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Zijun Liu,1,* Tianhao Bao,2 Zhilan Yang,2,* Ye Ruan,2 Changqing Gao,2 Jie Wu2 1The Second Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 2Affiliated Mental Health Center of Kunming Medical University, Kunming, Yunnan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie Wu, Affiliated Mental Health Center of Kunming Medical University, Kunming, Yunnan, 650224, People’s Republic of China, Email wujie@kmmu.edu.cn Tianhao Bao, Affiliated Mental Health Center of Kunming Medical University, Kunming, Yunnan, 650224, People’s Republic of China, Email Doctor@kmmu.edu.cnObjective: Based on Conservation of resources theory, process model of emotion regulation and attachment theory, the present study examined how psychological capital affects anxiety through the mediation of emotion regulation strategies and explored the moderating role of parent-child relationship.Methods: Using a longitudinal study method, 962 college students were surveyed twice at one-year intervals.Results: (1) College students’ emotion regulation strategies (including cognitive reappraisal and expressive suppression) partially mediated psychological capital and anxiety mood; (2) parent-child relationship moderated the pathways of psychological capital and expressive suppression on anxiety, respectively.Conclusion: College students with higher levels of parent-child relationship had stronger predictive effects of psychological capital and weaker predictive effects of expressive suppression on anxiety mood. The research findings clarify the combined effects of emotion regulation and parent-child relationships on anxiety among college students, providing valuable reference for the design and implementation of interventions to promote individual psychological well-being.Keywords: psychological capital, emotion regulation strategies, anxiety, parent-child relationship

Zirui Bian,1,* Tianzhe Bao,2,* Xuequan Sun,3,4 Ning Wang,1 Qian Mu,5 Ting Jiang,6 Zhongxiang Yu,6 Junhang Ding,2 Ting Wang,7 Qihui Zhou2 1Department of Bone, Huangdao District Central Hospital, Qingdao, People’s Republic of China; 2Qingdao Key Laboratory of Materials for Tissue Repair and Rehabilitation, School of Rehabilitation Sciences and Engineering, University of Health and Rehabilitation Sciences, Qingdao, People’s Republic of China; 3Weifang Eye Institute, Weifang Eye Hospital, Zhengda Guangming Eye Group, Weifang, People’s Republic of China; 4Zhengda Guangming International Eye Research Center, Qingdao Zhengda Guangming Eye Hospital, Qingdao University, Qingdao, People’s Republic of China; 5Department of Biomaterials, LongScience Biological (Qingdao) Co, LTD, Qingdao, People’s Republic of China; 6Heart Center, Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital), Qingdao University, Qingdao, People’s Republic of China; 7Department of Orthopaedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qihui Zhou; Junhang Ding, Tel +86-17660670299, Email qihuizhou@uor.edu.cn; dingjunhang@uor.edu.cnIntroduction: The emergence and rapid spread of multidrug-resistant bacteria (MRB) caused by the excessive use of antibiotics and the development of biofilms have been a growing threat to global public health. Nanoparticles as substitutes for antibiotics were proven to possess substantial abilities for tackling MRB infections via new antimicrobial mechanisms. Particularly, carbon dots (CDs) with unique (bio)physicochemical characteristics have been receiving considerable attention in combating MRB by damaging the bacterial wall, binding to DNA or enzymes, inducing hyperthermia locally, or forming reactive oxygen species.Methods: Herein, how the physicochemical features of various CDs affect their antimicrobial capacity is investigated with the assistance of machine learning (ML) tools.Results: The synthetic conditions and intrinsic properties of CDs from 121 samples are initially gathered to form the raw dataset, with Minimum inhibitory concentration (MIC) being the output. Four classification algorithms (KNN, SVM, RF, and XGBoost) are trained and validated with the input data. It is found that the ensemble learning methods turn out to be the best on our data. Also, ϵ-poly(L-lysine) CDs (PL-CDs) were developed to validate the practical application ability of the well-trained ML models in a laboratory with two ensemble models managing the prediction.Discussion: Thus, our results demonstrate that ML-based high-throughput theoretical calculation could be used to predict and decode the relationship between CD properties and the anti-bacterial effect, accelerating the development of high-performance nanoparticles and potential clinical translation. Keywords: carbon dots, machine learning, antibacterial, minimum inhibitory concentration, classification algorithms

