Squamous cell carcinoma of ear and temporal bone: A retrospective study on clinicopathological predictors.

BACKGROUND: Ear and temporal bone squamous cell carcinoma (ETBSCC) is a rare and aggressive malignant tumor with minimal clinicopathological studies. The object of this study was to retrospectively evaluate the predictive effect of clinicopathological variables on the 5-year overall survival (OS) rate of ETBSCC patients in a single tertiary medical center in Tianjin, China. METHODS: A cohort of 44 patients with diagnosed ETBSCC from December 2012 to August 2022 were retrospectively studied. Univariate and multivariate analysis were, respectively, performed for the assessment of clinicopathological predictors, including sex, age, history of chronic suppurative otitis media (CSOM), lesion side, diameter, the choice of surgical approach, parotidectomy, neck dissection, adjuvant therapies, T stage, lymph node metastasis, tumor grade, margin, perineural invasion (PNI), and Ki-67 index. RESULTS: Seventeen females and 27 males were included, with the mean age of 65 years old, ranging from 36 to 89 years. The 5-year OS rate was 43% (mean 51 months, 95% confidence interval [CI] = 39-64). Significant prediction of a worse prognosis for 5-year OS rate was observed under univariate analysis for advanced T stage, positive margin, identified PNI, and higher Ki-67 index, respectively. Advanced T stage was confirmed to be an independent prognostic factor strongly affecting 5-year OS rate among this cohort of patients using a multivariate cox proportional hazard model. CONCLUSION: We found that clinicopathological parameters, especially postoperative pathological parameters, play a critical role in predicting the prognosis of ETBSCC patients.

Chromosome-level genome assembly of bunching onion illuminates genome evolution and flavor formation in Allium crops.

The Allium genus is cultivated globally as vegetables, condiments, or medicinal plants and is characterized by large genomes and strong pungency. However, the genome evolution and genomic basis underlying their unique flavor formation remain poorly understood. Herein, we report an 11.27-Gb chromosome-scale genome assembly for bunching onion (A. fistulosum). The uneven bursts of long-terminal repeats contribute to diversity in genome constituents, and dispersed duplication events largely account for gene expansion in Allium genomes. The extensive duplication and differentiation of alliinase and lachrymatory factor synthase manifest as important evolutionary events during flavor formation in Allium crops. Furthermore, differential selective preference for flavor-related genes likely lead to the variations in isoalliin content in bunching onions. Moreover, we reveal that China is the origin and domestication center for bunching onions. Our findings provide insights into Allium genome evolution, flavor formation and domestication history and enable future genome-assisted breeding of important traits in these crops.

Magnon-tuning non-volatile magnetic dynamics in a CoZr/PMN-PT structure.

Magnon-tuning non-volatile magnetic dynamics is investigated in a CoZr/PMN-PT structure by measuring ferromagnetic resonance at room temperature. The electric-field control of ferromagnetic resonance shows loop-like behavior, which indicates non-volatile electric-field control of the magnetism. Further, fitting the curves of in-plane rotating angle versus ferromagnetic resonance field under different electric fields shows that the effective magnetic field changes in loop-like manner with the electric field. The resulting change in non-volatile saturation magnetization with electric field is consistent with that of a polarization electric field curve. A 1.04% change of saturation magnetization is obtained, which can be attributed to a magnon-driven magnetoelectric coupling at the CoZr/PMN-PT interface. This magnon-driven magnetoelectric coupling and its dynamic magnetic properties are significant for developing future magnetoelectric devices.

