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Arytera littoralis Blume 1847 is an evergreen small tree belonging to the Sapindaceae family. It is distributed in South China to SE Asia and the Solomon Islands. However, the chloroplast genome of A. littoralis has yet to be reported. In this study, the complete chloroplast genome of Arytera littoralis was determined. The total genome size was 161,091 bp in length, consisting of two inverted repeats (IRs) (28,432 bp) separated by the large single-copy (LSC) (85,737 bp) and small single-copy (SSC) (18,490 bp) regions. The genome contained 133 genes, including 87 protein-coding genes, 37 tRNA genes, and eight rRNA genes. The GC content of the complete chloroplast genome was 37.8%. A maximum-likelihood (ML) phylogenetic tree of A. littoralis and 13 related species from the family Sapindaceae indicated that A. littoralis was close to a clade composed of Sapindus, Nephelium, Litchi, and Dimocarpus. This study will offer essential genetic resources of A. littoralis and provide insights into the phylogeny and evolution of Sapindaceae.

Background The incidence density of metabolic dysfunction-associated fatty liver disease (MAFLD) and the effect of a healthy lifestyle on the risk of MAFLD remain unknown. We evaluated the prevalence and incidence density of MAFLD and investigated the association between healthy lifestyle and the risk of MAFLD. Methods A cross-sectional analysis was conducted on 37,422 participants to explore the prevalence of MAFLD. A cohort analysis of 18,964 individuals was conducted to identify the incidence of MAFLD, as well as the association between healthy lifestyle and MAFLD. Cox proportional hazards regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) with adjustments for confounding factors. Results The prevalence of MAFLD, non-alcoholic fatty liver disease, and their comorbidities were 30.38%, 28.09%, and 26.13%, respectively. After approximately 70 thousand person-years of follow-up, the incidence densities of the three conditions were 61.03, 55.49, and 51.64 per 1,000 person-years, respectively. Adherence to an overall healthy lifestyle was associated with a 19% decreased risk of MAFLD (HR, 0.81; 95% CI, 0.72 to 0.92), and the effects were modified by baseline age, sex, and body mass index (BMI). Subgroup analyses revealed that younger participants, men, and those with a lower BMI experienced more significant beneficial effects from healthy lifestyle. Conclusion Our results highlight the beneficial effect of adherence to a healthy lifestyle on the prevention of MAFLD. Health management for improving dietary intake, physical activity, and smoking and drinking habits are critical to improving MAFLD.

Post translational modifications (PTMs) can change the properties of a protein by covalent addition of functional groups to one or more amino acids, and influence almost all aspects of normal cell biology and pathogenesis. Lactylation is a novel identified PTM, and has been found in both histone and non-histone proteins. Since associated with the end product of glycolysis-- lactate, lactylation modification could provide a new perspective for understanding the relationship between metabolic reprogramming and epigenetic modifications. Accumulated evidences suggest that lactylation play important roles in tumor progression and links to poor prognosis in clinical studies. Histone lactylation can affect gene expression in tumor cells and immunological cells, further promoting tumor progression and immune suppression. Lactylation on non-histone proteins can also regulate tumor progression and drug resistance. In this review, we aimed to summarize the roles of lactylation in cancer progression, microenvironment interactions and immune suppression, try to identify new molecular targets for cancer therapy and provide a new direction for combined targeted therapy and immunotherapy.

C-type lectin receptors (CLRs) are essential to execute host defense against fungal infection. Nevertheless, a comprehensive understanding of the molecular underpinnings of CLR signaling remains a work in progress. Here, we searched for yet-to-be-identified tyrosine-phosphorylated proteins in Dectin-1 signaling and linked the stress-response protein valosin containing protein (VCP)/p97 to Dectin-1 signaling. Knockdown of VCP expression or chemical inhibition of VCP's segregase activity dampened Dectin-1-elicited SYK activation in BMDMs and BMDCs, leading to attenuated expression of proinflammatory cytokines/chemokines such as TNF-α, IL-6 and CXCL1. Biochemical analyses demonstrated that VCP and its cofactor UFD1 form a complex with SYK and its phosphatase SHP-1 following Dectin-1 ligation, and knockdown of VCP led to a more prominent SYK and SHP-1 association. Further, SHP-1 became polyubiquitinated upon Dectin-1 activation, and VCP or UFD1 overexpression accelerated SHP-1 degradation. Conceivably, VCP may promote Dectin-1 signaling by pulling the ubiquitinated SHP-1 out of the SYK complex for degradation. Finally, genetic ablation of VCP in the neutrophil and macrophage compartment rendered the mice highly susceptible to infection by Candida albicans, an observation also phenocopied by administering the VCP inhibitor. These results collectively demonstrate that VCP is a previously unappreciated signal transducer of the Dectin-1 pathway and a crucial component of antifungal defense, and suggest a new mechanism regulating SYK activation.

Abstract Background Observational studies have suggested an association between birth weight and type 2 diabetes mellitus, but the causality between them has not been established. We aimed to obtain the causal relationship between birth weight with T2DM and quantify the mediating effects of potential modifiable risk factors. Methods Two-step, two-sample Mendelian randomization (MR) techniques were applied using SNPs as genetic instruments for exposure and mediators. Summary data from genome-wide association studies (GWAS) for birth weight, T2DM, and a series of fatty acids traits and their ratios were leveraged. The inverse variance weighted (IVW) method was the main analysis approach. In addition, the heterogeneity test, horizontal pleiotropy test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) test, and leave-one-out analysis were carried out to assess the robustness. Results The IVW method showed that lower birth weight raised the risk of T2DM (β: −1.113, 95% CI: −1.573 ∼ −0.652). Two-step MR identified 4 of 17 candidate mediators partially mediating the effect of lower birth weight on T2DM, including ratio of polyunsaturated fatty acids to monounsaturated fatty acids (proportion mediated: 7.9%), ratio of polyunsaturated fatty acids to total fatty acids (7.2%), ratio of omega-6 fatty acids to total fatty acids (8.1%) and ratio of linoleic acid to total fatty acids ratio (6.0%). Conclusions Our findings supported a potentially causal effect of birth weight against T2DM with considerable mediation by modifiable risk factors. Interventions that target these factors have the potential to reduce the burden of T2DM attributable to low birth weight.