Bingcong Zhao,1,2 Zhigang Li,3 Chuan Shi,4 Yan Liu,5 Yang Sun,3 Bin Li,1,2 Jie Zhang,6 Zhizhong Gong,7 Yuanzheng Wang,8 Xuehong Ma,9 Xinjing Yang,10 Huili Jiang,3 Yuanbo Fu,1,2 Xin Wang,1,2 Yang Li,6 Hengchia Liu,6 Tuya Bao,3 Yutong Fei11– 13 1Department of Acupuncture and Moxibustion, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 2Beijing Key Laboratory of Acupuncture Neuromodulation, Beijing, People’s Republic of China; 3School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 4Psychological Assessment Center, Peking University Sixth Hospital, Beijing, People’s Republic of China; 5Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 6Department of Psychosomatic Medicine, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 7Division of Medical Affairs, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing, People’s Republic of China; 8Department of Integrative TCM and Western Medicine, Peking University First Hospital, Beijing, People’s Republic of China; 9Department of Acupuncture & Moxibustion, Dongfang Hospital, the Second Clinical Medical College of Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 10Department of Traditional Chinese Medicine, South China Hospital of Shenzhen University, Shenzhen, People’s Republic of China; 11Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 12Institute of Excellence in Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, People’s Republic of China; 13Beijing GRADE Centre, Beijing, People’s Republic of ChinaCorrespondence: Tuya Bao, School of Acupuncture-Moxibustion and Tuina, Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, People’s Republic of China, Email tuyab@263.net Yutong Fei, Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing, 100029, People’s Republic of China, Email feiyt@bucm.edu.cnPurpose: Anxious depression (AD) is a common, distinct depression subtype. This exploratory subgroup analysis aimed to explore the effects of acupuncture as an add-on therapy of selective serotonin reuptake inhibitors (SSRIs) for patients with AD or non-anxious depression (NAD).Patients and Methods: Four hundred and sixty-five patients with moderate-to-severe depression from the AcuSDep pragmatic trial were included in analysis. Patients were randomly assigned to receive MA+SSRIs, EA+SSRIs, or SSRIs alone (1:1:1) for six weeks. AD was defined by using dimensional criteria. The measurement instruments included 17-items Hamilton Depression Scale (HAMD-17), Self-Rating Depression Scale (SDS), Clinical Global Impression (CGI), Rating Scale for Side Effects (SERS), and WHO Quality of Life-BREF (WHOQOL-BREF). Comparison between AD and NAD subgroups and comparisons between groups within either AD or NAD subgroups were conducted.Results: Eighty percent of the patients met the criteria for AD. The AD subgroup had poorer clinical manifestations and treatment outcomes compared to those of the NAD subgroup. For AD patients, the HAMD response rate, remission rate, early onset rate, and the score changes on each scale at most measurement points on the two acupuncture groups were significantly better than the SSRIs group. For NAD patients, the HAMD early onset rates of the two acupuncture groups were significantly better than the SSRIs group.Conclusion: For AD subtype patients, either MA or EA add-on SSRIs showed comprehensive improvements, with small-to-medium effect sizes. For NAD subtype patients, both the add-on acupuncture could accelerate the response to SSRIs treatment. The study contributed to the existing literature by providing insights into the potential benefits of acupuncture in combination with SSRIs, especially for patients with AD subtypes. Due to its limited nature as a post hoc subgroup analysis, prospectively designed, high-quality trials are warranted.Clinical Trials Registration: ChiCTR-TRC-08000297.Keywords: anxious depression, non-anxious depression, acupuncture, SSRIs, subgroup analysis

