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BACKGROUND: Maintaining intracellular equilibrium is essential for the viability of tumor cells, which tend to be particularly vulnerable to environmental stressors. Consequently, targeting the disruption of this homeostasis offers a promising approach for oncological treatments. LW-213, a novel derivative of wogonin, effectively induces apoptosis in cancer cells by initiating endoplasmic reticulum (ER) stress, although the precise molecular pathways involved remain intricate and multifaceted. PURPOSE: This research aimed to explore how LW-213 prompts apoptosis in non-small cell lung cancer (NSCLC) cells and to clarify the detailed mechanisms that govern this process. METHODS: Various NSCLC cell lines were utilized to delineate the apoptotic effects induced by LW-213. Advanced methodologies, including RNA sequencing (RNA-seq), Western blotting (WB), immunofluorescence (IF), immunoprecipitation (IP), flow cytometry (Fc), real-time quantitative polymerase chain reaction (RT-qPCR), and electron microscopy, were employed to investigate the underlying molecular interactions. The efficacy and mechanistic action of LW-213 were also assessed in a xenograft model using nude mice. RESULTS: We demonstrated that LW-213, a small molecule cationic amphiphilic drug (CAD), inhibited Niemann-Pick C1 (NPC1) function and induced lysosomal membrane damage, thereby activating the phosphoinositide-initiated membrane tethering and lipid transport (PITT) pathway. This activation promoted cholesterol transport from the ER to the lysosome, perpetuating a cholesterol-deficient state in the ER, including massive exocytosis of Ca2+ and activation of FAM134B-mediated reticulophagy. Ultimately, excessive reticulophagy induced lethal ER stress. CONCLUSIONS: In summary, our study elucidates an organelle domino reaction initiated by lysosome damage and a series of self-rescue mechanisms that eventually lead to irreversible lethal effects, revealing a potential drug intervention strategy.

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BACKGROUND: Although the electrocardiographic and electrophysiological properties of ventricular arrhythmias (VAs) from the vicinity of the lateral tricuspid annulus (TA) have been reported in previous studies, their precise site of origin have not been addressed. OBJECTIVE: The purpose of this study was to describe the precise origin of lateral TA-VA and the relevant anatomy. METHODS: Consecutive patients with idiopathic lateral TA-VAs were reviewed and analyzed. Three-dimensional mapping system combined with intracardiac echocardiography (ICE) was used for anatomic reconstruction, mapping, and ablation. RESULTS: During the study period, 63 patients with lateral TA-VAs were included. Under ICE view, a prominent enfoldment structure was observed under the valve along the lateral TA. The muscular bundle was documented in all patients (100%) within the subvalvular enfoldment with an average number and diameter of 4 ± 2 and 4.10 ± 0.73 mm, respectively. Initial ablation was attempted via the anterograde approach in 15 patients but succeeded in none. To reach the ventricular side of the TA, the catheter needed to enter the ventricular chamber and retroflexed toward the atrial side with a reverse curve. The earliest activation site was found at the valvular end of muscular bundles in 51 of the 63 patients (80.9%) with a local activation time of -26.78 ± 4.63 ms. The VAs were eliminated after an average of 4 ± 2 seconds of ablation. CONCLUSION: The ventricular side adjacent to the lateral TA exhibits a subvalvular enfoldment-like structure, which is rich in muscular bundles and serves as the origin of TA-VAs in most patients. To reach the origins, a reverse technique is required.