Abstract Background Non-alcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) shares common pathophysiological mechanisms with type 2 diabetes, making them significant risk factors for type 2 diabetes. The present study aimed to assess the epidemiological feature of type 2 diabetes in patients with NAFLD or MAFLD at global levels. Methods Published studies were searched for terms that included type 2 diabetes, and NAFLD or MAFLD using PubMed, EMBASE, MEDLINE, and Web of Science databases from their inception to December 2022. The pooled global and regional prevalence and incidence density of type 2 diabetes in patients with NAFLD or MAFLD were evaluated using random-effects meta-analysis. Potential sources of heterogeneity were investigated using stratified meta-analysis and meta-regression. Results A total of 395 studies (6,878,568 participants with NAFLD; 1,172,637 participants with MAFLD) from 40 countries or areas were included in the meta-analysis. The pooled prevalence of type 2 diabetes among NAFLD or MAFLD patients was 28.3% (95% confidence interval 25.2–31.6%) and 26.2% (23.9–28.6%) globally. The incidence density of type 2 diabetes in NAFLD or MAFLD patients was 24.6 per 1000-person year (20.7 to 29.2) and 26.9 per 1000-person year (7.3 to 44.4), respectively. Conclusions The present study describes the global prevalence and incidence of type 2 diabetes in patients with NAFLD or MAFLD. The study findings serve as a valuable resource to assess the global clinical and economic impact of type 2 diabetes in patients with NAFLD or MAFLD.

Abstract In situ monitoring of endogenous amino acid loss through sweat can provide physiological insights into health and metabolism. However, existing amino acid biosensors are unable to quantitatively assess metabolic status during exercise and are rarely used to establish blood-sweat correlations because they only detect a single concentration indicator and disregard sweat rate. Here, we present a wearable multimodal biochip integrated with advanced electrochemical electrodes and multipurpose microfluidic channels that enables simultaneous quantification of multiple sweat indicators, including phenylalanine and chloride, as well as sweat rate. This combined measurement approach reveals a negative correlation between sweat phenylalanine levels and sweat rates among individuals, which further enables identification of individuals at high metabolic risk. By tracking phenylalanine fluctuations induced by protein intake during exercise and normalizing the concentration indicator by sweat rates to reduce interindividual variability, we demonstrate a reliable method to correlate and analyze sweat-blood phenylalanine levels for personal health monitoring.

Metal–insulator transition has long been one of the key subjects in condensed matter systems. Herein, the emergence of a large energy gap (Eg, 0.8–1.0 eV) in Bi(110) two‐atomic‐layer nanoribbons grown on a SnSe(001) substrate is reported, which normally has an intrinsic semimetal‐like characteristic. The existence of this abnormally large Eg in Bi(110) is, however, determined by Bi coverage. When coverage is above ≈64 ± 2%, Eg vanishes, and instead, a Bi(110) semimetal‐like phase appears through a singular insulator–metal transition. Measurements using qPlus atomic force microscopy demonstrate that either insulating or semimetal‐like Bi(110) possesses a distorted black phosphorous structure with noticeable atomic buckling. Density function theory fully reproduces the semimetal‐like Bi(110) on SnSe(001). However, none of the insulating phases with this large Eg could be traced. Although the underlying mechanism of the large Eg and the insulator‐metal transition requires further exploration, experiments demonstrate that similar results can be achieved for Bi grown on SnS, the structural analog of SnSe, exhibiting an even larger Eg of ≈2.3 eV. The experimental strategy may be generalized to utilization of group‐IV monochalcogenides to create Bi(110) nanostructures with properties unachievable on other surfaces, providing an intriguing platform for exploring the interesting quantum electronic phases.

The occurence and development of tumors is a complicated process, which not only depends on the mutation or deletion of genes, but also is affected by epigenetic regulation. Accumulating evidences have shown that epigenetic modifications play fundamental roles in transcriptional regulation, heterochromatin formation, X chromosome inactivation, DNA damage response and tumor development. SET domain containing lysine methyltransferase 7 (SETD7) was initially identified as an important lysine methyltransferase, which methylated histone and non-histone proteins. These modifications play fundamental roles. Once this modification disorders, it can directly lead to cell abnormalities and cause many diseases. Studies have shown that SETD7 is related to the occurence and development of various tumors, but the methylation sites of SETD7 and its regulatory mechanism have not been fully elucidated. This article summarizes the research progress of the role of SETD7 on histone and non-histone methylation modification in tumors and the molecular mechanism, in order to provide new therapeutic targets for tumor pathogenesis and diagnosis.

Arsenic (As) species analysis is important for the risk evaluation of seafood. Until now, there has been limited information on the change of As species during digestion. Here, the As species in different types of seafood before and after in vitro digestion were investigated. Although inorganic As was not detected in digested fish samples, As(V) contents in digested crabs and scallops were 17.12 ± 1.76 and 138.69 ± 7.53, respectively, which were approximately 2–3 times greater than those of the pre-digestion samples. In further experiments, arsenocholine, dimethylarsinate, arsenobetaine, and monomethylarsonate were all convertible to As(V) during in vitro digestions with different rates. The transformation demonstrates a complex process and could be affected by many factors, such as pH, time, and digestion juice composition, of which pH seemed to be particularly important. Free radicals were responsible for the oxidation in the transformation reactions. Unlike arsenobetaine, arsenocholine seemed to be able to directly transform to monomethylarsonate without the intermediate dimethylarsinate. This study reveals and validates the potential of other species (oAs or/and unknown species) to convert to iAs, identifies the main factors affecting this process, and proposes a reaction pathway. There is an important implication for promoting a more accurate risk assessment of arsenic in foodstuffs.

Hymenasplenium obtusidentatum, a new fern species of the H. excisum subclade of Hymenasplenium (Aspleniaceae) from south and southwestern China was described. Molecular phylogenetic analyses and morphological observations of H. obtusidentatum and related species clearly indicated that this is a distinct taxonomic entity. Phylogenetically, H. obtusidentatum was confirmed to represent a diverging lineage in the H. excisum subclade of Hymenasplenium and was closely related to one lineage that includes accessions identified as H. obscurum, H. pseudobscurum and H. tholiformis. Morphologically, H. obtusidentatum can be distinguished by the combination of its lamina base truncate, stipe not shiny and with color of reddish brown to dark brown, and pinna marginal teeth that are not sharp, but blunt or rounded. A complete species description and comparison with related species in the H. excisum subclade were provided. The holotype of H. obtusidentatum was designated.