MCOLN1 Promotes Proliferation and Predicts Poor Survival of Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: MCOLN1 (mucolipin subfamily, member 1) was first identified as an autophagic regulator, which was essential for efficient fusion of both autophagosomes and late endosomes with lysosomes. This study is aimed at investigating the role of MCOLN1 in the development of pancreatic ductal adenocarcinoma (PDAC). METHODS: Immunohistochemistry (IHC) assay was conducted to evaluate the expression level of MCOLN1 in 82 human PDAC tumor tissues. Overall survival (OS) and recurrence-free survival (RFS) analysis was performed to assess the prognosis of patients. Colony formation and MTT assays [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide] were performed to measure the proliferation capacity of tumor cells. The expression level of related genes was measured by RT-PCR (reverse transcription polymerase chain reaction) and western blot assays. The animal model was used to examine the effects of indicated protein on tumorigenesis in vivo. RESULTS: The results of IHC showed that a high level of MCOLN1 expression was associated with the poor clinical characteristics of PDAC patients. OS and RFS were significantly worse in patients with high MCOLN1 expression. Silencing of MCOLN1 dramatically blocked the proliferation of PDAC cells. Mechanism studies confirmed that knockdown of MCOLN1 decreased the expression of Ki67 and PCNA (proliferating cell nuclear antigen), two markers of cell proliferation. In vivo, MCOILN1 depletion reduced the formation and growth of tumors in mice. CONCLUSION: The high level of MCOLN1 expression was associated with poor clinical outcomes of PDAC patients. MCOLN1 ablation could inhibit PDAC proliferation of both in vitro and in vivo, which provide a new insight and novel therapeutic target for the treatment of PDAC.

A mitochondria-targeted iridium(iii)-based photoacid generator induces dual-mode photodynamic damage within cancer cells.

A mitochondria-targeted photodynamic therapy (PDT) agent was designed and synthesized. Upon light irradiation, it can produce photoacid and its photolysis products can further sensitize 1O2 generation, causing dual-mode (oxygen-independent and oxygen-dependent) photodynamic damage in mitochondria and killing cancer cells effectively even under hypoxic conditions.

Cyclometalated iridium(iii) complexes induce mitochondria-derived paraptotic cell death and inhibit tumor growth in vivo.

The development of iridium complexes as potent anticancer agents has received increasing attention in recent years. In this study, four cyclometalated Ir(iii) complexes with good photophysical properties and potent anticancer activity have been synthesized and characterized. They are taken up by human lung adenocarcinoma A549 cells very quickly and specifically target mitochondria. Mechanism studies reveal that one of them, namely IrM2, induces paraptosis accompanied by excessive mitochondria-derived cytoplasmic vacuoles. Meanwhile, IrM2 affects the ubiquitin-proteasome system (UPS) and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, IrM2 rapidly induces a series of mitochondria-related dysfunctional events, including the loss of mitochondrial membrane potential, cellular ATP depletion, mitochondrial respiration inhibition and reactive oxygen species (ROS) elevation. The rapid loss of mitochondrial functions, elevation of ROS and impairment of the UPS induced by IrM2 lead to the collapse of mitochondria and the subsequent cytoplasmic vacuolation before the cells are ready to start the mechanisms of apoptosis and/or autophagy. Among the ROS, superoxide anion radicals play a critical role in IrM2-mediated cell death. In vivo studies reveal that IrM2 can significantly inhibit tumor growth in a mouse model. This work gives useful insights into the design and anticancer mechanisms of new metal-based anticancer agents.

Chloroplast genomic resources for phylogeny and DNA barcoding: a case study on Fritillaria.

The genus Fritillaria comprises approximately 130 perennial herbaceous species. In the Pharmacopoeia of the People's Republic of China, the bulbs of 11 Fritillaria species are used in Chinese herbal medicines. However, the traditional methods of morphological classification cannot accurately identify closely related species of Fritillaria. Previous studies have attempted to identify these species with universal molecular markers, but insufficient phylogenetic signal was available. In this study, the complete chloroplast genomes of eight Fritillaria species were compared. The length of the eight Fritillaria chloroplast genomes ranges from 151,009 bp to 152,224 bp. A total of 136 SSR loci were identified, including 124 polymorphic SSR loci. For large repeat sequences, 108 repeat loci and four types of repeats were observed. Ten highly variable regions were identified as potential molecular markers. These SSRs, large repeat sequences and highly variable regions provide important information for the development of genetic markers and DNA fingerprints. Phylogenetic analyses showed that the topological structures of all data sets (except the IR regions) were in complete agreement and well resolved. Overall, this study provides comprehensive chloroplast genomic resources, which will be valuable for future studies of evolution and species identification in Fritillaria.

Activation of c-Jun/JNK signaling predicts poor prognosis in nasopharyngeal carcinoma.

