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Long-term dynamic adaptation of multiple myeloma cells to the acidic extracellular microenvironment
No full text[[abstract]]Multiple myeloma (MM) is the second most common blood cancer worldwide. Although significant improvements have been made with introduction of novel agents, relapsed or refractory MM is almost inevitable after a progression-free period. Unlike other hematological cancers, MM is often immersed in an acidic pH microenvironment. Few studies have attempted to address the acute impact of microenvironmental acidification on MM cells, but little is known about how tumor cells could sense, respond, reprogram, and ultimately adapt to the prolonged acidotic stress. Here, we generated and established a series of MM cell lines exposed to different time periods of extracellular acidity. We observed a distinct and long-term process of reversible adaptive eplasticity in acid-treated MM cells with altered proliferative responses, metabolic phenotype switches, reprogrammed mitochondrial dynamics and lipid droplet formation. Thirty-four target molecules were further identified to be significantly associated with the overall survival of MM patients - most of these were previously unable to be screened and detected by short-term analyses of the effects of microenvironmental acidity on MM cell
Percutaneous coronary intervention with a drug-eluting stent is associated with better survival than coronary artery bypass grafting in patients on peritoneal dialysis in Taiwan
No full text[[abstract]]Background: The optimal revascularization strategy for coronary artery disease in patients under peritoneal dialysis (PD) is unclear. Recently, we reported that percutaneous coronary intervention (PCI) with a drug-eluting stent (DES) is associated with better survival than coronary artery bypass grafting (CABG) in patients under either hemodialysis or PD. We aim to perform a dedicated subgroup analysis to study the comparative effectiveness in patients under PD. Methods:This retrospective population-based cohort study included PD patients hospitalized for either CABG or PCI with a DES between January 1, 2009, and December 31, 2015, identified in the Taiwan National Health Insurance Research Database. Inverse probability of treatment weighting was used to balance the baseline characteristics. Multivariable logistic regression models and Cox proportional hazard models were used to examine the risks of in-hospital mortality and long-term survival, respectively. Results: From the 4,165 dialysis patients in our cohort, we selected 333 PD patients receiving either CABG (86 patients) or PCI with a DES (247 patients) for analysis. Compared with patients receiving PCI with a DES, the risk of in-hospital mortality was significantly higher in patients receiving CABG [adjusted odds ratio, 5.70; 95% confidence interval (CI) 1.42-22.83; P = 0.014]. The overall mortality was also significantly higher in patients receiving CABG [adjusted hazard ratio, 1.53; 95% CI 1.13-2.08; P = 0.006]. The long-term mortality hazard associated with CABG remained consistent in several sensitivity analyses (Figure 1). Conclusion: CABG was associated with both higher in-hospital and long-term mortality than PCI with a DES in our national cohort of Taiwan PD patients
Harnessing electronic health records and artificial intelligence for enhanced cardiovascular risk prediction: A comprehensive review
No full text[[abstract]]Electronic health records (EHR) have revolutionized cardiovascular disease (CVD) research by enabling comprehensive, large-scale, and dynamic data collection. Integrating EHR data with advanced analytical methods, including artificial intelligence (AI), transforms CVD risk prediction and management methodologies. This review examines the advancements and challenges of using EHR in developing CVD prediction models, covering traditional and AI-based approaches. While EHR-based CVD risk prediction has greatly improved, moving from models that integrate real-world data on medication use and imaging, challenges persist regarding data quality, standardization across health care systems, and geographic variability. The complexity of EHR data requires sophisticated computational methods and multidisciplinary approaches for effective CVD risk modeling. AI's deep learning enhances prediction performance but faces limitations in interpretability and the need for validation and recalibration for diverse populations. The future of CVD risk prediction and management increasingly depends on using EHR and AI technologies effectively. Addressing data quality issues and overcoming limitations from retrospective data analysis are critical for improving the reliability and applicability of risk prediction models. Integrating multidimensional data, including environmental, lifestyle, social, and genomic factors, could significantly enhance risk assessment. These models require continuous validation and recalibration to ensure their adaptability to diverse populations and evolving health care environments, providing reassurance about their reliability
Characterization of the binding features between SARS-CoV-2 5'-proximal transcripts of genomic RNA and nucleocapsid proteins