For a long time, people have suffered from uncertainty, complexity, and a low success rate in generating and screening antibodies against small molecules, which have become the core bottlenecks of immunochemistry. Here, the influence of antigen preparation on antibody generation was investigated at both molecular and submolecular levels. Neoepitopes (amide-containing neoepitopes) formed in the preparation of complete antigens are one of the most important factors limiting the efficiency of generating hapten-specific antibodies, which was verified by different haptens, carrier proteins, and conjugation conditions. Amide-containing neoepitopes present electron-dense structural components on the surface of prepared complete antigens and, therefore, induce the generation of the corresponding antibody with much higher efficiency than target hapten. Crosslinkers should be carefully selected and not overdosed. According to these results, some misconceptions in the conventional anti-hapten antibody production were clarified and corrected. By controlling the content of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) during the synthesis of immunogen to limit the formation of amide-containing neoepitopes, the efficiency of hapten-specific antibody generation could be significantly improved, which verified the correctness of the conclusion and provided an efficient strategy for antibody preparation. The result of the work is of scientific significance in the preparation of high-quality antibodies against small molecules.

There is now increasing demand to improve the sensitivity of various immunoassays for fluoroquinolones (FQs) and other food hazards. In this study, different coating antigens were prepared by adjusting the content of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) to explore its influence on the immunoassay sensitivity of FQs. The results indicated that, unlike traditional assumptions, a reasonable EDC dosage should be addressed to reach the best analytical efficiency, and excessive EDC could enhance the hapten-carrier conjugation but significantly reduce the detection sensitivity. For the FQs investigated, the hapten:EDC:BSA proportion of 20:2.5:50 (Mole ratio:74:34:1) seemed the best for preparation of coating antigens, and the sensitivity could be improved more than 1000 times both for indirect competitive enzyme linked immunosorbent assay ELISA (ic-ELISA) and gold immunochromatography assay (GICA) due to two key factors including coupling-ratios and amide bond groups. Such an improved efficiency was also validated well with different food samples, which indicated the reasonable optimization of EDC in coating antigen synthesis may be widely used as a new, simple and more effective strategy to improve the immunoassay for low molecular targets in medical, environment and food detection filed.

Background: Vitamin D has anti-inflammatory efficacy against ulcerative colitis (UC), however, the mechanism is yet little understood. Objective: To investigate the immunomodulatory effects of vitamin D against the UC, and to explore the potential downstream mechanisms. Materials and methods: Serum vitamin D, Interferon-γ (IFN-γ) and Interleukin (IL)-17 levels of the patients with UC were quantified using enzyme-linked immunosorbent assay (ELISA). Long non-coding RNAs (lncRNAs) levels were determined by using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Peripheral blood mononuclear cells (PBMCs) were collected from healthy control subjects, stimulated with CD4+ T lymphocytes or helper T cells 17(Th17) differentiation conditions, and then exposed to calcitriol (vitamin D active form) or certain lentiviral treatment, followed by subsequent molecular level testing. For in vivo assay, mice were given 3% dextran sulfate sodium (DSS) to induce colitis. Results: Compared with the control group, vitamin D levels in the UCs were statistically lower, and there was a negative correlation between IL-17 and vitamin D in the UCs. The lncRNA OIP5-AS1 could decrease under calcitriol treatment in both CD4+ T cells and Th17 differentiation. The lncRNA OIP5-AS1 was a microRNA (miR)-26a-5p sponge and therefore modulated the Th17 cells and IL-6 expression. The lncRNA OIP5-AS1/miR-26a-5p/IL-6 axis mediated the regulation of calcitriol-induced Th17 differentiation. Calcitriol had therapeutic effects on the UC mouse models by regulating the lncRNA OIP5-AS1 related pathway. Conclusion: Vitamin D might have anti-inflammatory potential in the treatment of the UC.

Pimpinella L. is one of the large genera in the Apiaceae family. In a previous study, the molecular phylogenies of Pimpinella were explored using nuclear ribosomal DNA internal transcribed spacers (ITS) and several chloroplast DNA segments. There have been few studies conducted on chloroplast genomes in Pimpinella, which has limited systematic understanding of this genus. We assembled the complete chloroplast genomes of nine Pimpinella species from China using data generated from next generation sequencing (NGS). The chloroplast (cp) DNA used were standard double-stranded molecules, ranging from 146,432 base pairs (bp) (P. valleculosa) to 165,666 bp (P. purpurea) in length. The circular DNA contained a large single-copy (LSC) region, small single-copy (SSC) region, and pair of inverted repeats (IRs). The cp DNA of the nine species contained 82–93 protein-coding genes, 36–37 transfer RNA (tRNA) genes, and eight ribosomal RNA (rRNA) genes, respectively. Four species (P. smithii, P. valleculosa, P. rhomboidea, and P. purpurea) exhibited striking distinctions in genome size, gene number, IR boundary, and sequence identity. We confirmed the non-monophyly of the Pimpinella species on the basis of the nine newly identified plastomes. The distant relationship between the above-mentioned four Pimpinella species and Pimpinelleae was indicated with high support values. Our study provides a foundation for future in-depth phylogenetic and taxonomic studies of genus Pimpinella.

Shewanella xiamenensis is widely found in spoilage fish, shrimp and other seafoods. Under suitable conditions, ornithine can be synthesized into putrescine, which may spoil food or endanger health. Our research used a wild strain of Shewanella xiamenensis isolated from “Yi Lu Xian” salted fish (a salting method for sea bass) as a research object. According to the database of National Center of Biotechnology Information (NCBI), the target ornithine decarboxylase (ODC) gene SpeF was successfully amplified using the wild strain of Shewanella xiamenensis as the template. Sequencing alignment showed that the SpeF of the wild strain had more than 98% homology compared with the standard strain. The amino acid substitution occurred in the residues of 343, 618, 705, and 708 in the wild strain. After optimizing the expression conditions, a heterologous expression system of ODC was constructed to achieve a high yield of expression. The amount of 253.38 mg of ODC per liter of LB broth was finally expressed. High performance liquid chromatography (HPLC) and subsequent ODC activity verification experiments showed that hetero-expressed ODC showed a certain enzyme activity for about 11.91 ± 0.38 U/mg. Our study gives a new way to the development of a low-cost and high-yield strategy to produce ODC, providing experimental materials for further research and elimination of putrescine in food hazards.