A significant proportion of patients with nasopharyngeal carcinoma (NPC) will develop regional relapse or distant metastasis after treatment. This present study evaluated the role of c-Jun/JNK signaling pathways in NPC and its relationship with prognosis. Our study enrolled 122 patients diagnosed with NPC and 136 chronic nasosinusitis patients. Immunohistochemistry was applied to detect positive expression of c-Jun, JNK, p-c-Jun, and p-JNK proteins. Receiver operating characteristic (ROC) curve was then adopted to assess the diagnostic value of c-Jun/JNK signaling pathways for NPC. Activated c-Jun/JNK signaling pathways were observed in NPC patients. Activation of c-Jun/JNK signaling was associated with TNM staging of NPC, as NPC patients with stage III-IV had higher positive expression rates of c-Jun, JNK, p-c-Jun, and p-JNK proteins compared to NPC patients with stage I-II. According to ROC curve results, areas under the curve of c-Jun, JNK, p-c-Jun, and p-JNK protein expression were 0.943, 0.968, 0.963, and 0.938, respectively. The 1-, 3-, and 5-year survival rates and mean survival times of dead patients were lower and shorter in patients with positive expressions of c-Jun, JNK, p-c-Jun, and p-JNK than those with negative expression (all P < 0.05). Overexpression of c-Jun/JNK is associated with development and progression of NPC, indicating that c-Jun/JNK serves as a predictive indicator for early diagnosis and prognosis of NPC.

Long intergenic noncoding RNA 01296 aggravates gastric cancer cells progress through miR-122/MMP-9.

Long non-coding RNAs (lncRNAs) play important roles on tumor development and progression in gastric cancer (GC). However, the biological function and regulatory mechanisms of LINC01296 in GC still remain unknown. The objective of this study is to investigate the clinical significance and pathological roles of LINC01296 in GC. Results showed that LINC01296 was up-regulated in GC tissue and correlated with poor prognosis. In vitro, LINC01296 knockdown was up-regulated in GC cells and LINC01296 knockdown suppressed GC cells proliferation, migration and invasion, and promoted apoptosis. In vivo xenograft assays, results showed LINC01296 knockdown significantly inhibited GC tumor growth. Bioinformatics analysis revealed that LINC01296 sponged miR-122, which was proved to target MMP-9. Western blot and RT-PCR showed that LINC01296 was positively correlated with MMP-9 expression, while miR-122 was negatively correlated to it. Overall, results indicate that LINC01296 acts as oncogenic lncRNA in GC carcinogenesis, suggesting the LINC01296/miR-122/MMP-9 regulatory pathway in GC tumorigenesis.

Genome Size Diversity in Lilium (Liliaceae) Is Correlated with Karyotype and Environmental Traits.

Genome size (GS) diversity is of fundamental biological importance. The occurrence of giant genomes in angiosperms is restricted to just a few lineages in the analyzed genome size of plant species so far. It is still an open question whether GS diversity is shaped by neutral or natural selection. The genus Lilium, with giant genomes, is phylogenetically and horticulturally important and is distributed throughout the northern hemisphere. GS diversity in Lilium and the underlying evolutionary mechanisms are poorly understood. We performed a comprehensive study involving phylogenetically independent analysis on 71 species to explore the diversity and evolution of GS and its correlation with karyological and environmental traits within Lilium (including Nomocharis). The strong phylogenetic signal detected for GS in the genus provides evidence consistent with that the repetitive DNA may be the primary contributors to the GS diversity, while the significant positive relationships detected between GS and the haploid chromosome length (HCL) provide insights into patterns of genome evolution. The relationships between GS and karyotypes indicate that ancestral karyotypes of Lilium are likely to have exhibited small genomes, low diversity in centromeric index (CVCI) values and relatively high relative variation in chromosome length (CVCL) values. Significant relationships identified between GS and annual temperature and between GS and annual precipitation suggest that adaptation to habitat strongly influences GS diversity. We conclude that GS in Lilium is shaped by both neutral (genetic drift) and adaptive evolution. These findings will have important consequences for understanding the evolution of giant plant genomes, and exploring the role of repetitive DNA fraction and chromosome changes in a plant group with large genomes and conservation of chromosome number.

Complete chloroplast genome sequences of Lilium: insights into evolutionary dynamics and phylogenetic analyses.

