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Abstract Background Studies have found that in healthy individuals without nasal disease, changes in posture cause an increase in nasal resistance, especially in the prone posture. Many patients with obstructive sleep apnea syndrome (OSAS) sleep in a prone posture, but no studies have examined the effect of this change in posture on nasal resistance in patients with OSAS. Therefore, we conducted this study to investigate this posture-related physical phenomenon in individuals with OSAS. Methods We evaluated the nasal patency of 29 patients diagnosed with OSAS using the visual analog scale (VAS), acoustic rhinometry, and video-endoscopy in the sitting, supine, and prone postures. Results In the OSAS group, both supine and prone postures significantly influenced subjective nasal blockage and led to a notable reduction in the minimal cross-sectional area (mCSA) as determined by acoustic rhinometry, compared to the sitting posture. The prone posture exhibited a more pronounced effect than the supine posture. Endoscopic evaluations further revealed increased hypertrophy of the inferior turbinate in the supine posture for the right nasal passage and the prone posture for the left. However, no significant differences were observed between the prone and supine postures. Conclusion In OSAS patients, nasal resistance significantly increased in supine and prone postures compared to sitting, with the prone posture showing a greater effect. Clinicians should consider a patient’s habitual sleep posture and the effects of postural changes when assessing OSAS severity and devising treatment plans. Level of Evidence 4.

Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its irreversible destructive impact on the joints. Chondrocytes play a pivotal role in the production and maintenance of the cartilage matrix. However, the presence of inflammatory cytokines can hinder chondrocyte proliferation and promote apoptosis. Isoliquiritigenin (ISL), a flavonoid, potentially exerts protective effects against various inflammatory diseases. However, its specific role in regulating the nuclear factor E2-associated factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in chondrocytes in RA remains unclear. To investigate this, this study used human chondrocytes and Sprague-Dawley rats to construct in vitro and in vivo RA models, respectively. The study findings reveal that cytokines markedly induced oxidative stress, the activation of matrix metalloproteinases, and apoptosis both in vitro and in vivo. Notably, ISL treatment significantly mitigated these effects. Moreover, Nrf2 or HO-1 inhibitors reversed the protective effects of ISL, attenuated the expression of Nrf2/HO-1 and peroxisome proliferator-activated receptor gamma-coactivator-1α, and promoted chondrocyte apoptosis. This finding indicates that ISL primarily targets the Nrf2/HO-1 pathway in RA chondrocytes. Moreover, ISL treatment led to improved behavior scores, reduced paw thickness, and mitigated joint damage as well as ameliorated oxidative stress in skeletal muscles in an RA rat model. In conclusion, this study highlights the pivotal role of the Nrf2/HO-1 pathway in the protective effects of ISL and demonstrates the potential of ISL as a treatment option for RA.

Atrial fibrillation (AF), characterized by structural remodeling involving atrial myocardial degradation and fibrosis, is linked with obesity and transforming growth factor beta 1 (TGF-β1). Aldehyde dehydrogenase 2 (ALDH2) deficiency, highly prevalent in East Asian people, is paradoxically associated with a lower AF risk. This study investigated the impact of ALDH2 deficiency on diet-induced obesity and AF vulnerability in mice, exploring potential compensatory upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme-oxygenase 1 (HO-1). Wild-type (WT) and ALDH2*2 knock-in (KI) mice were administered a high-fat diet (HFD) for 16 weeks. Despite heightened levels of reactive oxygen species (ROS) post HFD, the ALDH2*2 KI mice did not exhibit a greater propensity for AF compared to the WT controls. The ALDH2*2 KI mice showed equivalent myofibril degradation in cardiomyocytes compared to WT after chronic HFD consumption, indicating suppressed ALDH2 production in the WT mice. Atrial fibrosis did not proportionally increase with TGF-β1 expression in ALDH2*2 KI mice, suggesting compensatory upregulation of the Nrf2 and HO-1 pathway, attenuating fibrosis. In summary, ALDH2 deficiency did not heighten AF susceptibility in obesity, highlighting Nrf2/HO-1 pathway activation as an adaptive mechanism. Despite limitations, these findings reveal a complex molecular interplay, providing insights into the paradoxical AF–ALDH2 relationship in the setting of obesity.

