Identification of potential key molecules and signaling pathways for psoriasis based on weighted gene coexpression network analysis

lNTRODUCTlON

Psoriasis is a common chronic, recurrent, immune-regulatory skin and joint disease. It has a variety of clinical skin manifestations, but the most common clinical manifestations are erythematous, scaling papules, and plaques[1]. Previous studies have found that psoriasis is affected by family history and age[2]. Mechanical stress, air pollutants, sun exposure, infection, lifestyle, obesity, dyslipidemia, and mental stress are associated with the progression of psoriasis[3]. The pathogenesis of psoriasis is more complicated and often requires long-term treatment. Mild to moderate psoriasis can be treated topically with a combination of glucocorticoids, vitamin D analogues, and phototherapy. Moderate to severe psoriasis usually requires systemic treatment[4]. Psoriasis is also associated with many diseases, for example cardiometabolic diseases, malignant tumors, infections and mood disorders[5]. So far, psoriasis is still a treatable, but incurable, disease. Therefore, identification of key genes and signaling pathways are of great significance for understanding the molecular mechanism of psoriasis and provides potential basis for the treatment and management of psoriasis.

MicroRNAs (miRNAs) are a class of small non-coding single-stranded RNAs that regulate gene expression[6]. MiRNAs play a vital role in the progression of diseases, for example cancer, infectious diseases, and immune diseases[7]. MiRNAs can regulate cell proliferation, keratinocyte differentiation,apoptosis, and atypical immune activation in psoriasis[8]. Previous studies have found that miR-187 can inhibit the proliferation of keratinocytes by targeting B7 homolog 3 protein. In addition, in the mouse model of psoriasis, overexpression of miR-187 can reduce acanthosis and reduce the severity of the disease[9]. MiR-183-3p can inhibit the proliferation and migration of keratinocytes in psoriasis by inhibiting growth factor receptor binding 2-associated binding protein 1[10]. MiR-320b negatively regulates keratinocyte proliferation in psoriasis by targeting AKT serine/threonine kinase 3[11]. The low expression of miR-31 in dermal mesenchymal stem cells (DMSCs) in patients with psoriasis results in the increased expression of some of its target genes, which in turn promotes the activation of T lymphocyte by inhibiting the proliferation of DMSCs, thereby contributing to the pathogenesis of psoriasis[12]. Previous studies have found that miR-146 regulates inflammatory responses in keratinocytes and skin fibroblasts, which may affect the pathogenesis of psoriasis[13]. Furthermore, in human keratinocytes, the expression of miR-146a is induced by pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-1B (IL-1B), and IL-17a, and the expression of miR-146b is induced by interferon-γ (IFN-γ) and IL-22. MiR-203 promotes keratinocyte proliferation by targeting liver X receptor-α and peroxisome proliferator-activated receptor-γ in psoriasis[14]. MiR-125 regulates keratinocytes proliferation by regulating targeted genes[15,16]. MiR-197 over expression inhibits keratinocytes proliferation induced by IL-22 and keratinocytes migration[17]. In addition, miR-99 also plays an important role in regulating the abnormal proliferation and differentiation of keratinocytes in psoriasis[18]. These studies demonstrate that miRNAs play a vital role in the pathogenesis of psoriasis.Currently, miRNAs studies in psoriasis and dermatology are relatively new. Therefore, the identification of key miRNAs in psoriasis is helpful to elucidate the molecular mechanism of psoriasis.

There were vessels,white adipocytes,fibroblasts and collagen as the mesenchyma(Figure 3D).16

Weighted gene co-expression network analysis (WGCNA) can be used for finding clusters (modules)of highly correlated genes[19]. WGCNA has been used to identify key genes for many diseases,including cancer[20], cardiovascular disease[21], and immunological diseases[22]. In addition, WGCNA has also been used to identify key mRNAs and long noncoding RNAs in psoriasis. So far, we have not found studies that use WGCNA to identify key miRNAs in psoriasis. Therefore, we use WGCNA to identify key modules and miRNAs related to psoriasis and explore potential key pathways related to psoriasis through the targeting relationship of miRNA-mRNA.