Tong Bao,1,&ast; Liru Qin,2,&ast; Guimei Hou,1 Hongmei Jiang,1 Lifeng Wang,1 Ying Wang,1 Junhui Wu,1 Jinli Wang,3 Yunlei Pang4 1Department of Ophthalmological Examination, Chifeng Chaoju Eye Hospital, Chifeng, People’s Republic of China; 2Department of Ophthalmology, Inner Mongolia Baogang Hospital, Baotou, People’s Republic of China; 3Department of Cataract, Chifeng Chaoju Eye Hospital, Chifeng, People’s Republic of China; 4Department of Ophthalmic Plastic Surgery, Chifeng Chaoju Eye Hospital, Chifeng, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinli Wang, Department of Cataract, Chifeng Chaoju Eye Hospital, Chifeng, People’s Republic of China, Email chaojueyewjl66@163.com Yunlei Pang, Department of Ophthalmic Plastic Surgery, Chifeng Chaoju Eye Hospital, Chifeng, People’s Republic of China, Email 29483645@qq.comObjective: To investigate the association between the peripheral refractive errors of the fundus in different regions and moderate and high myopia.Methods: In this case-control study, 320 children and adolescents aged 6 to 18 years were recruited. Peripheral refractive errors were measured using multispectral retinal refractive topography (MRT). Spherical equivalent (SE) and cylinder errors were classified into low, moderate, and high categories based on the magnitude range. Logistic regression was performed to test the factors associated with myopia.Results: There were 152 participants with low myopia and 168 participants with moderate and high myopia included in the current study. Participants with moderate and high myopia were most likely to be older, with larger axial length (AL), lower SE, less time to watch electronic devices on the weekend, a higher difference between central refractive error and paracentral refractive error from the superior side of the retina (RDV-S), but a smaller difference between the central refractive error and paracentral refractive error from the inferior side of the retina (RDV-I) than those with low myopia (all P < 0.05). After logistic analysis, female sex (odds ratio [OR] = 4.14; 95% confidence interval [CI] = 2.16– 7.97, P < 0.001), AL (OR = 6.88, 95% CI = 4.33– 10.93, P < 0.001), and RDV-I (OR = 0.52, 95% CI = 0.32– 0.86, P = 0.010) were independent factors for moderate and high myopia.Conclusion: Our study demonstrated that the retina peripheral refraction of the eyes (RDV-I) was associated with moderate and high myopia, and RDV-S was only associated with high myopia.Keywords: peripheral refractive errors, myopia, spherical equivalent, logistic analysis, ocular biometrics

Abstract The epidemiology of vertebral fractures (VF) in underrepresented populations is not well-documented. This cohort study was part of a longitudinal osteoporosis research project with the aim of determining the prevalence, incidence, and risk factors for VF. 401 individuals (155 men) aged 50 years and older without a clinical diagnosis of VF were took radiographs at baseline and 2 years later. VF were ascertained using the Genant's semi-quantitative method. Bone mineral density (BMD) of femoral neck and lumbar spine were measured by dual-energy X-ray absorptiometry (Hologic Inc). The association between VF and risk factors was analyzed by the multiple logistic regression. The 95% confidence interval for prevalence and incidence was estimated by exact Poisson test. At baseline, the prevalence of VF was 12.2% (n = 49, 95% CI 9.0–16.2%) and increased with advancing age with one-fifth of those aged 70 and older having a VF. During the follow-up period, we observed 6 new VF, making the incidence of 6.6/1000 person-years (n = 6, 95% CI 2.4–14.3). The risk of prevalent VF was associated with male gender (OR: 2.67; 95% CI 1.28–5.87) and T-score at the femoral neck (OR per one SD decrease: 1.1; 1.03–1.17). These data indicate that VF is common among adults, and that lower femoral neck BMD was a risk factor for VF.

