the expression of tight junctional proteins, leading to the disruption of the airway epithelial barrier. In addition, E protein triggered the activation of Toll-like receptor (TLR) 2/4 and downstream c-Jun N-terminal kinase (JNK) signaling, resulting in an increased intracellular Cl− concentration ([Cl−]i) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl−]i contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E protein. Overall, these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 infection.

Background & Aims: Effective anti-fibrotic drugs and new non-invasive evaluation methods for liver fibrosis (LF) are urgently needed. Our study aimed to evaluate the histological effects of the Qizhu (QZ) formula on LF and to explore a non-invasive Near-infrared photoacoustic imaging (NIR-PAI) kinetic model for liver function detection and pharmacodynamic evaluation. Methods: C57BL/6 J mice were randomly divided into six groups (n=6). An LF model was induced by CCl4 for 8 weeks, followed by an 8-week treatment period. Histological and serological parameters were assessed, and indocyanine green (ICG) metabolism (maximum peak time [Tmax] and half-life [T1/2]) was monitored by NIR-PAI. Spearman correlation analysis was conducted to evaluate correlations. Results & Conclusions: Histological and serological results confirmed the anti-fibrotic effects of QZ. NIR-PAI kinetic parameters indicated that QZ shortened the Tmax and T1/2 of ICG. There were good correlations between ICG metabolism and liver histopathology. The non-invasive NIR-PAI kinetic model shows potential in liver function detection and pharmacodynamic evaluation.

ABSTRACTOur objective was to assess the impact of fortified high-dose docosahexaenoic acid (DHA) and arachidonic acid (ARA) in infant formula powders (IFs) on stability. We compared and evaluated the stability of IFs containing high and low doses of DHA and ARA over a 6-month storage period at 37°C. While most formulations showed minimal changes in unsaturated fatty acid content of during storage, significant losses of DHA and ARA were observed in some high-dose formulations. Furthermore, this study noted consistent trends in the changes of vitamin C and vitamin E across both formula groups. Notably, the high-dose group formulas exhibited a higher presence of volatile organic compounds (VOCs) during storage, along with a more pronounced increase in thiobarbituric acid-reactive substance values (TBARS). In conclusion, the inclusion of high doses of DHA and ARA in IFs may compromise their oxidative stability.

Abstract Endothelial dysfunction is a critical feature of acute respiratory distress syndrome (ARDS) associated with higher disease severity and worse outcomes. Preclinical in vivo models of sepsis and ARDS have failed to yield useful therapies in humans, perhaps due to interspecies differences in inflammatory responses and heterogeneity of human host responses. Use of microphysiological systems (MPS) to investigate lung endothelial function may shed light on underlying mechanisms and targeted treatments for ARDS. We assessed the response to plasma from critically ill sepsis patients in our lung endothelial MPS through measurement of endothelial permeability, expression of adhesion molecules, and inflammatory cytokine secretion. Sepsis plasma induced areas of endothelial cell (EC) contraction, loss of cellular coverage, and luminal defects. EC barrier function was significantly worse following incubation with sepsis plasma compared to healthy plasma. EC ICAM‐1 expression, IL‐6 and soluble ICAM‐1 secretion increased significantly more after incubation with sepsis plasma compared with healthy plasma. Plasma from sepsis patients who developed ARDS further increased IL‐6 and sICAM‐1 compared to plasma from sepsis patients without ARDS and healthy plasma. Our results demonstrate the proof of concept that lung endothelial MPS can enable interrogation of specific mechanisms of endothelial dysfunction that promote ARDS in sepsis patients.

BackgroundCircadian rhythm disruptions are a common concern for poststroke patients undergoing rehabilitation and might negatively impact their functional outcomes. ObjectiveOur research aimed to uncover unique patterns and disruptions specific to poststroke rehabilitation patients and identify potential differences in specific rest-activity rhythm indicators when compared to inpatient controls with non–brain-related lesions, such as patients with spinal cord injuries. MethodsWe obtained a 7-day recording with a wearable actigraphy device from 25 poststroke patients (n=9, 36% women; median age 56, IQR 46-71) and 25 age- and gender-matched inpatient control participants (n=15, 60% women; median age 57, IQR 46.5-68.5). To assess circadian rhythm, we used a nonparametric method to calculate key rest-activity rhythm indicators—relative amplitude, interdaily stability, and intradaily variability. Relative amplitude, quantifying rest-activity rhythm amplitude while considering daily variations and unbalanced amplitudes, was calculated as the ratio of the difference between the most active 10 continuous hours and the least active 5 continuous hours to the sum of these 10 and 5 continuous hours. We also examined the clinical correlations between rest-activity rhythm indicators and delirium screening tools, such as the 4 A’s Test and the Barthel Index, which assess delirium and activities of daily living. ResultsPatients who had a stroke had higher least active 5-hour values compared to the control group (median 4.29, IQR 2.88-6.49 vs median 1.84, IQR 0.67-4.34; P=.008). The most active 10-hour values showed no significant differences between the groups (stroke group: median 38.92, IQR 14.60-40.87; control group: median 31.18, IQR 18.02-46.84; P=.93). The stroke group presented a lower relative amplitude compared to the control group (median 0.74, IQR 0.57-0.85 vs median 0.88, IQR 0.71-0.96; P=.009). Further analysis revealed no significant differences in other rest-activity rhythm metrics between the two groups. Among the patients who had a stroke, a negative correlation was observed between the 4 A’s Test scores and relative amplitude (ρ=–0.41; P=.045). Across all participants, positive correlations emerged between the Barthel Index scores and both interdaily stability (ρ=0.34; P=.02) and the most active 10-hour value (ρ=0.42; P=.002). ConclusionsThis study highlights the relevance of circadian rhythm disruptions in poststroke rehabilitation and provides insights into potential diagnostic and prognostic implications for rest-activity rhythm indicators as digital biomarkers.

Ceftolozane, a novel cephalosporin, combined with tazobactam, a known β-lactamase inhibitor, shows robust antipseudomonal activity, although it doesn't cover carbapenemases. Our review of data from 2012 to 2021 in Taiwan highlights TOL/TAZ's in-vitro performance.TOL/TAZ is most effective against Pseudomonas aeruginosa (91.3–94.4 % susceptible, with an MIC