MATERlALS AND METHODS

Data sources and processing

The miRNA and mRNA data were obtained from the Gene Expression Omnibus (GEO) database[23].The keyword we searched in the GEO database was “psoriasis”. Cell line or animal level studies and single-sample studies were excluded. Five datasets GSE13355, GSE66511, GSE145054, GSE142582, and GSE129373 were involved in this study (Table 1). All data were derived from skin samples. GSE13355 and GSE66511 were mRNA data from GPL570 and GPL16288 platform, respectively. GSE145054,GSE142582, and GSE129373 were miRNA data from GPL19117, GPL20301, and GPL11154, respectively.The gene expression matrix files in GSE13355 and GSE145054 were downloaded. The GPL annotation file was used to annotate the expression matrix. The probe ID was converted to the gene symbol.Multiple probes correspond to the same gene, taking the average value. The probe that corresponds to multiple genes was removed. The original data of gene expression profile in GSE66511, GSE142582, and GSE129373 were downloaded, and performed by logarithm processing. Then, the combat function in“sva” R package was used to remove batch effects.

Differential expression analysis

Results of previous studies demonstrate that down-regulation of interleukin 1 receptor associated kinase 3 by hsa-miR-33b-3p can alleviate the inflammation and apoptosis induced by IL-1B in CHON-001 cells[63]. As a key miRNA of major depression disorder and Kawasaki disease, hsa-miR-33b-3p play an important role in their pathogenesis[64,65]. Hsa-miR-33b-3p has also been reported in cancer[66]. In the miRNA-mRNA regulatory network, phospholipase C beta 4 (PLCB4) is the only negatively regulated target DEmRNA of hsa-miR-33b-3p. Neutrophils are an important part of the innate immune system and an early line of defense against microbial invasion. PLCB4 can regulate the number of neutrophils[67]. In addition, KEGG functional analysis result demonstrated that PLCB4 was enriched in chemokine signaling pathway. Thus, we hypothesized that hsa-miR-33b-3p may play a vital molecular role in psoriasis by targeting PLCB4 to regulate chemokine signaling pathway.

Functional enrichment analysis

To investigate the possible involvement of DEmRNAs in the biological processes related to psoriasis, we performed Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) functional enrichment analyses. David database was used for the enrichment analysis of DEmRNAs[25], and the screening criterion was

＜ 0.05. GO enrichment analysis, which is comprised of biological processes(BP), cellular components (CC), and molecular functions (MF). The “GOplot” R package was used tovisualize the enrichment results.

Construction of weighted gene co-expression network

The “WGCNA” R package was used to analyze the co-expression network of all miRNAs. To detect outliers, the “hclust” function was used to cluster the sample data. Subsequently, to construct a scalefree topology, the “pickSoftThreshold” function was used to select an appropriate soft threshold power regulator (height 0.90, β value 2). Calculate the adjacency matrix based on the kernel value. The adjacency matrix was transformed into topological overlap matrix (TOM) and corresponding dissimilarity matrix (1-TOM). Genes with similar expression patterns were gathered together, and modules were divided according to the function of “cutreeDynamic” with default parameters. Since the modules identified by the dynamic tree cutting algorithm may be similar, they are combined with a truncation of 0.25 height[26].

Hub modules and miRNAs

Functional analysis of 83 target DEmRNAs was performed using David database (

＜ 0.05). GO enrichment results demonstrated that most of the target DEmRNAs were distributed in signal transduction (GO:BP), immune response (GO:BP), integral component of membrane (GO:CC), plasma membrane (GO:CC), ATP binding (GO:MF), and other biological functions (Figure 7A-C). KEGG enrichment results demonstrated that the target DEmRNAs were significantly enriched in influenza A,hepatitis C, measles, and chemokine signaling pathway (Figure 7D and Table 4).

MiRNA-mRNA network

To explore the correlation between miRNA and mRNA, we constructed a miRNA-mRNA regulatory network. Target mRNAs of miRNAs were predicted using miRDB (http://mirdb.org) database.MiRNA-mRNA pairs involved in common DEmRNA and negatively regulated were selected to construct the network. Cytoscape (www.cytoscape.org/) was used to visualize the miRNA-mRNA regulatory network.