Lilium is a large genus that includes approximately 110 species distributed throughout cold and temperate regions of the Northern Hemisphere. The species-level phylogeny of Lilium remains unclear; previous studies have found universal markers but insufficient phylogenetic signals. In this study, we present the use of complete chloroplast genomes to explore the phylogeny of this genus. We sequenced nine Lilium chloroplast genomes and retrieved seven published chloroplast genomes for comparative and phylogenetic analyses. The genomes ranged from 151,655 bp to 153,235 bp in length and had a typical quadripartite structure with a conserved genome arrangement and moderate divergence. A comparison of sixteen Lilium chloroplast genomes revealed ten mutation hotspots. Single nucleotide polymorphisms (SNPs) for any two Lilium chloroplast genomes ranged from 8 to 1,178 and provided robust data for phylogeny. Except for some of the shortest internodes, phylogenetic relationships of the Lilium species inferred from the chloroplast genome obtained high support, indicating that chloroplast genome data will be useful to help resolve the deeper branches of phylogeny.

Analysis of global gene expression profiles during the flowering initiation process of Lilium × formolongi.

The onset of flowering is critical for the reproductive development of plants. Lilium × formolongi is a lily hybrid that flowers within a year after sowing. We successfully identified four important stages during vegetative growth and flowering initiation of L. × formolongi under long day conditions. The plant tissues from the four stages were used in a genome-wide transcriptional analysis to investigate stage-specific changes of gene expression in L. × formolongi. In total, the sequence reads of the four RNA-sequencing libraries were assembled into 52,824 unigenes, of which 37,031 (70.10%) were differentially expressed. The global expression dynamics of the differentially expressed genes were predominant in flowering induction phase I and the floral differentiation stage, but down-regulated in flowering induction phase II. Various transcription factor families relevant to flowering were elucidated, and the members of the MADS-box, SBP and CO-like transcription factor families were the most represented. There were 85 differentially expressed genes relevant to flowering. CONSTANS-LIKE, FLOWERING LOCUS T, TREHALOSE-6-PHOSPHATE SYNTHASE and SQUAMOSA PROMOTER BINDING PROTEIN-LIKE homologs were discovered and may play significant roles in the flowering induction and transition process of L. × formolongi. A putative gene regulatory network, including photoperiod, age-dependent and trehalose-6-phosphate flowering pathways, was constructed. This is the first expression dataset obtained from a transcriptome analysis of photoperiod-mediated flowering pathway in lily, and it is valuable for the exploration of the molecular mechanisms of flowering initiation and the short vegetative stage of L. × formolongi.

A novel classification system for the evaluation and reconstruction of oral defects following oncological surgery.

Accurate evaluation of oral tissue defects following oncological surgery is necessary for the subsequent reconstruction. However, there is currently no effective classification system for oral defects in the clinical setting. The present study therefore developed a clinical classification system for the evaluation and reconstruction of oral defects. A retrospective cohort study was performed. A two-dimensional classification system based on coronal computed tomography/magnetic resonance imaging was developed and validated by 145 cases with oral defects. Oral defects could be classified into 6 types (I-VI) horizontally and 2 classes (a and b) vertically. The proportion of the various types was as follows: Type I, 35.9%; type II, 21.4%; type III, 23.4%; type IV, 4.8%; type V, 2.1%; and type VI, 12.4%. Among them, 91 cases (62.8%) were class a and 54 cases (37.2%) were class b. Type Ia-Va represented the unilateral 1-5 subsites involving superficial oral defects without mandibular continuity destruction (88 cases, 60.7%). Type Ib-Vb (+M) represented the unilateral 1-5 subsites involving deep oral defects with segmental mandibular continuity destruction (38 cases, 26.2%). Type I-V (+S) represented the unilateral through and through oral defects with cheek skin involvement (10 cases, 6.9%). Type VI represented bilateral oral defects (18 cases, 12.4%). The present classification system for the evaluation of the oral defects was simple and practical, and could identify the common types of oral defects and guide the reconstruction.

Evaluation of putative reference genes for quantitative real-time PCR normalization in Lilium regale during development and under stress.