Gynecologic tract melanoma is a malignant tumor with poor prognosis. Because of the low survival rate and the lack of a standard treatment protocol related to this condition, the investigation of the mechanisms underlying melanoma progression is crucial to achieve advancements in the relevant gynecological surgery and treatment. Mitochondrial transfer between adjacent cells in the tumor microenvironment regulates tumor progression. This study investigated the effects of endothelial mitochondria on the growth of melanoma cells and the activation of specific signal transduction pathways following mitochondrial transplantation. Mitochondria were isolated from endothelial cells (ECs) and transplanted into B16F10 melanoma cells, resulting in the upregulation of proteins associated with tumor growth. Furthermore, enhanced antioxidation and mitochondrial homeostasis mediated by the Sirt1-PGC-1α-Nrf2-HO-1 pathway were observed, along with the inhibition of apoptotic protein caspase-3. Finally, the transplantation of endothelial mitochondria into B16F10 cells promoted tumor growth and increased M2-type macrophages through Nrf2/HO-1-mediated pathways in a xenograft animal model. In summary, the introduction of exogenous mitochondria from ECs into melanoma cells promoted tumor growth, indicating the role of mitochondrial transfer by stromal cells in modulating a tumor’s phenotype. These results provide valuable insights into the role of mitochondrial transfer and provide potential targets for gynecological melanoma treatment.

Exosomes containing glucose-regulated protein 78 (GRP78) are involved in cancer malignancy. GRP78 is thought to promote the tumor microenvironment, leading to angiogenesis. No direct evidence for this role has been reported, however, mainly because of difficulties in accurately measuring the GRP78 concentration in the exosomes. Recently, exosomal GRP78 concentrations were successfully measured using an ultrasensitive ELISA. In the present study, GRP78 concentrations in exosomes collected from gastric cancer AGS cells with overexpression of GRP78 (OE), knockdown of GRP78 (KD), or mock GRP78 (mock) were quantified. These three types of exosomes were then incubated with vascular endothelial cells to examine their effects on endothelial cell angiogenesis. Based on the results of a tube formation assay, GRP78-OE exosomes accelerated angiogenesis compared with GRP78-KD or GRP78-mock exosomes. To investigate the mechanisms underlying this effect, we examined the Ser473 phosphorylation state ratio of AKT, which is involved in the angiogenesis process, and found that AKT phosphorylation was increased by GRP78-OE exosome application to the endothelial cells. An MTT assay showed that GRP78-OE exosome treatment increased the proliferation rate of endothelial cells, and a wound healing assay showed that this treatment increased the migration capacity of the endothelial cells. These findings demonstrated that GRP78-containing exosomes promote the tumor microenvironment and induce angiogenesis.

KCNH2 loss-of-function mutations cause long QT syndrome type 2 (LQT2), an inherited cardiac disorder associated with life-threatening ventricular arrhythmia. Through whole-exome sequencing, we discovered a novel AGCGACAC deletion (S981fs) in the hERG gene of an LQT2 patient. Using a heterologous expression system and patch clamping, we found that the mutant K channel had reduced cell surface expression and lower current amplitude compared to the wild type. However, functional expression was restored by lowering temperature and using potassium channel inhibitors or openers (E4031, cisapride, nicorandil). Co-immunoprecipitation experiments confirmed the assembly of mutant proteins with wild-type hERG. Confocal imaging showed decreased hERG distribution on the cell membrane in cells expressing S981fs. Notably, treatment with G418 significantly increased hERG current in wild-type/S981fs heterozygotes. In conclusion, our study identifies a novel hERG mutation leading to impaired Kv11.1 function due to trafficking and nonsense-mediated RNA decay defects. These findings shed light on the mechanisms underlying LQT2 and offer potential therapeutic avenues.