In vitro validation

According to screening criteria, 7 normal and 7 patient skin tissue samples were obtained. Firstly,total RNA of the samples was extracted using TRIzol. Then, fastKing cDNA first strand synthesis kit and miRNA first strand cDNA synthesis kit (Tailing Reaction) were used for mRNA and miRNA reverse transcription, respectively. Subsequently, SuperReal PreMix Plus (SYBR Green) and miRNA quantitative PCR kit (SYBR Green Method) were used to perform real-time polymerase chain reaction(RT-PCR) validation of mRNA and miRNA, respectively. GAPDH, ACTB, and hsa-U6 were internal reference. ABI7300 fluorescence quantitative PCR instrument was used for detection. Finally, the 2

method was used for relative quantitative analysis of the data[28]. This study complied with the Declaration of Helsinki. Informed consent was obtained from the participants. All experimental procedures were approved by the ethics committee of Chinese PLA General Hospital, No. S2021-012-01.

1993年是毛主席誕辰100周年，李建明說，那年有關(guān)毛主席紀(jì)念品的收藏又小小地火了一把。那年在大同市云中商城，李建明用自己的紅色收藏搞了一次小展覽。

We collected skin tissue samples from healthy control individuals and patients with psoriasis. Basic information (including age, sex,

) of patients and healthy controls were recorded in detail during sample collection (Table 2). The specific inclusion criteria of patients with psoriasis: (1) Patients had at least one well-circumscribed erythematous and squamous lesion, which had been confirmed by at least two dermatologists; (2) Patient’s pathological tissues were confirmed by clinical histopathology; (3)Patients had no systemic anti-psoriatic treatment 2 wk before the skin biopsy; and (4) Patients had no topical anti-psoriatic treatment 1 wk before the skin biopsy. Patients with psoriasis who were treated with immune-related drugs before sampling and whose clinical information was incomplete were excluded. The individuals in the normal control group were sex and age matched with the psoriasis group, and without history of psoriasis or other autoimmune diseases.

Statistical analysis

All statistical analyses were performed using R software. Limma R package was used to screen for DEmRNAs and DEmiRNAs. Pearson’s method was used to analyze the correlation between ME and psoriasis. RT-PCR validation data were statistically analyzed by one-way ANOVA.

＜ 0.05 was statistically significant.

RESULTS

Analysis of DEmRNAs and DEmiRNAs

After pretreatment of the raw data, 15780 mRNAs and 837 miRNAs were screened out (Figure 1).Compared with the control group, 639 DEmRNAs were identified in the psoriasis group (adj.

value ＜0.01 and |logFC| ＞ 1). Among them, 497 were up-regulated and 142 were down-regulated. Compared with the control group, 84 DEmiRNAs were identified in the psoriasis group (adj.

value ＜ 0.01 and|logFC| ＞ 1.5). Among them, 70 were up-regulated and 14 were down-regulated. Heat maps showed that there were significant differences of mRNA (Figure 2A) and miRNA (Figure 2B) expression between psoriasis group and control group. The volcano maps of DEmRNAs and DEmiRNAs were shown in Figure 2C and D.

The correlation between modules and psoriasis was analyzed by Pearson’s method. The results showed that turquoise module had the highest correlation with psoriasis (

= 0.96) (Figure 5A). Therefore,turquoise module was considered the hub module. Subsequently, 21 miRNAs were screened out from the turquoise module as candidate hub miRNAs (MM ＞ 0.8 and GS ＞ 0.5) (Figure 5B). Intersection of DEmiRNAs and candidate hub miRNAs was obtained (Figure 5C). Ten intersecting miRNAs were identified as real hub miRNA. Among them, 5 hub miRNAs were up-regulated (hsa-miR-21-3p, hsamiR-21-5p, hsa-miR-31-5p, hsa-miR-18a-5p, and hsa-miR-33b-3p) and 5 hub miRNAs were downregulated (hsa-miR-181a-2-3p, hsa-miR-181a-5p, hsa-miR-6510-3p, hsa-miR-30a-3p, and hsa-miR-30c-2-3p).

Analysis of biological functional

Current research results highlighted that silencing hsa-miR-181a-2-3p could enhance cadmiuminduced inflammatory response and activation of inflammasome[55]. In the research, we found that hsamiR-181a-2-3p was negatively regulated with multiple DEmRNAs. Among these DEmRNAs, OAS3 was found to be involved in hepatitis C and measles in KEGG functional enrichment. Some researchers have found that the OAS3 is concerned with the occurrence and progression of psoriasis through transcriptomic analysis, which is consistent with our analysis[56,57]. Thus, we hypothesized that hsamiR-181a-2-3p may play a regulatory role in the progression of psoriasis by targeting OAS3 to mediate hepatitis C and measles. This provides potential molecular research directions for further research on the pathogenesis of psoriasis.