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BACKGROUND: Immune checkpoint inhibitors, which have attracted much attention in recent years, have achieved good efficacy, but their use is limited by the high incidence of acquired drug resistance. Therefore, there is an urgent need to develop new immunotherapy drugs. Compound taxus chinensis capsule (CTC) is an oral paclitaxel compound drug, clinical results showed it can change the number of regulatory T cells and T helper cell 17 in peripheral blood. Regulating the balance between regulatory T cells and T helper cell 17 is considered to be an effective anticancer strategy. Paclitaxel and ginsenoside metabolite compound K are the main immunomodulatory components, it is not clear that paclitaxel combined with compound K can inhibit tumor development by regulating the balance between regulatory T cell and T helper cell 17. METHODS: MTT, EdU proliferation and plate colony formation assay were used to determine the concentration of paclitaxel and compound K. AnnexinV-FITC/PI staining, ELISA, Western Blot assay, Flow Cytometry and Immunofluorescence were used to investigate the effect of paclitaxel combined with compound K on Lewis cell cultured alone or co-cultured with splenic lymphocyte. Finally, transplanted tumor C57BL/6 mice model was constructed to investigate the anti-cancer effect in vivo. RESULTS: According to the results of MTT, EdU proliferation and plate colony formation assay, paclitaxel (10 nM) and compound K (60 µM) was used to explore the mechanism. The results of Flow Cytometry demonstrated that paclitaxel combined with compound K increased the number of T helper cell 17 and decreased the number of regulatory T cells, which induced pyroptosis of cancer cells. The balance was mediated by the JAK-STAT pathway according to the results of Western Blot and Immunofluorescence. Finally, the in vivo results showed that paclitaxel combined with compound K significantly inhibit the progression of lung cancer. CONCLUSIONS: In this study, we found that paclitaxel combined with compound K can activate CD8+ T cells and induce pyroptosis of tumor cells by regulating the balance between regulatory T cells and T helper cell 17. These results demonstrated that this is a feasible treatment strategy for lung cancer.

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OBJECTIVE: This study aimed to assess biventricular function and mechanics in patients with the chronic high-altitude disease (CHAD) using cardiovascular MRI and explore the possible risk factors associated with ventricular remodeling. METHODS: In this prospective study, consecutive CHAD patients and healthy controls at high-altitude (HA) and at sea level (SL) underwent cardiovascular MRI. Right ventricular (RV) and left ventricular (LV) function and global strain parameters were compared. To identify risk factors associated with ventricular remodeling, multiple linear regression analyses were used. RESULTS: A total of 33 patients with CHAD (42.97 years ± 11.80; 23 men), 33 HA (41.18 years ± 8.58; 21 men), and 33 SL healthy controls (43.48 years ± 13.40; 21 men) were included. A Significantly decreased biventricular ejection fraction was observed in patients (all p < 0.05). Additionally, the HA group displayed lower magnitudes of biventricular longitudinal peak strain (PS) (RV, - 13.67% ± 4.05 vs. - 16.22% ± 3.03; LV, - 14.68% ± 2.20 vs. - 16.19% ± 2.51; both p < 0.05), but a higher LV circumferential PS (- 20.74% ± 2.02 vs. - 19.17% ± 2.34, p < 0.05) than the SL group. Moreover, multiple linear regression analyses revealed that HGB (ß = 0.548) was related to the LV remodeling index, whereas BUN (ß = 0.570) was associated with the RV remodeling index. CONCLUSIONS: With the deterioration of RV function in patients with CHAD, LV function was also impaired concomitantly. Hypoxia-induced erythrocytosis may contribute to LV impairment, while BUN was considered an independent risk factor for RV remodeling. KEY POINTS: • A significantly lower biventricular ejection fraction was observed in patients, with a decreased magnitude of left ventricular (LV) peak systolic strain rate (radial and circumferential) and peak diastolic strain rate (all p < 0.05). • High-altitude healthy natives showed a lower biventricular longitudinal peak strain (all p < 0.05). • Hemoglobin was related to LV remodeling (ß = 0.548), while BUN (ß = 0.570) was independently associated with RV remodeling in CHAD patients.

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AIMS: The electrocardiographic and electrophysiological characteristics of ventricular arrhythmia (VA) arising from the intramural basal inferior septum (BIS) have not been specifically addressed to date. The aim of the current study was to characterize intramural BIS-VA and distinguish it from those with endocardial origins besides clarifying the anatomical configurations of the pyramidal space. METHODS AND RESULTS: Fifty-five consecutive patients undergoing catheter ablation of VAs from BIS were identified and divided into three groups: the left ventricular (LV)-BIS group (n = 28), right ventricular (RV)-BIS group (n = 8), and intramural group (Intra, n = 19). Compared with the LV-BIS and RV-BIS groups, patients in the Intra group presented with no adequate earliest activation time at the two-sided BIS and epicardial coronary system [right: 7.79 ± 2.38 vs. left: 7.16 ± 2.59 vs. the middle cardiac vein (MCV): 6.26 ± 1.73 ms, P = 0.173] and poor-matched pacing-produced QRS at each site. Under the intracardiac echocardiography view, the pyramidal base was the broadest part of the septum and served as the division of the two-sided BIS. Focal ablation yielded promising acute-term and long-term procedural success in the LV-BIS and RV-BIS groups. But for the Intra group, VAs disappeared only after stepwise ablation successively targeted early preferential exit. After follow-up, three patients in the Intra group had recurrent VA, and all of them were treated well by a redo procedure or drug therapy. CONCLUSION: Intramural VAs were relatively common in the BIS region in our series. Intra-procedural mapping was important to distinguish the intramural VAs from other VAs by comparing the local activation time and pacing mapping. Procedural success could be achieved by stepwise ablation on the counterpart sides of the BIS and within the MCV.