Background: This study was to perform an economic evaluation to understand clinical outcomes and health resource use between hip fracture patients receiving hospital-based postfracture fracture liaison service (FLS) care and those receiving usual care (UC) in Taiwan. Methods: This cohort study included hospital-based data of 174 hip fracture patients who received FLS care (FLS group) from National Taiwan University Hospital, and 1697 propensity score-matched patients who received UC (UC group) of National Health Insurance claim-based data. Two groups had similar baseline characteristics but differed in hip fracture care after propensity score matching. Clinical outcomes included refracture-free survival (RFS), hip-refracture-free survival (HRFS), and overall survival (OS). Health resource use included inpatient, outpatient, and pharmacy costs within 2 years follow-up after the index of hip fracture. The economic evaluation of the FLS model was analyzed using the net monetary benefit regression framework based on the National Health Insurance perspective. Results: The FLS group had longer RFS than the UC group, with an adjusted difference of 44.3 days (95% confidence interval: 7.2–81.4 days). Two groups did not differ in inpatient and outpatient costs during follow-up, but the FLS group had a higher expenditure than the UC group on osteoporosis-related medication. The probability of FLS being cost-effective was >80% and of increasing RFS, HRFS, and OS was 95%, 81%, and 80%, respectively, when the willingness-to-pay threshold was >USD 65/gross domestic product per day. Conclusion: FLS care was cost-effective in reducing refracture occurrence days for patients initially diagnosed with hip fractures.

Chemotherapy is the treatment of choice for gastric cancer, but the currently available therapeutic drugs have limited efficacy. Studies have suggested that gastric cancer stem cells may play a key role in drug resistance in chemotherapy. Therefore, new agents that selectively target gastric cancer stem cells in gastric tumors are urgently required. Sirtuin-3 (SIRT3) is a deacetylase that regulates mitochondrial metabolic homeostasis to maintain stemness in glioma stem cells. Targeting the mitochondrial protein SIRT3 may provide a novel therapeutic option for gastric cancer treatment. However, the mechanism by which stemness is regulated through SIRT3 inhibition in gastric cancer remains unknown. We evaluated the stemness inhibition ability of the SIRT3 inhibitor 4′-bromo-resveratrol (4-BR), an analog of resveratrol in human gastric cancer cells. Our results suggested that 4-BR inhibited gastric cancer cell stemness through the SIRT3-c-Jun N-terminal kinase pathway and may aid in gastric cancer stem-cell–targeted therapy.

(1) Background: Physiological changes in nasal patency in response to posture contribute to sleep-related problems. Previously, we reported that the supine and prone positions cause a significant decrease in nasal patency in subjective and objective assessments of healthy individuals. Therefore, we conducted a study to evaluate the effect of posture on nasal patency in patients with allergic rhinitis (AR); (2) Methods: The present study comprised 30 patients diagnosed with AR and 30 healthy subjects without nasal disease (non-AR). Changes in nasal patency were evaluated in the sitting, supine, and prone positions. We used the visual analog scale to evaluate subjective nasal blockage. Acoustic rhinometry and endoscopy were used to objectively measure changes in nasal patency; (3) Results: In the non-AR group, the prone position had a significant effect on subjective nasal blockage compared with the sitting position, with significant decreases in the minimal cross-sectional area (mCSA) measured by acoustic rhinometry. Furthermore, endoscopy demonstrated a significantly increased inferior turbinate hypertrophy in the non-AR group. In the AR group, there was no statistical difference in subjective nasal blockage symptoms between the different positions. However, in objective examinations (acoustic rhinometry and endoscopy), the prone position showed significantly decreased nasal patency; (4) Conclusions: In patients with AR, subjective nasal blockage did not significantly increase in the supine or prone position. Endoscopy demonstrated increased inferior turbinate hypertrophy in supine and prone positions resulting in a significant reduction in nasal cavity mCSA, indicating an objective reduction in nasal patency.

Cancer stemness is the process by which cancer cells acquire chemoresistance and self-renewal in the tumor microenvironment. Glucose-regulated protein 78 (GRP78) is a biomarker for gastric cancer and is involved in cancer stemness. By inducing cancer stemness in various types of cancer, the polarization of macrophages into tumor-associated macrophages (TAMs) controls tumor progression. Betulinic acid (BA) is a bioactive natural compound with anticancer properties. However, whether GRP78 regulates TAM-mediated cancer stemness in the tumor microenvironment and whether BA inhibits GRP78-mediated cancer stemness in gastric cancer remain unknown. In this study, we investigated the role of GRP78 in gastric cancer stemness in a tumor microenvironment regulated by BA. The results indicated that BA inhibited not only GRP78-mediated stemness-related protein expression and GRP78-TGF-β-mediated macrophage polarization into TAMs, but also TAM-mediated cancer stemness. Therefore, BA is a promising candidate for clinical application in combination-chemotherapy targeting cancer stemness.