WGCNA

WGCNA was performed on 837 miRNAs. The samples were clustered to remove abnormal samples(GSM3711960 and GSM3711959) (Figure 4A and B). After calculation, when the soft threshold β was 2, itwas approximately a scale-free topology (Figure 4C). After determining the soft threshold, the cluster tree graph was constructed. Subsequently, with the minimum number of genes for modules set to 20,the modules with dissimilarity ＜ 25% merged using the dynamic tree cutting method. Finally, 6 modules were determined (Figure 4D).

試驗(yàn)地位于宜春市袁州區(qū)洪江鄉(xiāng)，地處明月山國(guó)家級(jí)風(fēng)景名勝區(qū)、國(guó)家森林公園內(nèi)玉華山保護(hù)區(qū)內(nèi)，海拔600 m左右，土壤肥沃的溝谷，生境區(qū)年平均氣溫 14 ℃，有效積溫4 161 ℃，極端低溫-9.2 ℃，年降雨量1 857 mm，年平均相對(duì)濕度在85%以上。

Uncovering of hub modules and miRNAs

1978年12月，黨的十一屆三中全會(huì)拉開了我國(guó)改革開放的序幕，同年十一月份，當(dāng)時(shí)的國(guó)家物資總局組織有關(guān)部門和地方領(lǐng)導(dǎo)赴日本考察，首次將物流的概念引入國(guó)內(nèi)。

MiRNA-mRNA regulatory network

Target mRNAs of 10 hub miRNAs were predicted using miRDB database, but only 8 hub miRNAs (4 up-regulated and 4 down-regulated) were predicted to the corresponding target mRNAs. Eleven target mRNAs of up-regulated hub miRNAs (hsa-miR-21-3p, hsa-miR-21-5p, hsa-miR-18a-5p, and hsa-miR-33b-3p) were matched with DEmRNAs, and 72 target mRNAs of down-regulated hub miRNAs (hsamiR-181a-2-3p, hsa-miR-181a-5p, hsa-miR-30a-3p, and hsa-miR-30c-2-3p) were matched with DEmRNAs. Ninety-seven negatively regulated miRNA-mRNAs were involved in the miRNA-mRNA regulatory network (Figure 6); for example, hsa-miR-21-3p/hsa-miR-18a-5p-F3, hsa-miR-21-5p-claudin 8(CLDN8), hsa-miR-33b-3p-PLCB4, hsa-miR-30a-3p-IL-1B, hsa-miR-181a-5p-C-C motif chemokine ligand 8 (CCL8), hsa-miR-181a-5p/hsa-miR-30c-2-3p-C-X-C motif chemokine ligand 9 (CXCL9), and hsa-miR-30c-2-3p-KYNU.

Functional enrichment of target DEmRNAs

To identify the important modules associated with psoriasis, the module eigengene (ME) of each module was calculated using the “moduleEigengenes” function. Then, the correlation between ME and psoriasis was analyzed using Pearson method. Subsequently, the module with the highest correlation with psoriasis was identified as the hub module. According to module connectivity (MM) and clinical trait relationship (GS) of each gene in the hub module, the candidate hub miRNAs were screened out[27]. The screening criteria were MM ＞ 0.8 and GS ＞ 0.5. Finally, the intersection of candidate hub miRNAs and DEmiRNAs were selected as real hub miRNAs.

RT-PCR validation

IL-1B, CXCL9, CLDN8, CCL8, hsa-miR-181a-5p, hsa-miR-30a-3p, and hsa-miR-21-5p related to psoriasis were selected from hub miRNAs and target DEmRNAs for

validation. Primers for each mRNAs and miRNAs were shown in Table 5. IL-1B, CXCL9 and CCL8 were up-regulated and CLDN8 and hsamiR-181a-5p were down-regulated in psoriasis tissues (Figure 8). Among them, IL-1B, CXCL9, and CLDN8 showed significant difference in expression levels. In addition, we found that expression trends of hsa-miR-30a-3p and hsa-miR-21-5p were contrary to the results of bioinformatics analysis. The reason for the inconsistency between RT-PCR and bioinformatics analysis results may be the small sample size.Further research is needed.