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Tourette syndrome (TS) is a neurodevelopment disorder characterized by motor and phonic tics. We investigated the topological alterations in pediatric TS using morphological topological analysis of brain structures. We obtained three-dimensional T1-weighted magnetic resonance imaging (MRI) sequences from 59 drug-naïve pediatric patients with TS and 87 healthy controls. We identified morphological topographical alterations in the brains of patients with TS compared to those of the healthy controls via GRETNA software. At the global level, patients with TS exhibited increased global efficiency (E glob ) (p = 0.012) and decreased normalized characteristic path length (λ) (p = 0.027), and characteristic path length (Lp) (p = 0.025) compared to healthy controls. At the nodal level, we detected significant changes in the nodal betweenness, nodal degree, and nodal efficiency in the cerebral cortex-striatum-thalamus-cortex circuit. These changes mainly involved the bilateral caudate nucleus, left thalamus, and gyri related to tics. Nodal betweenness, nodal degree, and nodal efficiency in the right superior parietal gyrus were negatively correlated with the motor tic scores of the Yale Global Tic Severity Scale (YGTSS) (r = -0.328, p = 0.011; r = -0.310, p = 0.017; and r = -0.291, and p = 0.025, respectively). In contrast, nodal betweenness, nodal degree, and nodal efficiency in the right posterior cingulate gyrus were positively correlated with the YGTSS phonic tic scores (r = 0.353, p = 0.006; r = 0.300, p = 0.021; r = 0.290, and p = 0.026, respectively). Nodal betweenness in the right supplementary motor area was positively correlated with the YGTSS phonic tic scores (r = 0.348, p = 0.007). The nodal degree in the right supplementary motor area was positively correlated with the YGTSS phonic tic scores (r = 0.259, p = 0.048). Diagnosis by age interactions did not display a significant effect on brain network properties at either the global or nodal level. Overall, our findings showed alterations in the gray matter morphological networks in drug-naïve children with TS. These findings enhance our understanding of the structural topology of the brain in patients with TS and provide useful clues for exploring imaging biomarkers of TS.

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This article explores the use of ambient radio frequency (RF) signals for human presence detection through deep learning. Using Wi-Fi signal as an example, we demonstrate that the channel state information (CSI) obtained at the receiver contains rich information about the propagation environment. Through judicious preprocessing of the estimated CSI followed by deep learning, reliable presence detection can be achieved. Several challenges in passive RF sensing are addressed. With presence detection, how to collect training data with human presence can have a significant impact on the performance. This is in contrast to activity detection when a specific motion pattern is of interest. A second challenge is that RF signals are complex-valued. Handling complex-valued input in deep learning requires careful data representation and network architecture design. Finally, human presence affects CSI variation along multiple dimensions; such variation, however, is often masked by system impediments, such as timing or frequency offset. Addressing these challenges, the proposed learning system uses preprocessing to preserve human motion-induced channel variation while insulating against other impairments. A convolutional neural network (CNN) properly trained with both magnitude and phase information is then designed to achieve reliable presence detection. Extensive experiments are conducted. Using off-the-shelf Wi-Fi devices, the proposed deep-learning-based RF sensing achieves near-perfect presence detection during multiple extended periods of test and exhibits superior performance compared with leading edge passive infrared sensors. A comparison with existing RF-based human presence detection also demonstrates its robustness in performance, especially when deployed in a completely new environment. The learning-based passive RF sensing thus provides a viable and promising alternative for presence or occupancy detection.