Synthetic antisense oligonucleotides (ASOs) are emerging as an attractive platform to treat various diseases. By specifically binding to a target mRNA transcript through Watson–Crick base pairing, ASOs can alter gene expression in a desirable fashion to either rescue loss of function or downregulate pathogenic protein expression. To be clinically relevant, ASOs are generally synthesized using modified analogs to enhance resistance to enzymatic degradation and pharmacokinetic and dynamic properties. Phosphorothioate (PS) belongs to the first generation of modified analogs and has played a vital role in the majority of approved ASO drugs, mainly based on the RNase H mechanism. In contrast to RNase H-dependent ASOs that bind and cleave target mature mRNA, splice-switching oligonucleotides (SSOs) mainly bind and alter precursor mRNA splicing in the cell nucleus. To date, only one approved SSO (Nusinersen) possesses a PS backbone. Typically, the synthesis of PS oligonucleotides generates two types of stereoisomers that could potentially impact the ASO’s pharmaco-properties. This can be limited by introducing the naturally occurring phosphodiester (PO) linkage to the ASO sequence. In this study, towards fine-tuning the current strategy in designing SSOs, we reported the design, synthesis, and evaluation of several stereo-random SSOs on a mixed PO–PS backbone for their binding affinity, biological potency, and nuclease stability. Based on the results, we propose that a combination of PO and PS linkages could represent a promising approach toward limiting undesirable stereoisomers while not largely compromising the efficacy of SSOs.

How stem cells give rise to epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find four spatially distinct stem cell populations at the top and bottom of rete ridges and transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling suggests that basal cell populations serve as crucial signaling hubs to maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest that transitional basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed transitional basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity.

Chronic inflammation is frequently observed in patients with myeloproliferative neoplasms (MPN). Here the authors observe elevated levels of IL-1α and IL-1β in MPN patients and show that IL-1 contributes to clonal expansion and bone marrow fibrosis in a mouse model of MPN, proposing targeting of IL1R1 as therapeutic intervention.

ABSTRACT How stem cells give rise to human interfollicular epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find at least four spatially distinct stem cell populations that decorate the top and bottom of rete ridge architecture and hold transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling through co-variance of cognate ligand-receptor pairs indicate that the basal cell populations distinctly serve as critical signaling hubs that maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest the “transitional” basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed “transitional” basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity.

Synthetic antisense oligonucleotides (ASOs) are emerging as an attractive platform to treat various diseases. By specifically binding to a target mRNA transcript through Watson–Crick base pairing, ASOs can alter gene expression in a desirable fashion to either rescue loss of function or downregulate pathogenic protein expression. To be clinically relevant, ASOs are generally synthesized using modified analogs to enhance resistance to enzymatic degradation and pharmacokinetic and dynamic properties. Phosphorothioate (PS) belongs to the first generation of modified analogs and has played a vital role in the majority of approved ASO drugs, mainly based on the RNase H mechanism. In contrast to RNase H-dependent ASOs that bind and cleave target mature mRNA, splice-switching oligonucleotides (SSOs) mainly bind and alter precursor mRNA splicing in the cell nucleus. To date, only one approved SSO (Nusinersen) possesses a PS backbone. Typically, the synthesis of PS oligonucleotides generates two types of stereoisomers that could potentially impact the ASO's pharmaco-properties. This can be limited by introducing the naturally occurring phosphodiester (PO) linkage to the ASO sequence. In this study, towards fine-tuning the current strategy in designing SSOs, we reported the design, synthesis, and evaluation of several stereo-random SSOs on a mixed PO–PS backbone for their binding affinity, biological potency, and nuclease stability. Based on the results, we propose that a combination of PO and PS linkages could represent a promising approach toward limiting undesirable stereoisomers while not largely compromising the efficacy of SSOs. [ABSTRACT FROM AUTHOR]

Perturbations of Ca2+ signaling in podocytes may deteriorate kidney function and eventually lead to proteinuria. Here the authors show that insulin can affect the function of the calcium regulator Ora1 in podocytes, which is critical for maintaining kidney filter integrity.