DlSCUSSlON

Although psoriasis is widespread and has significant negative impact on patients’ quality of life, it has not yet been fully diagnosed and treated. In the research, we used the WGCNA method to identify 10 hub miRNAs that may be related to the pathogenesis of psoriasis. Then, target mRNAs of hub miRNAs were predicted by using miRDB database. Only 8 hub miRNAs were predicted to the corresponding target mRNAs. Subsequently, to understand the key biological functions involved in DEmRNAs and target DEmRNAs, we performed GO and KEGG functional analysis. Results demonstrated that they were significantly enriched in immune-related biological functions, for example, immune response, cell chemotaxis, and chemokine signaling pathway.

Hsa-miR-21-5p is abnormally expressed in psoriasis, but the specific molecular mechanism remains unclear[29]. In this study, results demonstrated that hsa-miR-21-5p expression was up-regulated and negatively regulated with CLDN8. CLDN8 is down-regulated in psoriasis and has an important molecular regulatory role[30]. CLDN8 has also been identified as a key downstream component of the IL-9 and IL-23 inflammatory cascade[31,32]. In addition, KEGG functional enrichment analysis showed that CLDN8 was enriched in hepatitis C. Cohen

[33] found that psoriasis is associated with hepatitis C[33]. Cathelicidin, toll like receptor 9 (TLR9), IFN-γ, and TNF-α are inflammatory cytokines. Hepatitis C may increase susceptibility to psoriasis by up-regulating these inflammatory factors[34,35]. Thus, we hypothesized that hsa-miR-21-5p may play a vital regulatory role in hepatitis C through regulating CLDN8 and, thus, affect the pathogenesis of psoriasis.

Hsa-miR-30a-3p can affect the migration and proliferation of cancer cells by targeting related genes[36,37]. Hsa-miR-30a-3p is also contacted with platelet apoptosis and adhesion in immune thrombocytopenia[38]. However, we have not found any report about hsa-miR-30a-3p in psoriasis. In this study, we found that hsa-miR-30a-3p was up-regulated and negatively regulated with multiple DEmRNAs in psoriasis. It may play a vital regulatory role in psoriasis by targeting these DEmRNAs. We found the pro-inflammatory factor IL-1B in target DEmRNAs of hsa-miR-30a-3p. IL-1B has been found to play an important role in autoimmune or autoinflammatory conditions[39]. IL-1B is abundant in the tissue fluid of psoriasis and participates in the disease progression through dual effects[40]. First, it induces insulin resistance through p38 mitogen-activated protein kinase (p38MAPK), preventing insulin-dependent differentiation of keratinocytes, while IL-1B promotes keratinocyte proliferation, both hallmarks of psoriasis. Through KEGG functional enrichment analysis, we also found that IL-1B participates in multiple signal pathways, for example, measles, toll-like receptor signaling pathway, and cytokinecytokine receptor interaction. Measles can relieve psoriasis through an immunosuppressive effect[41].Toll-like receptor signaling pathway play an important role in psoriasis by affecting keratinocyte production[42]. The cytokine-cytokine receptor interaction is related to the occurrence and progression of psoriasis through combined transcriptomic analysis[43], which is consistent with our analysis. Thus,we hypothesized that hsa-miR-30a-3p may play a vital molecular role in the progression of psoriasis by targeting DEmRNAs to regulate multiple biological signaling pathways.

陳靜(2004)對(duì)中國(guó)大學(xué)生的文化認(rèn)同狀況進(jìn)行了調(diào)查。調(diào)查表明，中國(guó)涉外大學(xué)生對(duì)西方文化持開放心態(tài)，并對(duì)西方文化認(rèn)同度較高，然而即便如此，他們?nèi)匀徽J(rèn)為中國(guó)文化是“根”，還是認(rèn)同中國(guó)文化[9]。但是他們也存在一些問題，如對(duì)西方文化的了解不夠客觀，對(duì)民族文化了解不夠深刻等。劉圣明（2007）在高職英語專業(yè)學(xué)生中發(fā)現(xiàn)了“生產(chǎn)性”取向[10]。楊梅（2011）對(duì)大一新生的調(diào)查表明，生產(chǎn)性變化在極少部分好學(xué)生中偶有表現(xiàn)[11]。劉瓊、彭艷（2006）提倡將“生產(chǎn)性”學(xué)習(xí)作為外語教學(xué)的目的[12]。