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BACKGROUND: With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated. METHODS AND RESULTS: We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases. CONCLUSIONS: Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.

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BACKGROUND: Left ventricular thrombus (LVT) is reported to be a common complication in acute myocardial infarction (AMI) patients. And it has the potential to cause systemic embolism. This retrospective study was to present the current situation of LVT in clinical practice, as well as to evaluate the clinical characteristics and the risk factors of LVT after AMI. METHODS: LVT cases (n = 96) were identified from 13,732 AMI (non-ST elevation myocardial infarction was excluded) patients in Fuwai Hospital's electronic medical records system from January 2003 to January 2013. The controls (n = 192) were gender- and age-matched AMI patients without LVT during this period. A conditional logistic regression (fitted by the Cox model) was performed to identify the independent risk factors. RESULTS: The incidence of LVT after AMI was 0.7%. Univariate analysis indicated that the anterior myocardial infarction (especially extensive anterior myocardial infarction), lower left ventricular ejection fraction (LVEF), LVEF ≤40%, severe regional wall motion abnormalities (RWMA), pericardial effusion, and left ventricular aneurysm were all related to LVT after AMI. The independent risk factors obtained from the conditional logistic regression analysis were lower LVEF (odds ratio (OR) = 0.891, 95% confidence interval (CI ): 0.828-0.960), extensive anterior myocardial infarction (OR = 6.403, 95% CI: 1.769-23.169), severe RWMA (OR = 7.348, 95% CI: 1.323-40.819), and left ventricular aneurysm (OR = 6.955, 95% CI: 1.673-28.921). CONCLUSIONS: This study indicated that lower LVEF, extensive anterior myocardial infarction, severe RWMA, and left ventricular aneurysm were independent risk factors of LVT after AMI. It also suggested that further efforts are needed for the LVT diagnosis after AMI in clinical practice.

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Assortative mating - correlation between male and female traits - is common within populations and has the potential to promote genetic diversity and in some cases speciation. Despite its importance, few studies have sought to explain variation in the extent of assortativeness across populations. Here, we measure assortative mating based on an ecologically important trait, diet as inferred from stable isotopes, in 16 unmanipulated lake populations of three-spine stickleback. As predicted, we find a tendency toward positive assortment on the littoral-pelagic axis, although the magnitude is consistently weak. These populations vary relatively little in the strength of assortativeness, and what variation occurs is not explained by hypothesized drivers including habitat cosegregation, the potential for disruptive selection, costs to choosiness, and the strength of the relationship between diet and body size. Our results support recent findings that most assortative mating is positive, while suggesting that new approaches may be required to identify the environmental variables that drive the evolution of nonrandom mating within populations.

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Migration among populations is widely thought to undermine adaptive divergence, assuming gene flow arises from random movement of individuals. If individuals instead differ in dispersal behavior, phenotype-dependent dispersal can reduce the effective rate of gene flow or even facilitate divergence. For example, parapatric populations of lake and stream stickleback tend to actively avoid dispersing into the adjoining habitat. However, the behavioral basis of this nonrandom dispersal was previously unknown. Here, we show that lake and stream stickleback exhibit divergent rheotactic responses (behavioral response to currents). During the breeding season, wild-caught inlet stream stickleback were better than lake fish at maintaining position in currents, faced upstream more, and spent more time in low-current areas. As a result, stream fish expended significantly less energy in currents than did lake fish. These divergent rheotactic responses likely contribute to divergent habitat use by lake and stream stickleback. Although rheotactic differences were absent in nonbreeding fish, divergent behavior of breeding-season fish may suffice for assortative mating by breeding location. The resulting reproductive isolation between lake and stream fish may explain the fine-scale evolutionary differentiation in parapatric stickleback populations.