Laboratory-evolved RNAs bind a wide variety of targets and serve highly diverse functions, including as diagnostic and therapeutic aptamers. The majority of aptamers have been identified using in vitro selection (SELEX), a molecular evolution technique based on selecting target-binding RNAs from highly diverse pools through serial rounds of enrichment and amplification. In vitro selection typically yields multiple distinct motifs of highly variable abundance and target-binding affinities. The discovery of new aptamers is often limited by the difficulty of characterizing the selected motifs, because testing of individual sequences tends to be a tedious process. To facilitate the discovery of new aptamers within in vitro selected pools, we developed Apta-Seq, a multiplex analysis based on quantitative, ligand-dependent 2' acylation of solvent-accessible regions of the selected RNA pools, followed by reverse transcription (SHAPE) and deep sequencing. The method reveals, in a single sequencing experiment, the identity, structural features, and target dissociation constants for aptamers present in the selected pool. Application of Apta-Seq to a human genomic pool enriched for ATP-binding RNAs yielded three new aptamers, which together with previously identified human aptamers suggest that ligand-binding RNAs may be common in mammals.

Abstract Background Although endovascular treatment of the thoracic aorta (TEVAR) has become an elective procedure for treatment of complicated type B aortic dissection, its role in treating post dissection thoraco-abdominal aortic aneurysm (TAAA), is still limited. This is a case of aortic vascular disease, which reports the use of a new endovascular device. Case presentation : We present the case of a 62 year old male patient with a history of hypertension, active smoker, who presented penetrating descending thoracic aortic ulcer in the setting of a chronic abdominal aortic dissection. The patient was treated using a new stent graft capable of in situ fenestration that allowed crossing the stent-graft membrane, implanting a covered stent to exclude the re-entry at the level of the left renal artery and redirecting the blood flow through the true lumen. Conclusions This case report demonstrates the feasibility of a novel stent-graft concept. Larger studies with longer follow-up are essential to fully evaluate the safety and effectiveness of this new design.

The mechanisms regulating stem cells to give rise to human interfollicular epidermis are unclear. Here, the authors use single cell RNA sequencing to identify heterogeneity within the human neonatal interfollicular epidermis and distinct spatial positioning of at least four basal stem cell populations.

Cancer is one of the leading causes of death worldwide, and conventional cancer therapies such as surgery, chemotherapy, and radiotherapy do not address the underlying molecular pathologies, leading to inadequate treatment and tumor recurrence. Angiogenic factors, such as EGF, PDGF, bFGF, TGF-β, TGF-α, VEGF, endoglin, and angiopoietins, play important roles in regulating tumor development and metastasis, and they serve as potential targets for developing cancer therapeutics. Nucleic acid-based therapeutic strategies have received significant attention in the last two decades, and antisense oligonucleotide-mediated intervention is a prominent therapeutic approach for targeted manipulation of gene expression. Clinical benefits of antisense oligonucleotides have been recognized by the U.S. Food and Drug Administration, with full or conditional approval of Vitravene, Kynamro, Exondys51, and Spinraza. Herein we review the scope of antisense oligonucleotides that target angiogenic factors toward tackling solid cancers. Keywords: antisense oligonucleotides, nucleic acids, angiogenesis, antisense, modified oligonucleotides, cancer

Performance guarantees and tests of thermal power plants are usually carried out at 100% rate output capacity. However, fossil-fired power plants have decreased full load hours, affecting energy efficiency, and are subjected to frequent load changes caused by variable renewable electricity and potential grid stability. Therefore, this study is conducted to calculate and draw the characteristic curves for all stable loads of coal-fired power units including the 60%, 75%, and 100% rate output. The study focuses on the corrected plant net heat rates—gross unit outputs, net standard coal consumption rates—throttle steam pressures, and corrected plant net efficiencies—carbonic emission rates. In addition, the experimental investigation for energy efficiency and carbonic emission of the latest larger-scale (+600 MW) coal-fired power generation units in Vietnam are also implemented using a performance guarantee calculation software called “PG_Cal” version 0.0, which is based on a mass and energy balance method by MATLAB programing language. From the results of this study, it is suggested that the performance guarantees and tests of new coal-fired units should be carried out at different stable loads, including minimum load. Vietnam should apply the ultra-supercritical technology for new units in order to increase their efficiency and decrease carbon dioxide emissions.