The efficiently renewable bioethanol can help to alleviate energy crisis and environmental pollution. Genetically modified strains for efficient use of xylose and developing lignocellulosic hydrolysates play an essential role in facilitating cellulosic ethanol production. Here we present a promising strain GRE3OE via GRE3 overexpressed in a previously reported Saccharomyces cerevisiae strain WXY70. A comprehensive evaluation of the fermentation level of GRE3OE in alkaline-distilled sweet sorghum bagasse, sorghum straw and xylose mother liquor hydrolysate. Under simulated corn stover hydrolysate, GRE3OE produced 53.39 g/L ethanol within 48 h. GRE3OE produced about 0.498 g/g total sugar in sorghum straw hydrolysate solution. Moreover, GRE3OE consumed more xylose than WXY70 in the high-concentration xylose mother liquor. Taken together, GRE3OE could be a candidate strain for industrial ethanol development, which is due to its remarkable fermentation efficiency during different lignocellulosic hydrolysates.

Single-domain antibodies (sdAbs) showed the incredible advantages of small molecular weight, excellent affinity, specificity, and stability compared with traditional IgG antibodies, so their potential in binding hidden antigen epitopes and hazard detection in food, agricultural and veterinary fields were gradually explored. Moreover, its low immunogenicity, easy-to-carry target drugs, and penetration of the blood-brain barrier have made sdAbs remarkable achievements in medical treatment, toxin neutralization, and medical imaging. With the continuous development and maturity of modern molecular biology, protein analysis software and database with different algorithms, and next-generation sequencing technology, the unique paratope structure and different antigen binding modes of sdAbs compared with traditional IgG antibodies have aroused the broad interests of researchers with the increased related studies. However, the corresponding related summaries are lacking and needed. Different antigens, especially hapten antigens, show distinct binding modes with sdAbs. So, in this paper, the unique paratope structure of sdAbs, different antigen binding cases, and the current maturation strategy of sdAbs were classified and summarized. We hope this review lays a theoretical foundation to elucidate the antigen-binding mechanism of sdAbs and broaden the further application of sdAbs.

Abstract Tumor progression requires the communication between tumor cells and tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are major components of stromal cells. CAFs contribute to metastasis process through direct or indirect interaction with tumor cells; however, the underlying mechanism is largely unknown. Here, we reported that autophagy was upregulated in lung cancer-associated CAFs compared to normal fibroblasts (NFs), and autophagy was responsible for the promoting effect of CAFs on non-small cell lung cancer (NSCLC) cell migration and invasion. Inhibition of CAFs autophagy attenuated their regulation on epithelial–mesenchymal transition (EMT) and metastasis-related genes of NSCLC cells. High mobility group box 1 (HMGB1) secreted by CAFs mediated CAFs’ effect on lung cancer cell invasion, demonstrated by using recombinant HMGB1, HMGB1 neutralizing antibody, and HMGB1 inhibitor glycyrrhizin (GA). Importantly, the autophagy blockade of CAFs revealed that HMGB1 release was dependent on autophagy. We also found HMGB1 was responsible, at least in part, for autophagy activation of CAFs, suggesting CAFs remain active through an autocrine HMGB1 loop. Further study demonstrated that HMGB1 facilitated lung cancer cell invasion by activating the NFκB pathway. In a mouse xenograft model, the autophagy specific inhibitor chloroquine abolished the stimulating effect of CAFs on tumor growth. These results elucidated an oncogenic function for secretory autophagy in lung cancer-associated CAFs that promotes metastasis potential, and suggested HMGB1 as a novel therapeutic target.

ObjectivesThe aim of this meta-analysis was to assess the quantitative associations between fruit and vegetable intake and cognitive disorders in older adults.DesignA meta-analysis.Setting and ParticipantsWe used the PubMed, Web of Science and Scopus databases for a literature search to 12 April 2022. We preliminarily retrieved 11,759 studies, 16 of which met the inclusion criteria including six cross-sectional studies, nine cohort studies and one case-control study, incorporating 64,348 participants and 9,879 cases.MethodsUsing the three databases, we identified observational studies exploring the association. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model.ResultsSixteen studies were included in the meta-analysis, and the results showed that increased fruit and vegetable consumption in older adults was associated with a decline in the prevalence of cognitive disorders (OR: 0.79, 95% CI: 0.76–0.83). Moreover, intake of fruits (OR: 0.83, 95% CI: 0.77–0.89) and vegetables (OR: 0.75, 95% CI: 0.70–0.80) alone were both associated with a lower prevalence of cognitive disorders. Subgroup analyses indicated that the intake of fruits and vegetables was associated with the prevalence of cognitive impairment (OR: 0.72, 95% CI: 0.76–0.80) and dementia (OR: 0.84, 95% CI: 0.78–0.91) but not Alzheimer’s disease (OR: 0.88, 95% CI: 0.76–1.01).Conclusion and ImplicationsOur meta-analysis provides evidence that the intake of fruits and vegetables is inversely proportional and linearly associated with the prevalence of cognitive disorders in older adults. Future research is required to further investigate the preventive effects of the frequency, quantity, and duration of eating vegetables and fruits on cognitive disorders in older adults.

Hearing loss, a common chronic condition, severely affects the quality of human life. However, the longitudinal relationships between household solid fuel use and hearing loss are unclear. To explore the associations between household solid fuel use and hearing loss in a Chinese population. There were 8835 participants enrolled in this prospective cohort study. Hearing function was assessed by asking the following self-reported question. Cox proportional hazards regression models were used to examine the relationships between baseline household solid fuel use and hearing loss incidence. After 6 (range, 2–7) years of follow-up, 1654 (18.72%) of 8835 participants developed hearing loss. This study demonstrated that increasing baseline solid fuel exposure was associated with a higher rate of poor hearing function (P for trend