Hsa-miR-181a-5p is involved in the catabolic pathway of chondrocytes and oxidative stress in osteoarthritis[44]. Hsa-miR-181a-5p can also regulate the pathogenesis of sepsis-related inflammation through CRNDE/hsa-miR-181a-5p/TLR4 pathway[45]. In a case-control study, hsa-miR-181a-5p was significantly down-regulated in psoriasis[29]. The miRNA-mRNA regulatory network results demonstrated that hsa-miR-181a-5p was negatively regulated with multiple DEmRNAs. Among these DEmRNAs, we found inflammatory mediators CXCL9 and CCL8. CXCL9 is an important chemokine involved in T cell recruitment and is up-regulated in the plasma of patients with psoriasis[46,47].Increased CXCL9 expression can aggravate the progression of psoriasis[48]. CXCL9 and hsa-miR-30c-2-3p were also negatively regulated in the miRNA-mRNA regulatory network. Oncology studies have shown that hsa-miR-30c-2-3p play a vital role in tumor pathogenesis by regulating the proliferation,apoptosis, migration, and invasion of cancer cells[49,50]. So far, we have not found any studies on hsamiR-30c-2-3p in psoriasis. This article may be the first to report that hsa-miR-30c-2-3p plays a role in the pathogenesis of psoriasis. As a chemokine, CCL8 is involved in immune regulation and inflammatory processes in a variety of diseases[51-53]. Although no relevant studies on CCL8 have been found in psoriasis, the expression of CCL8 is up-regulated in atopic dermatitis[54]. In addition, CXCL9 and CCL8 were found to be enriched in chemokine signaling pathway and cytokine-cytokine receptor interaction by functional analysis. Therefore, this further suggests that hsa-miR-181a-5p and hsa-miR-30c-2-3p may play a regulatory role in psoriasis by targeting DEmRNAs to mediate multiple biological signaling pathways.

Functional analysis of 639 DEmRNAs was performed using David database (

＜ 0.05). GO enrichment results showed that most of the DEmRNAs were distributed in inflammatory response (GO:BP),immune response (GO:BP), cytosol (GO:CC), extracellular exosome (GO:CC), protein homodimerization activity (GO:MF), and other biological functions (Figure 3A-C). KEGG enrichment results demonstrated that DEmRNAs were significantly enriched in metabolic pathways, influenza A, chemokine signaling pathway, and cytokine-cytokine receptor interaction (Figure 3D and Table 3).

植物乳桿菌、清酒乳桿菌、彎曲乳桿菌和屎腸球菌，它們的最適生長(zhǎng)溫度為20～37℃；當(dāng)溫度高于37℃時(shí)，4種乳酸菌的生長(zhǎng)量下降，當(dāng)溫度達(dá)到50℃時(shí)，4種乳酸菌的生長(zhǎng)水平非常低；在20℃以下低溫范圍培養(yǎng)均有較好的耐低溫表現(xiàn)。因此，4種乳酸菌均為耐低溫菌株，有望成為川西北高寒牧區(qū)青貯料調(diào)制用青貯添加劑。

The expression of hsa-miR-21-3p in psoriasis was significantly increased[58]. Moreover, hsa-miR-21-3p plays a pro-inflammatory role in keratinocytes, and high expression in the skin is concerned with psoriasis[59]. So far, we have not found relevant reports about hsa-miR-18a-5p in psoriasis. However,hsa-miR-18a-5p promotes the proliferation and migration of pulmonary smooth muscle cells by targeting notch receptor 2[60]. Oncology studies have shown that hsa-miR-18a-5p promotes melanoma cell proliferation by targeting EPH receptor A7 signaling[61]. Hsa-miR-18a-5p can affect keratinocytes apoptosis by targeting B-cell lymphoma/leukemia-2-like protein 10 in patients with toxic epidermal necrolysis and is related to the skin erythema or erosion area of drug eruptions[62]. The miRNA-mRNA regulatory network regulatory network result demonstrates that hsa-miR-21-3p and hsa-miR-18a-5p jointly negatively regulate coagulation factor III, tissue factor (F3). This finding provides new research ideas for the pathogenesis of psoriasis in the future.