Locked nucleic acid is a prominent nucleic acid analog with unprecedented target binding affinity to cDNA and RNA oligonucleotides and shows remarkable stability against nuclease degradation. Incorporation of locked nucleic acid nucleotides into an antisense oligonucleotide (AO) sequence can reduce the length required without compromising the efficacy. In this study, we synthesized a series of systematically truncated locked nucleic acid-modified 2′-O-methyl AOs on a phosphorothioate (PS) backbone that were designed to induce skipping exon 23 from the dystrophin transcript in H-2Kb-tsA58 mdx mouse myotubes in vitro. The results clearly demonstrated that shorter AOs (16- to 14-mer) containing locked nucleic acid nucleotides efficiently induced dystrophin exon 23 skipping compared with the corresponding 2′-O-methyl AOs. Our remarkable findings contribute significantly to the existing knowledge about the designing of short LNA-modified oligonucleotides for exon-skipping applications, which will help reduce the cost of exon-skipping AOs and potential toxicities, particularly the 2′-OMe-based oligos, by further reducing the length of AOs.

Background: Inflammatory cytokines (e. g. IL-13) and mechanical perturbations (e. g. scrape injury) to the epithelium release profibrotic factors such as TGF-beta(2), which may, in turn, stimulate subepithelial fibrosis in asthma. We hypothesized that prolonged IL-13 exposure creates a plastic epithelial phenotype that is profibrotic through continuous secretion of soluble mediators at levels that stimulate subepithelial fibrosis. Methods: Normal human bronchial epithelial cells (NHBE) were treated with IL-13 (0, 0.1, 1, or 10 ng/ml) for 14 days (day 7 to day 21 following seeding) at an air-liquid interface during differentiation, and then withdrawn for 1 or 7 days. Pre-treated and untreated NHBE were cocultured for 3 days with normal human lung fibroblasts (NHLF) embedded in rat-tail collagen gels during days 22-25 or days 28-31. Results: IL-13 induced increasing levels of MUC5AC protein, and TGF-beta(2), while decreasing beta-Tubulin IV at day 22 and 28 in the NHBE. TGF-beta(2), soluble collagen in the media, salt soluble collagen in the matrix, and second harmonic generation (SHG) signal from fibrillar collagen in the matrix were elevated in the IL-13 pre-treated NHBE co-cultures at day 25, but not at day 31. A TGF-beta(2) neutralizing antibody reversed the increase in collagen content and SHG signal. Conclusion: Prolonged IL-13 exposure followed by withdrawal creates an epithelial phenotype, which continuously secretes TGF-beta(2) at levels that increase collagen secretion and alters the bulk optical properties of an underlying fibroblast-embedded collagen matrix. Extended withdrawal of IL-13 from the epithelium followed by co-culture does not stimulate fibrosis, indicating plasticity of the cultured airway epithelium and an ability to return to a baseline. Hence, IL-13 may contribute to subepithelial fibrosis in asthma by stimulating biologically significant TGF-beta(2) secretion from the airway epithelium.

Abstract Integrin alpha-4 (ITGA4) is a validated therapeutic target for multiple sclerosis (MS) and Natalizumab, an antibody targeting ITGA4 is currently approved for treating MS. However, there are severe side effects related to this therapy. In this study, we report the development of a novel DNAzyme that can efficiently cleave the ITGA4 transcript. We designed a range of DNAzyme candidates across various exons of ITGA4. RNV143, a 30mer arm-loop-arm type DNAzyme efficiently cleaved 84% of the ITGA4 mRNA in human primary fibroblasts. RNV143 was then systematically modified by increasing the arm lengths on both sides of the DNAzymes by one, two and three nucleotides each, and incorporating chemical modifications such as inverted-dT, phosphorothioate backbone and LNA-nucleotides. Increasing the arm length of DNAzyme RNV143 did not improve the efficiency however, an inverted-dT modification provided the most resistance to 3′ → 5′ exonuclease compared to other modifications tested. Our results show that RNV143A could be a potential therapeutic nucleic acid drug molecule towards the treatment for MS.