Abstract Background Exposure to polycyclic aromatic hydrocarbons (PAHs) is related to decreased lung function. However, whether oxidative damage is involved in this relationship remains unclear. This study was aimed to explore the potential mediating role of oxidative DNA or lipid damage in the association between PAH exposure and lung function. Methods The urinary levels of monohydroxy polycyclic aromatic hydrocarbon metabolites (OH-PAHs) and lung function parameters were measured among 3367 participants from the baseline of the Wuhan-Zhuhai cohort. Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-isoprostane (8-iso-PGF2α) were determined to evaluate the individuals’ oxidative DNA and lipid damage degrees, respectively. Linear mixed models were used to investigate the associations of urinary OH-PAHs, 8-OHdG and 8-iso-PGF2α with lung function parameters. Mediation analysis was further conducted to assess the potential role of oxidative damage in the association between urinary OH-PAHs and lung function. Results Each one-percentage increase in the sum of urinary OH-PAHs, high-molecular-weight or low-molecular-weight OH-PAHs (ƩOH-PAHs, ƩHMW OH-PAH or ƩLMW OH-PAHs, respectively) was associated with a 0.2152-, 0.2076- or 0.1985- ml decrease in FEV1, and a 0.1891-, 0.2195- or 0.1634- ml decrease in FVC, respectively. Additionally, significantly positive dose-response relationships of ƩOH-PAHs, ƩHMW OH-PAH and ƩLMW OH-PAHs with urinary 8-OHdG or 8-iso-PGF2α, as well as an inverse dose-response relationship between urinary 8-OHdG and FVC, were observed (all P for trend

OBJECTIVES: Shift work is associated with metabolic disorders as it disturbs circadian rhythms. However, the potential association of shift work with knee osteoarthritis (KOA), a metabolic-related disease, has not been confirmed. The objective of this study was to quantify the association of shift work with the risk of KOA. METHODS: This retrospective cohort study comprising 13 741 retired workers from the Dongfeng Motor Corporation. KOA was defined by knee pain and clinical X-ray radiographs. Occupational history, including job description and shift work, was collected from face-to-face interviews using questionnaires. Cox proportional hazards regression models were used to estimate exposure–response relationships. RESULTS: During the 590 085 person-years of follow-up, a total of 847 cases of KOA (incidence of KOA was 143.5 per 100 000 person-years) were identified. After adjusting for potential confounders, shift work was independently associated with an elevated risk of KOA [hazard ratio (HR) 1.19, 95% confidence interval 1.03–1.36]. Compared with daytime workers, the risk of KOA increased with prolonged periods of shift work; the HR of KOA for participants with 1–9 years, 10–19 years, and ≥20 years shift work were 1.03 (95% CI 0.84–1.26), 1.19 (95% CI 0.98–1.46), and 1.42 (95% CI 1.15–1.76), respectively. The HR for KOA associated with shift work gradually decreased as the period after finishing shift work increased. CONCLUSION: Our results indicated that shift work could be an independent risk factor for KOA.

Abstract Background With the rapid development of the socioeconomic status, the mortality of several cancers has been changed in China during the past 30 years. We aimed to estimate the trends of mortality and years of life lost (YLLs) of various cancers in urban and rural areas of China from 1990 to 2017. Methods The mortality data were collected from Chinese yearbooks and the age structure of population from the Chinese sixth population census were used as reference to calculate age‐standardized mortality rates (ASMRs) and YLLs rates. Joinpoint regression analysis was implemented to calculate the annual percent change (APC) of mortality rates and YLL rates for cancers. YLLs owing to premature death were calculated as age‐specific cancer deaths multiplied by the reference life expectancy at birth of 80 years for male and 82.5 years for female. Results The ASMRs of all cancers showed significant decreasing trends for urban residents from 1990 to 2017, such downward trend without significance was also observed among rural residents. Interestingly, ASMRs of lung cancer and breast cancer have raised continuously in rural areas since 1990. The age‐standardized YYL rates for urban and rural residents decreased with 1.02% and 0.85% per year, respectively. YLLs in rural areas were higher than those in urban areas, whereas YLLs of urban outstripped those of rural finally with the increasing in YLLs of urban areas (216.71% for men and 207.87% for women). Conclusion The ASMRs and YLL rates of all cancers have declined in urban and rural areas from 1990 to 2017. YLLs increased in urban areas and remained higher level in rural areas after 2014 year. Preventive measures should be strengthened to against cancer, especially for lung cancer.

IntroductionPrevious research has shown that tea drinking has a bearing on Cognitive Disorders, but the conclusions are inconsistent. The purpose of this research was to systematically assess the published evidence pertaining to tea drinking and the risk of cognitive disorders in older adults using a meta-analysis, and to concurrently evaluate the dose-response association.DesignA meta-analysis.Setting and ParticipantsWe used the PubMed and Web of Science databases for a literature search until 30 May 2021. We initially retrieved 20,908 studies (14,884 from PubMed and 6,024 from the Web of Science), Thirty-six studies met the inclusion criteria (7 case-control, 16 cohort, and 13 cross-sectional studies), involved 224,980 participants.MethodsPooled odd ratios (ORs) with their corresponding 95% confidence intervals (CIs) were used to evaluate the strength of the association under a fixed- or random-effect model according to heterogeneity test results.ResultsThe results showed that drinking tea was negatively associated with cognitive disorders (OR: 0.76, 95% CI: 0.70–0.82). Moreover, dose-response associations were found between tea drinking and cognitive disorders (1 time/day: OR, 0.81; 95% CI, 0.70–0.95; 1 cup/day: OR, 0.86; 95% CI, 0.78–0.94). In addition, subgroup analyses were performed according to study designs, study population, types of tea drinking, outcomes and methods used to assess outcomes. Most of the results in the subgroup analyses were consistent with the main results.ConclusionThe results of the present study provided abundant evidence that tea drinking is inversely proportional with the occurrence of cognitive disorders in older adults. A linear dose-response association between tea drinking and decreased prevalence of cognitive disorders was found.