No full text[[abstract]]Packaging signals (PSs) of coronaviruses (CoVs) are specific RNA elements recognized by nucleocapsid (N) proteins that direct the selective packaging of genomic RNAs (gRNAs). These signals have been identified in the coding regions of the nonstructural protein 15 (Nsp 15) in CoVs classified under Embecovirus, a subgenus of betacoronaviruses (beta-CoVs). The PSs in other alpha- and beta-CoVs have been proposed to reside in the 5'-proximal regions of gRNAs, supported by comprehensive phylogenetic evidence. However, experimental data remain limited. In this study, we investigated the interactions between Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) 5'-proximal gRNA transcripts and N proteins using electrophoretic mobility shift assays (EMSAs). Our findings revealed that the in vitro synthesized 5'-proximal gRNA transcripts of CoVs can shift from a major conformation to alternative conformations. We also observed that the conformer comprising multiple stem-loops (SLs) is preferentially bound by N proteins. Deletions of the 5'-proximal structural elements of CoV gRNA transcripts, SL1 and SL5a/b/c in particular, were found to promote the formation of alternative conformations. Furthermore, we identified RNA-binding peptides from a pool derived from SARS-CoV N protein. These RNA-interacting peptides were shown to preferentially bind to wild-type SL5a RNA. In addition, our observations of N protein condensate formation in vitro demonstrated that liquid-liquid phase separation (LLPS) of N proteins with CoV-5'-UTR transcripts was influenced by the presence of SL5a/b/c. In conclusion, these results collectively reveal previously uncharacterized binding features between the 5'-proximal transcripts of CoV gRNAs and N proteins
Endothelial serotonin receptor 1B acts as a mechanosensor to drive atherosclerosis
No full text[[abstract]]BACKGROUND: Atherosclerosis is characterized by the accumulation of fatty and fibrotic plaques, which preferentially develop at curvatures and branches along the arterial trees that are exposed to disturbed flow. However, the mechanisms by which endothelial cells sense disturbed flow are still unclear. METHODS: The partial carotid ligation mouse model was used to investigate disturbed flow-induced atherogenesis. In vitro experiments were performed using the ibidi system to generate oscillatory shear stress and laminar shear stress. ApoE(-/-) mice with endothelium-specific knockout or overexpression of 5-HT(1B) (serotonin receptor 1B) were used to investigate the role of endothelial 5-HT(1B) in atherosclerosis. RNA sequencing analysis, immunofluorescence analysis, and molecular biological techniques were used to explore the role of 5-HT(1B) in mechanotransduction and endothelial activation. RESULTS: The data showed that human endothelial cells express a high level of 5-HT(1B), which is a serotonin receptor subtype. Endothelial 5-HT(1B) is upregulated in atherosclerotic areas of both humans and rodents and is increased by disturbed flow both in vivo and in vitro. Endothelium-specific overexpression of 5-HT(1B) exacerbates, whereas knockout or knockdown of 5-HT(1B) in endothelium inhibits disturbed flow-induced endothelial inflammation and atherogenesis in both male and female ApoE(-/-) mice. We reveal a previously unknown role of 5-HT(1B) as a mechanosensor in endothelial cells in response to mechanical stimuli. Upon activation by oscillatory shear stress, 5-HT(1B) recruits β-arrestin, orchestrates RhoA, and then activates mechanosensitive YAP (yes-associated protein), thereby enhancing endothelial inflammation and monocyte infiltration. Pharmacological blockade of 5-HT(1B) suppresses endothelial activation and atherogenesis via inhibition of YAP. CONCLUSIONS: Taken together, these results uncover that endothelial 5-HT(1B) acts as a mechanosensor for disturbed flow and contributes to atherogenesis. Inhibition of 5-HT(1B) could be a promising therapeutic strategy for atherosclerosis
Association between short-term ambient air pollution and psoriasis: A time-stratified case-crossover study
No full text[[abstract]]This time-stratified case-crossover study evaluated the association between short-term exposure to ambient air pollution and psoriasis. A total of 107 462 psoriasis cases between 2002 and 2016 were retrieved from Taiwan's National Health Insurance Research Database. Conditional logistic regression was used to estimate the association between air pollutants (O(3), CO, NO(2), SO(2), PM(2.5), and PM(10)) and psoriasis with each interquartile range (IQR) increase. Consistent associations for psoriasis for each IQR increase in NO(2) and CO exposure were noted at lag 0 both in single-pollutant and multiple-pollutant model. Exposure on lag 0 had the highest odds ratio (OR), decreasing consecutively from lag 1 to lag 3. Both NO(2) and CO had a stronger influence among men, older patients (>60 years old), and patients with chronic disease. Short-term NO(2) and CO exposure was associated with psoriasis. This link might provide insights into how air pollution, at least in part, affects the epidemiology and pathogenesis of psoriasis
Risk factors and economic impact of long-term nursing care after major trauma
No full text[[abstract]]Introduction The public could bear a heavy economic burden for trauma survivors needing long-term nursing care, especially in countries such as Taiwan that have universal health insurance coverage. The purpose of this study was to analyze the data from the National Health Insurance Research Database and to assess reimbursement to trauma patients with long-term sequelae who need nursing care. Methods This study included all patients who suffered major trauma (injury severity score >= 16) in Taiwan from 2003 to 2007. Ten years of follow-up were analyzed. Patients aged 18 to 70 who survived for more than 1 year after the index admission were enrolled. Patients who needed long-term nursing care (LTC) were compared with those who did not (non-LTC). Basic demographics and short-term outcomes were analyzed, and the 10-year healthcare expenditure was calculated. Results The study included 10,642 patients, 1,718 in the LTC group and 8,924 in the non-LTC group. Age, comorbidities, spinal cord injury, longer mechanical ventilation, longer ICU length of stay (LOS), and longer hospital LOS were identified as independent risk factors for LTC. The median 10-year healthcare expenditure was 43,979 USD in the LTC group vs. 9,057 USD in the non-LTC group (p < 0.001). Conclusions 16.14% of major trauma patients needed LTC at least 1 year after being discharged. The resource they receive in Taiwan is prominently less than the same patient group in the US. The NHI should invest more in post-discharge care for major trauma patients to optimize their care