Normalization to reference genes is the most common method to avoid bias in real-time quantitative PCR (qPCR), which has been widely used for quantification of gene expression. Despite several studies on gene expression, Lilium, and particularly L. regale, has not been fully investigated regarding the evaluation of reference genes suitable for normalization. In this study, nine putative reference genes, namely 18S rRNA, ACT, BHLH, CLA, CYP, EF1, GAPDH, SAND and TIP41, were analyzed for accurate quantitative PCR normalization at different developmental stages and under different stress conditions, including biotic (Botrytis elliptica), drought, salinity, cold and heat stress. All these genes showed a wide variation in their Cq (quantification Cycle) values, and their stabilities were calculated by geNorm, NormFinder and BestKeeper. In a combination of the results from the three algorithms, BHLH was superior to the other candidates when all the experimental treatments were analyzed together; CLA and EF1 were also recommended by two of the three algorithms. As for specific conditions, EF1 under various developmental stages, SAND under biotic stress, CYP/GAPDH under drought stress, and TIP41 under salinity stress were generally considered suitable. All the algorithms agreed on the stability of SAND and GAPDH under cold stress, while only CYP was selected under heat stress by all of them. Additionally, the selection of optimal reference genes under biotic stress was further verified by analyzing the expression level of LrLOX in leaves inoculated with B. elliptica. Our study would be beneficial for future studies on gene expression and molecular breeding of Lilium.

De novo transcriptome characterization of Lilium 'Sorbonne' and key enzymes related to the flavonoid biosynthesis.

Lily is an important cut-flower and bulb crop in the commercial market. Here, transcriptome profiling of Lilium 'Sorbonne' was conducted through de novo sequencing based on Illumina platform. This research aims at revealing basic information and data that can be used for applied purposes especially the molecular regulatory information on flower color formation in lily. In total, 36,920,680 short reads which corresponded to 3.32 GB of total nucleotides, were produced through transcriptome sequencing. These reads were assembled into 39,636 Unigenes, of which 30,986 were annotated in Nr, Nt, Swiss-Prot, KEGG, COG, GO databases. Based on the three public protein databases, a total of 32,601 coding sequences were obtained. Meanwhile, 19,242 Unigenes were assigned to 128 KEGG pathways. Those with the greatest representation by unique sequences were for ''metabolic pathways'' (5,406 counts, 28.09 %). Our transcriptome revealed 156 Unigenes that encode key enzymes in the flavonoid biosynthesis pathway including CHS, CHI, F3H, FLS, DFR, etc. MISA software identified 2,762 simple sequence repeats, from which 1,975 primers pairs were designed. Over 2,762 motifs were identified, of which the most frequent was AG/CT (659, 23.86 %), followed by A/T (615, 22.27 %) and CCG/CGG (416, 15.06 %). Based on the results, we believe that the color formation of the Lilium 'Sorbonne' flower was mainly controlled by the flavonoid biosynthesis pathway. Additionally, this research provides initial genetic resources that will be valuable to the lily community for other molecular biology research, and the SSRs will facilitate marker-assisted selection in lily breeding.

Effects of M II stage oocytes zona pellucida birefringence on pregnancy outcome.

OBJECTIVE: To explore the effects of different M II stage oocytes zona pellucida birefringence on pregnancy outcome. METHODS: A total of 46 couples with infertile which induced by single cause received in-vitro fertilization treatment were analyzed retrospectively, and randomly divided into the high zona birefringence (HZB)/HZB group, HZB/low zona birefringence (LZB) group and LZB/LZB group according to different oocytes zona pellucida birefringence. Intracytoplasmic sperm injection outcome was analyzed and compared. RESULTS: The proportion of HZB oocytes, implantation rate and the pregnancy rate were decreased in three groups (HZB/HZB group>HZB/LZB group>LZB/LZB group) (P<0.05). But there was no significantly different between the number of oocytes and fertilization rate of these groups (P>0.05). Logistic regression analysis showed that factors affect M II stage oocytes zona pellucida birefringence were age, basal FSH level and the LH level on the day of HCG injection. Age and FSH levels were negatively correlated with the single oocyte zona pellucida birefringence; While the LH level on the day of hCG injection was positively correlated with the single oocyte zona pellucida birefringence. CONCLUSIONS: The primary influence factors on M II stage oocytes zona pellucida are age, basal FSH level and the LH level on the day of hCG injection. The birefringence value of zona pellucida can affect the pregnancy outcome.

How do plants make mitochondria?