ObjectiveFrailty and depression, as two common conditions among older adults in China, have been shown to be closely related to each other. The aim of this study was to investigate the bidirectional effects between frailty and depressive symptoms in Chinese population.MethodsThe bidirectional effect of frailty with depressive symptoms was analyzed among 5,303 adults ≥ 60 years of age from the China Health and Retirement Longitudinal Study (CHARLS). Phenotype and a frailty index were used to measure frailty. Depressive symptoms were evaluated using the Epidemiological Studies Depression Scale (CES-D). Logistic regression and Cox proportional hazard regression models were used to determine the bidirectional effects of frailty and depressive symptoms in cross-sectional and cohort studies, respectively. Subgroup and sensitivity analyses were further used to further verify the associations.ResultsIn the cross-sectional study, the multivariate-adjusted ORs (95% CIs) for depressive symptoms among pre-frail and frail adults, as defined by the frailty index and phenotype, were 3.05 (2.68–3.49), and 9.78 (8.02–12.03), respectively. Depressed participants showed higher risks of pre-frailty and frailty [frailty index, 3.07 (2.69–3.50); and phenotypic frailty, 9.95 (8.15–12.24)]. During follow-up, the multivariate-adjusted HRs (95% CIs) for depressive symptoms among pre-frail and frail participants, as defined by the frailty index and phenotype, were 1.38 (1.22–1.57), and 1.30 (1.14–1.48), respectively. No significant relationship existed between baseline depressive symptoms and the incidence of frailty. Moreover, the results from subgroup and sensitivity analyses were consistent with the main results.ConclusionAlthough a cross-sectional bidirectional association between depressive symptom and frailty has been observed in older (≥60 years old) Chinese adults, frailty may be an independent predictor for subsequent depression. Moreover, no effect of depressive symptoms on subsequent frailty was detected. Additional bidirectional studies are warranted in China.

There are increasing demands for fast and simple detection of pathogens in foodstuffs. Fluorescence analysis has demonstrated significant advantages for easy operation and high sensitivity, although it is usually hindered by a complex matrix, low bacterial abundance, and long-term bacterial enrichment. Effective enrichment procedures are required to meet the requirements for food detection. Here, boronate-functionalized cellulose filter paper and specific fluorescent probes were combined. An integrated approach for the enrichment of detection of Staphylococcus aureus was proposed. The modification of polyethyleneimine demonstrated a significant effect in enhancing the bacterial enrichment, and the boronate affinity efficiency of the paper was increased by about 51~132%. With optimized conditions, the adsorption efficiency for S. aureus was evaluated as 1.87 × 108 CFU/cm2, the linear range of the fluorescent analysis was 104 CFU/mL~108 CFU/mL (R2 = 0.9835), and the lowest limit of detection (LOD) was calculated as 2.24 × 102 CFU/mL. Such efficiency was validated with milk and yogurt samples. These results indicated that the material had a high enrichment capacity, simple operation, and high substrate tolerance, which had the promising potential to be the established method for the fast detection of food pathogens.

Despite a growing preference for second-generation (2G) ethanol in industries, its application is severely restricted owing to a major obstacle of developing a suitable yeast strain for fermentation using feedstock biomasses. In this study, a yeast strain, Saccharomyces cerevisiae A31Z, for 2G bioethanol production was developed from an industrial strain, Angel, using metabolic engineering by the incorporation of gene clusters involved in the xylose metabolism combined with adaptive evolution for evolving its anti-inhibitory properties. This strain outcompeted its ancestors in xylose utilization and subsequent ethanol production and manifested higher tolerance against common inhibitors from lignocellulosic hydrolysates, and also it lowered the production of glycerol by-product. Furthermore, A31Z outperformed in ethanol production using industrial hydrolysate from dried distillers grains with solubles and whole corn. Overall, this study provided a promising path for improving 2G bioethanol production in industries using S. cerevisiae.

The effect of water source on cognitive functioning is poorly understood. The present study explored the associations between water source and cognition in 9921 participants from the China Health and Retirement Longitudinal Study (CHARLS). Cognitive functioning was measured from three aspects: orientation and attention, episodic memory, and visuo-construction. Water sources included tap and non-tap water. Generalized linear models and multiple logistic regression models were conducted to investigate the associations of cognitive scores with water source among the whole population and different subgroups. Results from cross-sectional analysis reported that participants without access to tap water showed a lower cognitive score (β = − 0.57; 95% CI: − 0.74, − 0.39) than those with tap water as a water source; and this phenomenon was pronounced for both sexes and across all residences. During 4-years’ follow-up, a greater decline of cognitive score was associated with no tap water use in the lowest quartile of baseline cognitive scores (β = − 0.67; 95% CI: − 1.26, − 0.08). Additionally, the utilization rate of tap water was lower in rural areas compared to urban areas. The lowest utilization rates were observed in urban areas of the Anhui province (0.38 in 2011 and 0.55 in 2015) and in rural areas of Inner Mongolia (0.09 in 2011 and 0.20 in 2015). These findings suggest that having no tap water may be a risk factor for cognition impairment, particularly for those with a low basic cognition score. Additionally, our results support the need to expand tap water use in China.

Cancer-associated fibroblasts (CAFs) are major component of tumor microenvironment (TME), which plays crucial roles in tumor growth, invasion and metastasis; however, the underling mechanism is not fully elucidated. Despite many studies are focused on the tumor promoting effect of CAFs-derived cytokines, the upstream regulators of cytokine release in CAFs is largely unknown. Here we found that miR-101-3p was downregulated in primary lung cancer-associated CAFs compared to normal fibroblasts (NFs). Ectopic overexpression of miR-101-3p suppressed CAFs activation, and abrogated the promoting effect of CAFs on migration and invasion of non-small cell lung cancer cells (NSCLC), through attenuating CAFs’ effect on epithelial mesenchymal transition (EMT) process, metastasis-related genes (MMP9, TWIST1) and AKT/endothelial nitric oxide synthase (eNOS) signaling pathway. Further study indicated that vascular endothelial growth factor A (VEGFA) was a novel target of miR-101-3p, and CAFs-derived VEGFA mediated the effect of miR-101-3p on migration and invasion of lung cancer cells, demonstrated by using recombinant VEGFA and VEGFA neutralizing antibody. Interestingly, the analysis of the Cancer Genome Atlas (TCGA) database revealed that lung cancer tissues expressed lower level of miR-101-3p than non-cancerous tissues, and low/medium-expression of miR-101-3p was associated with poor overall survival (OS) rate. Moreover, the mouse xenograft experiment also showed that CAFs accelerated tumor growth whereas miR-101-3p diminished CAFs’ effect. These findings revealed a novel mechanism that CAFs facilitated lung cancer metastasis potential via miR-101-3p/VEGFA/AKT signaling pathway, suggesting miR-101-3p as a potential candidate for metastasis therapy.