Calcium impregnated Silica gel in the domino reaction involving irreversible aldol addition, dehydration, and michael addition
No full text[[abstract]]An innovative method was developed for the performance of aldol additions in an irreversible fashion by the use of calcium metal impregnated silica gel (Ca@SiO2) as a remarkable reducing reagent. In this approach, Ca@SiO2 drove the reaction forward, prevented reversibility, and ensured the formation of the desired products. Thus, in the presence of Ca@SiO2 (3.0 equiv), aldehydes (1.0 equiv) condensed with ketones (1.0 equiv) in 2-MeTHF to yield alpha,beta-unsaturated enones in 71-90% yields at 25 degrees C. Additionally, a domino reaction involving successive aldol addition, dehydration, and Michael addition was developed for the preparation of 1,5-diketones. Accordingly, when aldehydes (1.0 equiv) were allowed to react with ketones (2.2 equiv) and Ca@SiO2(4.0 equiv), 1,5-diketones were produced in 67-88% yields. These reactions involved radical processes, where Ca@SiO2 abstracted two alpha hydrogen atoms from ketones and the oxygen atom from aldehydes to form CaH2@SiO2 and CaO@SiO2, respectively. These species were confirmed by powder X-ray diffraction analysis. The resultant impregnated silica gel species were solid and insoluble in the reaction mixtures, which made the addition reactions irreversible. This method represents a significant advancement in aldol condensation reactions and offers the advantages of both atom economy and atom efficiency
Functional and microstructural neurosubstrates between apathy and depressive symptoms in dementia
No full text[[abstract]]The overlapping features of depressive symptoms and apathy hinder their differentiation in clinical practice, and hence a greater understanding of their neurosubstrates in dementia and its subtypes is necessary. Ninety-two dementia patients (Alzheimer's disease [AD, n = 52]; subcortical ischemic vascular disease [SIVD, n = 40]), and 30 cognitively normal subjects were evaluated using the Apathy Evaluation Scale (AES), Beck's Depression Inventory (BDI), and brain magnetic resonance imaging (MRI). Grouped by AES/BDI scores, and hubs of depression/apathy were identified by comparing MRI metrics including fractional amplitude of low-frequency fluctuation (fALFF) of resting-state functional MRI, and mean kurtosis (MK) of diffusion kurtosis imaging. Associations between the hubs with depressive and apathy symptoms were analyzed. Comparing low-AES and high-AES groups, fALFF indicated pervasive changes mainly within the default mode network (DMN) and frontoparietal network (FPN). Comparing low-BDI and high-BDI groups, fALFF reflected changes within the DMN, FPN, and salience network (SAN). Contrarily, MK showed focal changes within DMN and SAN regions from the same group-wise comparisons. While fALFF was more correlated with DMN/FPN for AES than BDI and more significantly correlated with SIVD than AD, MK was more correlated with the left anterior cingulate cortex and right insula for AES than BDI, but more significantly correlated with AD than SIVD (all P < 0.01). Topologically, the fALFF hubs for AES and BDI centered at the posterior and anterior poles, respectively. These findings suggest that dual-modal MRI could reflect the distinct neuropathological basis for apathy and depressive symptoms in AD and SIVD
Deletion of RAP1 affects iron homeostasis, azole resistance, and virulence in Candida albicans
No full text[[abstract]]Rap1 is a DNA-binding protein conserved from yeast to mammals for its role in telomeric maintenance. Here, to explore additional functions of Candida albicans Rap1, we performed RNA sequencing analysis. Experimental validations further showed that Rap1 plays a role in iron regulation, especially under low-iron conditions. Moreover, Rap1 was involved in iron acquisition and modulation of iron-related genes. Rap1 was found to be associated with fluconazole resistance in a low-iron condition. Finally, we demonstrated that the deletion of RAP1 leads to reduced C. albicans virulence in a mouse model of infection. Together, this study reveals new functions of C. albicans Rap1, particularly in iron homeostasis, azole resistance, and virulence.IMPORTANCECandida albicans is an important pathogenic fungus that can cause superficial to life-threatening infections. Iron is essential for almost all organisms, yet it is highly restricted within the human host to defend against pathogens. To grow and survive in the iron-limited host environment, C. albicans has evolved multiple iron acquisition mechanisms. Understanding the regulation of iron homeostasis is, therefore, critical for elucidating C. albicans pathogenesis and virulence. This study explores the novel functions of C. albicans Rap1, with a focus on its contribution to iron acquisition and utilization. Our findings further highlight how iron availability impacts antifungal resistance and virulence through Rap1, providing insight into the complex iron regulatory machinery of C. albicans