Plant mitochondria can differ in size, shape, number and protein content across different tissue types and over development. These differences are a result of signaling and regulatory processes that ensure mitochondrial function is tuned in a cell-specific manner to support proper plant growth and development. In the last decade, the processes involved in mitochondrial biogenesis are becoming clearer, including; how dormant seeds transition from empty promitochondria to fully functional mitochondria with extensive cristae structures and various biochemical activities, the regulation of nuclear genes encoding mitochondrial proteins via regulators of the diurnal cycle in plants, the mitochondrial stress response, the targeting of proteins to mitochondria and other organelles and connections between the respiratory chain and protein import complexes. All these findings indicate that mitochondrial function is a part of an integrated cellular network, and communication between mitochondria and other cellular processes extends beyond the known exchange or transport of metabolites. Our current knowledge now needs to be used to gain more insight into the molecular components at various levels of this hierarchical and complex regulatory and communication network, so that mitochondrial function can be predicted and modified in a rational manner.

Carotenoid accumulation and carotenogenic gene expression during fruit development in novel interspecific inbred squash lines and their parents.

Carotenoid levels and composition during squash fruit development were compared in Cucurbita moschata , Cucurbita maxima , and two lines of their interspecific inbred lines, namely, Maxchata1 and Maxchata2. Eight genes associated with carotenoid biosynthesis were analyzed by quantitative RT-PCR. The two squash species and their interspecific inbred lines exhibited different qualitative and quantitative carotenoid profiles and regulatory mechanisms. C. moschata had the lowest total carotenoid content and mainly accumulated α-carotene and ß-carotene, as expected in a fruit with pale-orange flesh. Low carotenoid content in this species was probably due to the comparatively low expression of all genes investigated, especially PSY1 gene, compared to the other squashes. The predominant carotenoids in C. maxima were violaxanthin and lutein, which produced a corresponding yellow flesh color in mature fruit. The relationship between the expression of the CHYB and ZEP genes may result in almost equal concentrations of violaxanthin and lutein in C. maxima at fruit ripening. In contrast, their interspecific inbred lines principally accumulated lutein and ß-carotene, leading to orange flesh color. The PSY1 gene exhibited higher expression levels at earlier stages of fruit development in the Maxchata lines, potentially triggering the increased carotenoid accumulation seen in these fruits. Likewise, the higher transcription level of CHYB gene observed in the two interspecific inbred lines might be correlated with high lutein in these hybrids. However, this study could not explain the observed ß-carotene accumulation on the basis of gene expression.

Enhanced store-operated Ca²+ entry and TRPC channel expression in pulmonary arteries of monocrotaline-induced pulmonary hypertensive rats.

Pulmonary hypertension (PH) is associated with profound vascular remodeling and alterations in Ca(2+) homeostasis in pulmonary arterial smooth muscle cells (PASMCs). Previous studies show that canonical transient receptor potential (TRPC) genes are upregulated and store-operated Ca(2+) entry (SOCE) is augmented in PASMCs of chronic hypoxic rats and patients of pulmonary arterial hypertension (PAH). Here we further examine the involvement of TRPC and SOCE in PH with a widely used rat model of monocrotaline (MCT)-induced PAH. Rats developed severe PAH, right ventricular hypertrophy, and significant increase in store-operated TRPC1 and TRPC4 mRNA and protein in endothelium-denuded pulmonary arteries (PAs) 3 wk after MCT injection. Contraction of PA and Ca(2+) influx in PASMC evoked by store depletion using cyclopiazonic acid (CPA) were enhanced dramatically, consistent with augmented SOCE in the MCT-treated group. The time course of increase in CPA-induced contraction corresponded to that of TRPC1 expression. Endothelin-1 (ET-1)-induced vasoconstriction was also potentiated in PAs of MCT-treated rats. The response was partially inhibited by SOCE blockers, including Gd(3+), La(3+), and SKF-96365, as well as the general TRPC inhibitor BTP-2, suggesting that TRPC-dependent SOCE was involved. Moreover, the ET-1-induced contraction and Ca(2+) response in the MCT group were more susceptible to the inhibition caused by the various SOCE blockers. Hence, our study shows that MCT-induced PAH is associated with increased TRPC expression and SOCE, which are involved in the enhanced vascular reactivity to ET-1, and support the hypothesis that TRPC-dependent SOCE is an important pathway for the development of PH.