Purpose: This study aimed to determine the longitudinal association between hand grip strength (HGS) and the development of non-alcoholic fatty liver disease (NAFLD) in adults.Design: A cohort study.Methods: This study was conducted in a general Chinese population (n = 14,154) from 2013–2018. NAFLD was diagnosed by liver ultrasonography during evaluating alcohol consumption. The associations between the HGS and NAFLD were assessed using a multivariable Cox proportional hazards regression model.Results: During the study period with a mean follow-up duration of 3.20 years, 2,452 participants developed NAFLD. The risk of NAFLD decreased progressively with increasing HGS in both men and women (P for trend

Fullerenes are promising organic semiconducting materials for electronic applications, but of low conductivity due to limited intermolecular hybridization. Cui et al. show a black phosphorous substrate organizes C60 monolayers to form delocalized semiconducting band with tens times enhanced conductivity.

Background: Physical limitation, which has been linked to outdoor air pollution exposure in previous studies, is a risk factor for disability and even for premature death. Although people often spend more time indoors, the relationship between indoor air pollution and physical function has not been fully explored. Methods: The associations of household fuel types with self-reported and performance-based physical functioning were tested on a total of 12,458 participants in the China Health and Retirement Longitudinal Study (CHARL), using generalized linear models and logistic regression models. Additionally, subgroup analyses according to smoking status and number of chronic diseases, were performed regarding these associations. Results: Our results revealed that after adjusting for potential confounds, solid fuel use in cooking showed −0.08 (−0.13, −0.04) and −0.15 (−0.23, −0.06) declines in self-reported and performance-based physical functioning scores (higher scores means fewer physical limitations), when compared with cleaner groups, respectively. Considering these outcomes as binary variables, the ORs (95% CIs) for abnormal self-reported and performance-based physical functioning in the solid fuel cooking group were 1.226 (1.053–1.427) and 1.194 (1.072–1.330), respectively. No significant association between heating fuel use and physical functioning was observed. Additionally, no modification effect of smoking status and the number of chronic diseases on the association between cooking fuel use and performance-based physical functioning was observed (P > 0.05). Conclusion: Our findings suggested that solid cooking fuel use may be associated with self-reported and performance-based physical functioning decline of middle-aged and elder Chinese populations.

The reported haploid Saccharomyces cerevisiae strain F106 can utilize xylose for ethanol production. After a series of XR and/or XDH mutations were introduced into F106, the XR-K270R mutant was found to outperform others. The corresponding haploid, diploid, and triploid strains were then constructed and their fermentation performance was compared. Strains F106-KR and the diploid produced an ethanol yield of 0.45 and 0.48 g/g total sugars, respectively, in simulated corn hydrolysates within 36 h. Using non-detoxicated corncob hydrolysate as the substrate, the ethanol yield with the triploid was approximately sevenfold than that of the diploid at 40°C. After a comprehensive evaluation of growth on corn stover hydrolysates pretreated with diluted acid or alkali and different substrate concentrations, ethanol yields of the triploid strain were consistently higher than those of the diploid using acid-pretreatment. These results demonstrate that the yeast chromosomal copy number is positively correlated with increased ethanol production under our experimental conditions.

Xylose is the second most abundant sugar in lignocellulose, but it cannot be used as carbon source by budding yeast Saccharomyces cerevisiae. Rational promoter elements engineering approaches were taken for efficient xylose fermentation in budding yeast. Among promoters surveyed, HXT7 exhibited the best performance. The HXT7 promoter is suppressed in the presence of glucose and derepressed by xylose, making it a promising candidate to drive xylose metabolism. However, simple ectopic expression of both key xylose metabolic genes XYL1 and XYL2 by the HXT7 promoter resulted in massive accumulation of the xylose metabolic byproduct xylitol. Through the HXT7-driven expression of a reported redox variant, XYL1-K270R, along with optimized expression of XYL2 and the downstream pentose phosphate pathway genes, a balanced xylose metabolism toward ethanol formation was achieved. Fermented in a culture medium containing 50 g/L xylose as the sole carbon source, xylose is nearly consumed, with less than 3 g/L xylitol, and more than 16 g/L ethanol production. Hence, the combination of an inducible promoter and redox balance of the xylose utilization pathway is an attractive approach to optimizing fuel production from lignocellulose.

Background: To date, few studies have focused on the influence of indoor air pollution on cognitive impairment. Thus, we aimed to explore the association of household fuel use, the major cause of household air pollution, with cognitive functioning among a sample of middle-aged and older Chinese individuals. Methods: A total of 10,372 and 8,397 participants from the China Health and Retirement Longitudinal Study (CHARLS) were enrolled in the cross-sectional and follow-up analyses, respectively. Cognitive functioning was evaluated via a structured questionnaire in three dimensions: orientation and attention, episodic memory, and visuo-construction. The associations between household solid fuel use (for cooking and heating) and cognitive functioning were elucidated by generalized linear models. Furthermore, we explored the combined effect of solid fuel use in cooking and heating and examined the effects of switching cooking fuel types on a 4-year change in cognitive functioning. Results: In the cross-sectional study, solid fuel use for cooking or heating, separately or simultaneously, was positively associated with cognitive impairment, after adjusting for potential confounders. Similarly, in the follow-up study, solid cooking fuel use was associated with a greater decline in cognitive score overall (β = −0.24, 95% confidence interval [CI]: −0.45, −0.04), mostly in the episodic memory (β = −0.19, 95% CI: −0.34, −0.03) and visuo-construction (β = −0.03, 95% CI: −0.05, −0.01) dimensions; solid heating fuel use was associated only with a greater decrease in the orientation and attention dimension (β = −0.13, 95% CI: −0.25, −0.01). A combined effect of household fuel use was also observed (P

We observed the floral development of Hemiorchis burmanica and two species of Gagnepainia, which make up the sister group of Globba in Globbeae, as well as a selected number of species of Globba. Our observations revealed that in Gagnepainia, a “fifth staminode,” develops as part of the labellum, while it is generally lost in other Zingiberaceae. The fifth staminode, however, was not initiated in the labellum of Hemiorchis. A fifth staminode was also observed in Globba geoffrayi but was not found in all other species of Globba investigated. While the staminode becomes an integral part of the labellum in Gagnepainia, it remains small and almost aborts at later stages of development in G. geoffrayi. These results indicate that the development of a fifth staminode could be a recurring plesiomorphic trait for Globbeae, only retained in G. geoffrayi. The retention of the fifth staminode and its heterochronic shift may be linked with the mechanical constriction within the flower bud. The results may also support the interpretation of an atavistic expression of a once lost staminode.