Viruses and bacteria, which can rapidly spread through droplets and saliva, can have serious effects on people’s health. Viral activity is traditionally inhibited using chemical substances, such as alcohol or bleach, or physical methods, such as thermal energy or ultraviolet-light irradiation. However, such methods cannot be used in many applications because they have certain disadvantages, such as causing eye or skin injuries. Therefore, in the present study, the electrical stimulation method is used to stimulate a virus, namely, coronavirus 229E, and two types of bacteria, namely, Escherichia coli and Staphylococcus aureus, to efficiently reduce their infectivity of healthy cells (such as the Vero E6 cell in a viral activity-inhibition experiment). The infectivity effects of the aforementioned virus and bacteria were examined under varying values of different electrical stimulation parameters, such as the stimulation current, frequency, and total stimulation time. The experimental results indicate that the activity of coronavirus 229E is considerably inhibited through direct-current pulse stimulation with a current of 25 mA and a frequency of 2 or 20 Hz. In addition, E. coli activity was reduced by nearly 80% in 10 s through alternating-current pulse stimulation with a current of 50 mA and a frequency of 25 Hz. Moreover, a self-powered electrical stimulation device was constructed in this study. This device consists of a solar panel and battery to generate small currents with variable frequencies, which has advantages of self-powered and variable frequencies, and the device can be utilized on desks, chairs, or elevator buttons for the inhibition of viral and bacterial activities.

Chemotherapy is the treatment of choice for gastric cancer; however, the currently available therapeutic drugs for treatment have limited efficacy. Cancer stemness and the tumor microenvironment may play crucial roles in tumor growth and chemoresistance. Glucose-regulated protein 78 (GRP78) is an endoplasmic reticulum chaperone facilitating protein folding and cell homeostasis during stress and may participate in chemoresistance. Isoliquiritigenin (ISL) is a bioactive flavonoid found in licorice. In this study, we demonstrated the role of GRP78 in gastric cancer stemness and evaluated GRP78-mediated stemness inhibition, tumor microenvironment regulation, and chemosensitivity promotion by ISL. ISL not only suppressed GRP78-mediated gastric cancer stem cell–like characteristics, stemness-related protein expression, and cancer-associated fibroblast activation but also gastric tumor growth in xenograft animal studies. The findings indicated that ISL is a promising candidate for clinical use in combination chemotherapy.

Cancer stem cells (CSCs) are subpopulations of tumor masses with unique abilities in self-renewal, stemness maintenance, drug resistance, and the promotion of cancer recurrence. Recent studies have suggested that breast CSCs play essential roles in chemoresistance. Therefore, new agents that selectively target such cells are urgently required. Reactive oxygen species (ROS)-producing enzymes are the reason for an elevated tumor oxidant status. The nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcriptional factor, which upon detecting cellular oxidative stress, binds to the promoter region of antioxidant genes. By triggering a cytoprotective response, Nrf2 maintains cellular redox status. Cripto-1 participates in the self-renewal of CSCs. Herein, luteolin, a flavonoid found in Taraxacum officinale extract, was determined to inhibit the expressions of stemness-related transcriptional factors, the ATP-binding cassette transporter G2 (ABCG2), CD44, aldehyde dehydrogenase 1 activity as well as the sphere formation properties of breast CSCs. Furthermore, luteolin suppressed the protein expressions of Nrf2, heme oxygenase 1 (HO-1), and Cripto-1 which have been determined to contribute critically to CSC features. The combination of luteolin and the chemotherapeutic drug, Taxol, resulted in enhanced cytotoxicity to breast cancer cells. These findings suggest that luteolin treatment significantly attenuated the hallmarks of breast cancer stemness by downregulating Nrf2-mediated expressions. Luteolin constitutes a potential agent for use in cancer stemness-targeted breast cancer treatments.