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OBJECTIVE: To analyze the clinical features of statin-induced myopathy. METHOD: The statin-induced myopathy case reported as adverse drug reaction (ADR) to the Beijing Center for ADR Monitoring during January 2007 to December 2012 was summarized, patients were divided to myopathy group and rhabdomyolysis group, according to the absence or presence of rhabdomylysis. The clinical characteristics, medication history and outcome were compared between the two groups. RESULTS: A total of 160 statin-induced myopathy cases (54 in rhabdomyolysis group (33.8%) and 106 cases in myopathy group (66.3%)) were collected from the database (mean age: (64.22 ± 13.55) years old, 51.2% male, n = 82). The ADR occurred immediately after the first medication and up to 4 years after medication. Observed clinical features were myalgia, myositis, asymptommatic creatine kinase (CK) elevation or rhabdomyolysis. The average age were (68.54 ± 15.41) years old in rhabdomylysis group and (62.02 ± 12.41) years old in myopathy group (P = 0.004). There was no gender difference between the rhabdomylysis group and myopathy group (P = 0.406) . Twenty-four cases (44.4%) in rhabdomyolysis group and 26 cases (16.5%) in myopathy group were treated with high dose statin (P < 0.001). Percent of simvastatin treatment was significantly higher in rhabdomyolysis group (70.4% (38/54) ) than in myopathy group (32.1% (34/106), P < 0.001). Spearman correlation analysis showed that age, high-dose statin treatment and simvastatin use were all positively correlated with rhabdomylysis (P < 0.001), and the correlation coefficients (r value) were 0.305, 0.290 and 0.364, respectively. Four patients (aged from 71 to 85 years) died because of ADR and all 4 cases received high-dose statin treatment, 3 of them suffered from complex combined diseases, acute disease progression and complex multiple drug use history. CONCLUSIONS: Severe statin-induced myopathy, like rhabdomyolysis, is more likely to occur in old patients, in patients taking high-dose statin, especially simvastatin.

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Assortative mating occurs when there is a correlation (positive or negative) between male and female phenotypes or genotypes across mated pairs. To determine the typical strength and direction of assortative mating in animals, we carried out a meta-analysis of published measures of assortative mating for a variety of phenotypic and genotypic traits in a diverse set of animal taxa. We focused on the strength of assortment within populations, excluding reproductively isolated populations and species. We collected 1,116 published correlations between mated pairs from 254 species (360 unique species-trait combinations) in five phyla. The mean correlation between mates was 0.28, showing an overall tendency toward positive assortative mating within populations. Although 19% of the correlations were negative, simulations suggest that these could represent type I error and that negative assortative mating may be rare. We also find significant differences in the strength of assortment among major taxonomic groups and among trait categories. We discuss various possible reasons for the evolution of assortative mating and its implications for speciation.

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Landscape connectivity has been shown to alter community assembly and its consequences. Here we examine how strong, sudden changes in connectivity may affect community assembly by conducting experiments on the effects of "community mixing," situations where previously isolated communities become completely connected with consequent community reorganization. Previous theory indicates that assembly history dictates the outcome of mixing: mixing randomly assembled communities leads to a final community with random representation from the original communities, while mixing communities that were assembled via a long history of colonizations and extinctions leads to strong asymmetry, with one community dominating the other. It also predicts that asymmetry should be stronger in the presence of predators in the system. We experimentally tested and explored this theory by mixing aquatic microcosms inhabited by a complex food web of heterotrophic protists, and algae. Our results confirm the prediction that long assembly history can produce asymmetry under mixing and suggest these dynamics could be important in natural systems. However, in contrast to previous theory we also found asymmetry weaker under mixing of communities with more complex trophic structure.

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A key assumption of the ideal free distribution (IFD) is that there are no costs in moving between habitat patches. However, because many populations exhibit more or less continuous population movement between patches and traveling cost is a frequent factor, it is important to determine the effects of costs on expected population movement patterns and spatial distributions. We consider a food chain (tritrophic or bitrophic) in which one species moves between patches, with energy cost or mortality risk in movement. In the two-patch case, assuming forced movement in one direction, an evolutionarily stable strategy requires bidirectional movement, even if costs during movement are high. In the N-patch case, assuming that at least one patch is linked bidirectionally to all other patches, optimal movement rates can lead to source-sink dynamics where patches with negative growth rates are maintained by other patches with positive growth rates. As well, dispersal between patches is not balanced (even in the two-patch case), leading to a deviation from the IFD. Our results indicate that cost-associated forced movement can have important consequences for spatial metapopulation dynamics. Relevance to marine reserve design and the study of stream communities subject to drift is discussed.

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