阿斯頓·馬丁Vantage圓潤(rùn)的外觀和立體感十足的造型散發(fā)著令人難以抗拒的魅力，作為一輛兼顧性能和豪華質(zhì)感的跑車，我們也能理解為什么阿斯頓·馬丁會(huì)為Vantage的方向盤提供電動(dòng)調(diào)節(jié)功能了。這種搭配的好處在于，我們可以優(yōu)雅地坐在用料考究的真皮座椅上仔細(xì)調(diào)整方向盤的角度，甚至可以啟動(dòng)座椅通風(fēng)功能獨(dú)享最適宜的溫度。在這樣的精致氣息中，一股優(yōu)越感油然而生。

上述技術(shù)與產(chǎn)品分別在河套灌區(qū)上游磴口沙金套海、中游臨河九莊示范區(qū)進(jìn)行了示范應(yīng)用，充分顯示其優(yōu)越性，保證了較大面積滴灌系統(tǒng)灌水均勻性，取得了較好的示范效應(yīng)，可為黃河水滴灌提供可借鑒的成功經(jīng)驗(yàn)。

After the above pretreatment, differentially expressed mRNAs (DEmRNAs) and differentially expressed miRNAs (DEmiRNAs) were screened out by limma R package[24]. DEmRNAs screening criteria were adjusted

(adj.

) value ＜ 0.01 and |logFoldChange| (|logFC|) ＞ 1. DEmiRNAs screening criteria were adj.

value ＜ 0.01 and |logFC| ＞ 1.5.

This study has some limitations. First, sample size of

validation was small, leading to a certain degree of error between RT-PCR validation results and bioinformatics analysis results. Further studies with a larger sample size are needed. Secondly, the specific regulatory mechanism of the identified genes and signaling pathways in psoriasis remain unclear, so further research is needed.

千百年來，中國(guó)從來沒有像今天這樣，每天都在誕生遍地的熊熊燃燒的創(chuàng)業(yè)夢(mèng)想，然后又每天都有大批大批的創(chuàng)業(yè)者被拍死在商業(yè)浪潮的海灘上。其中的原因也許有很多很多，但不懂得“居安思危”，得意忘形、固步自封、坐井觀天、天下唯老子獨(dú)大的思維，一定是很多人被拍死在海灘上的重要原因之一。

CONCLUSlON

In conclusion, identification of potential key molecular markers and signaling pathways provides potential molecular research directions for further understanding the pathological mechanisms of psoriasis. This may also provide new research ideas for the prevention and treatment of psoriasis in the future.

ARTlCLE HlGHLlGHTS

Research conclusions

The identification of potential key molecular markers and signaling pathways provides potential research directions for further understanding the molecular mechanisms of psoriasis.

Research perspectives

This study provide new research ideas for the prevention and treatment of psoriasis in the future.

FOOTNOTES

Shu X contributed to the conception and design; Li CX performed the administrative support;Wang YL and Kang XD provide materials and samples; Shu X, Ran M, and Chen XX contributed to the data collection and collation; Shu X and Zhao ZK contributed to the data analysis and interpretation; All authors read and approved the final version of the manuscript.

All experimental procedures were approved by the ethics committee of Chinese PLA General Hospital, No. S2021-012-01.

All the authors report no relevant conflicts of interest for this article.

All data generated or analyzed during this study are included in this published article.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4.0/

China

由圖8可見，隨著聚乙烯靶高度的增加，中子探測(cè)效率增加，中子能量分辨率變化不大。因此，在聚乙烯靶高度方向(圖1中y方向)，應(yīng)盡量選擇尺寸大的聚乙烯靶，這樣可以在保持能量分辨率的條件下，提高中子探測(cè)效率。

Cheng-Xin Li 0000-0001-9862-031X.

Fan JR

Filipodia

我國(guó)建筑耗能巨大，冬季采暖大部分能耗是煤炭，耗能巨大且污染十分嚴(yán)重，國(guó)內(nèi)絕大多數(shù)采暖地區(qū)圍護(hù)結(jié)構(gòu)熱功能都比氣候相近的發(fā)達(dá)國(guó)家差許多，單位建筑面積采暖能耗是發(fā)達(dá)國(guó)家標(biāo)準(zhǔn)的3倍以上[3]，因此發(fā)展節(jié)能建筑、保護(hù)資源、保護(hù)環(huán)境，是中國(guó)發(fā)展進(jìn)程中的重大課題，也是人類發(fā)展進(jìn)程中必須認(rèn)真思考的時(shí)代課題，建筑節(jié)能任重道遠(yuǎn)。

Qi WW

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