The use of a graphics processing unit (GPU) together with a CPU, referred as GPU-accelerated computing, to accelerate tasks that requires extensive computations has been the trends for last a few years in high performance computing. In this paper, we propose a new paradigm of GPU-accelerated method to parallelize extraction of a set of features based on the gray-level co-occurrence matrix (GLCM), which may be the most widely, used method. The method is evaluated on various GPU devices and compared with its serial counterpart implemented and optimized in both Matlab and C on a single machine. A series of experimental tests focused on magnetic resonance (MR) brain images demonstrate that the proposed method is very efficient and superior to its serial counterpart, as it could achieve more than 25-105 folds of speedup for single precision and more than 15-85 folds of speedup for double precision on Geforce GTX 1080 along different size of ROIs.

Indium tin oxide (ITO) is widely used as a substrate for fabricating chips because of its optical transparency, favorable chemical stability, and high electrical conductivity. However, the wettability of ITO surface is neutral (the contact angle was approximately 90°) or hydrophilic. For reagent transporting and manipulation in biochip application, the surface wettability of ITO-based chips was modified to the hydrophobic or nearly hydrophobic surface to enable their use with droplets. Due to the above demand, this study used a 355-nm ultraviolet laser to fabricate a comb microstructure on ITO glass to modify the surface wettability characteristics. All of the fabrication patterns with various line width and pitch, depth, and surface roughness were employed. Subsequently, the contact angle (CA) of droplets on the ITO glass was analyzed to examine wettability and electrical performance by using the different voltages applied to the electrode. The proposed approach can succeed in the fabrication of a biochip with suitable comb-microstructure by using the optimal operating voltage and time functions for the catch droplets on ITO glass for precision medicine application. The experiment results indicated that the CA of droplets under a volume of 20 μL on flat ITO substrate was approximately 92° ± 2°; furthermore, due to its lowest surface roughness, the pattern line width and pitch of 110 μm exhibited a smaller CA variation and more favorable spherical droplet morphology, with a side and front view CA of 83° ± 1° and 78.5° ± 2.5°, respectively, while a laser scanning speed of 750 mm/s was employed. Other line width and pitch, as well as scanning speed parameters, increased the surface roughness and resulted in the surface becoming hydrophilic. In addition, to prevent droplet morphology collapse, the droplet’s electric operation voltage and driving time did not exceed 5 V and 20 s, respectively. With this method, the surface modification process can be employed to control the droplet’s CA by adjusting the line width and pitch and the laser scanning speed, especially in the neutral or nearly hydrophobic surface for droplet transporting. This enables the production of a microfluidic chip with a surface that is both light transmittance and has favorable electrical conductivity. In addition, the shape of the microfluidic chip can be directly designed and fabricated using a laser direct writing system on ITO glass, obviating the use of a mask and complicated production processes in biosensing and biomanipulation applications.

Background: Genetic predisposition of the inflammatory-host response may affect the development of psoriasis. Previous studies have shown that copy number variations (CNVs) of β-defensin genes (DEFB) are associated with the susceptibility of psoriasis in Caucasian populations. Objectives: This study aimed to assess the role of the CNVs of the DEFB4 gene and functional variants in the DEFB1 gene in Taiwanese patients with psoriasis. Methods: In total, 196 patients with psoriasis and 196 control individuals were analyzed for the presence of the DEFB4 CNVs using the paralogue ratio test, and also for the DEFB1 polymorphisms rs11362, rs1800972, and rs1799946, using a polymerase chain reaction. Results: None of the polymorphisms were found to be associated with psoriasis. The distribution of DEFB4 genomic CNVs did not significantly differ between the control group and psoriasis group. The frequencies of patients who carried a greater than the median (≥ 5) number of copies did not significantly differ in patients with psoriasis and controls. The multivariate analysis similarly revealed that the DEFB4 CNVs were not associated with psoriasis (odds ratio = 1.03, 95% confidence interval = 0.89–1.19, p = 0.720). No significant difference was detected in the genotype and allele distribution for any of the individual DEFB1 polymorphisms between the cases and the controls. Finally, the overall haplotype frequency profiles derived from the three polymorphisms did not significantly differ between the cases and the controls. Conclusion: Our results do not suggest that these genetic variants of the β-defensin genes contribute to the genetic background of psoriasis in Taiwanese patients.

Aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts such as 4-hydroxy-trans-2-nonenal (4-HNE). Previous meta-analyses have shown an increase in the risk of atrial fibrillation (AF) in patients with chronic alcohol consumption. ALDH2*2, a common dysfunctional polymorphism in the ALDH2 gene, has been linked to an increased risk of cancer and heart disease. We tested the effect of ALDH2 deficiency on alcohol-induced AF in a murine model of chronic-binge ethanol feeding, with ALDH2*2 knock-in (KI) mice generated by a CRISPR/CAS9 system. In addition, right atrial appendages were obtained from eight patients with AF undergoing open heart surgery. The results showed that burst atrial pacing induced a greater susceptibility to AF in ALDH2*2 KI mice exposed to chronic ethanol intoxication than in wild-type mice, resulting from a higher degree of 4-HNE accumulation and collagen deposition in their atria. Alda-1 attenuated transforming growth factor beta 1 (TGF-β1) expression and collagen deposition in the atria and reduced AF inducibility. Patients with AF and the ALDH2*2 allele exhibited greater oxidative stress and substrate remodeling in their atria than non-carriers. In conclusion, ALDH2 deficiency may increase the risk of chronic alcohol and tachypacing-induced AF through the accumulation of 4-HNE and increased ROS production.

The widely used rigid gas permeable (RGP) contact lenses provide higher oxygen permeability and tear exchange rate than do soft contact lenses. However, their wettability warrants improvement to enhance the wearing comfort. This study used UV laser (wavelength = 355 nm) to modify the surface properties of RGP contact lenses with materials of Boston XO® (Bausch & Lomb Incorporated). Briefly, the mesh pattern was fabricated on the RGP contact lens surface by using the laser and smoothed by using oxygen plasma; the enhanced hydrophilic efficiency was analyzed using contact angle measurement. The experiment results indicated that the contact angle of the lens material decreased by approximately 10°−20° when the pitch of mesh pattern was

BACKGROUND:Inherited cardiac conduction diseases (CCD) are rare but are caused by mutations in a myriad of genes. Recently, whole-exome sequencing has successfully led to the identification of causal mutations for rare monogenic Mendelian diseases. OBJECTIVE:To investigate the genetic background of a family affected by inherited CCD. METHODS AND RESULTS:We used whole-exome sequencing to study a Chinese family with multiple family members affected by CCD. Using the pedigree information, we proposed a heterozygous missense mutation (c.G695T, Gly232Val) in the lamin A/C (LMNA) gene as a candidate mutation for susceptibility to CCD in this family. The mutation is novel and is expected to affect the conformation of the coiled-coil rod domain of LMNA according to a structural model prediction. Its pathogenicity in lamina instability was further verified by expressing the mutation in a cellular model. CONCLUSIONS:Our results suggest that whole-exome sequencing is a feasible approach to identifying the candidate genes underlying inherited conduction diseases.

Matrix metalloproteinase (MMP) plays an important role in the pathogenesis of atrial fibrillation (AF). The MMP9 promoter has a functional polymorphism rs3918242 that can regulate the level of gene transcription. This study recruited 200 AF patients and 240 controls. The MMP9 rs3918242 was examined by polymerase chain reactions. HL-1 atrial myocytes were cultured and electrically stimulated. Right atrial appendages were obtained from six patients with AF and three controls with sinus rhythm undergoing open heart surgery. The MMP9 expression and activity were determined using immunohistochemical analysis and gelatin zymography, respectively. Rapid pacing induces MMP9 secretion from HL-1 myocytes in a time- and dose-dependent manner. The responsiveness of MMP9 transcriptional activity to tachypacing was significantly enhanced by rs3918242. The expression of MMP9 was increased in fibrillating atrial tissue than in sinus rhythm. However, the distribution of rs3918242 genotypes and allele frequencies did not significantly differ between the control and AF groups. HL-1 myocyte may secrete MMP9 in response to rapid pacing, and the secretion could be modulated by rs3918242. Although the MMP9 expression of human atrial myocyte is associated with AF, our study did not support the association of susceptibility to AF among Taiwanese subjects with the MMP9 rs3918242 polymorphism.