The matrix effect is a serious problem for the immunoassay of antibiotic residues, which greatly restricts its real application in fishery products as well as other foodstuffs. Till now the related information on the colloidal gold immunochromatographic assay (GICA) is still limited. Therefore, five species of fish as samples, and the interference of main matrix components on the analysis of ciprofloxacin was investigated. Some water-soluble proteins were demonstrated to have significant affluence on GICA. Moreover, magnesium is also an important source of the matrix interference was revealed for the first time, and its interaction with some immunoglobin (Ig)G was assumed to be a possible reason for this. Based on these results, corresponding approaches for elimination of the interference were also explored. The matrix interference was fully eliminated and the sensitivity of GICA was increased about 8 times for the quantitative analysis of ciprofloxacin via acid pre-treatment followed by pH adjustment.

Pimpinella smithii Wolff is endemic in China. In this study, the complete chloroplast genome of P. smithii was determined. The total genome size was 147,130 bp in length. It was found to possess the quadripartite structure, containing a pair of inverted repeats (IRs) of 18,264 bp, which were separated by large single copy (LSC) and small single copy (SSC) of 93,158 bp and 17,444 bp, respectively. A total of 129 genes were identified, including 85 protein-coding genes, 36 tRNA genes, and eight rRNA genes. The maximum-likelihood phylogenetic analysis indicated that P. smithii has close relationship with genus Angelica.

Exon-skipping therapies such as systemic i.v. administration of morpholino are being explored as a means of treating Duchenne muscular dystrophy. Here the authors show that adding a glucose-fructose mix can enhance uptake of phosphorodiamidate morpholino oligomer and its therapeutic effect in mdxmice.

[This corrects the article DOI: 10.1371/journal.pone.0111079.].

Microelectromechanical switch has become an essential component in a wide variety of applications, ranging from biomechanics and aerospace engineering to consumer electronics. Electrostatically actuated microbeams and microplates are chief parts of many MEMS instruments. In this study, the nonlinear characteristics of coupled longitudinal–transversal vibration are analyzed, while an electrostatically actuated microbeam is designed considering that the frequency ratio is two to one between the first longitudinal vibration and transversal vibration. The nonlinear governing equations are truncated into a set of coupled ordinary differential equations by the Galerkin method. Then the equations are solved using the multiple-scales method and the nonlinear dynamics of the internal resonance is investigated. The influence of bias voltage, longitudinal excitation and frequency detuning parameters are mainly analyzed. Results show that using the pseudo-arclength continuation method, the nonlinear amplitude–response curves can be plotted continuously. The saturation and jump phenomena are greatly affected by the bias voltage and the detuning frequency. Beyond the critical excitation amplitude, the response energy will transfer from the longitudinal motion to the transversal motion, even the excitation is employed on the longitudinal direction. The large-amplitude jump of the low-order vibration mode can be used to detect the variation of the conditions or parameters, which shows great potential in improving precision of MEMS switches.

Antisense oligonucleotide (AO)-mediated exon-skipping therapeutics shows great promise in correcting frame-disrupting mutations in the DMD gene for Duchenne muscular dystrophy. However, insufficient systemic delivery limits clinical adoption. Previously, we showed that a glucose/fructose mixture augmented AO delivery to muscle in mdx mice. Here, we evaluated if fructose alone could enhance the activities of AOs with different chemistries in mdx mice. The results demonstrated that fructose improved the potency of AOs tested with the greatest effect on phosphorodiamidate morpholino oligomer (PMO), resulted in a 4.25-fold increase in the number of dystrophin-positive fibres, compared to PMO in saline in mdx mice. Systemic injection of lissamine-labeled PMO with fructose at 25 mg/kg led to increased uptake and elevated dystrophin expression in peripheral muscles, compared to PMO in saline, suggesting that fructose potentiates PMO by enhancing uptake. Repeated intravenous administration of PMO in fructose at 50 mg/kg/week for 3 weeks and 50 mg/kg/month for 5 months restored up to 20% of wild-type dystrophin levels in skeletal muscles with improved functions without detectable toxicity, compared to untreated mdx controls. Collectively, we show that fructose can potentiate AOs of different chemistries in vivo although the effect diminished over repeated administration.

Antisense oligonucleotide (AO)-mediated exon-skipping therapeutics shows great promise for Duchenne muscular dystrophy (DMD) patients. However, recent failure with drisapersen, an AO candidate drug in phase 3 trial, highlights the importance of exploring other effective AO chemistries for DMD. Previously, we demonstrated the appreciable biological activity of peptide nucleic acid (PNA) AOs in restoring dystrophin expression in dystrophin-deficient mdx mice intramuscularly. Here, we further explore the systemic potential and feasibility of PNA AOs in mediating exon skipping in mdx mice as a comprehensive systemic evaluation remains lacking. Systemic delivery of PNA AOs resulted in therapeutic level of dystrophin expression in body-wide peripheral muscles and improved dystrophic pathology in mdx mice without any detectable toxicity. Up to 40% of dystrophin restoration was achieved in gastrocnemius, to a less extent with other skeletal muscles, with no dystrophin in heart. Notably, comparable systemic activity was obtained between PNA AOs and phosphorodiamidate morpholino oligomer, a DMD AO chemistry in phase 3 clinical trial, under an identical dosing regimen. Overall, our data demonstrate that PNA is viable for DMD exon-skipping therapeutics with 20 mer showing the best combination of activity, solubility, and safety and further modifications to increase PNA aqueous solubility can enable longer, more effective therapeutics without the associated toxicity.

A readily available animal model is essential for rapidly identifying effective treatments for Duchenne muscular dystrophy (DMD), a devastating neuromuscular disorder caused by the lack of dystrophin protein, which results from frame-disrupting mutations in the DMD gene. Currently, the mdx mouse is the most commonly used model for antisense oligonucleotide (AO)-mediated exon skipping pre-clinical studies, with a mild phenotype. However, the accessibility of mdx mouse colonies particularly in developing countries can constrain research. Therefore in this study we explore the feasibility of using wild-type mice as models to establish exon-skipping efficiency of various DMD AO chemistries and their conjugates. Four different strains of wild-type mice and six different AO chemistries were investigated intramuscularly and the results indicated that the same exon-skipping efficiency was achieved for all tested AOs as that from mdx mice. Notably, levels of exon-skipping obtained in C57BL6 and C3H and mdx mice were most closely matched, followed by ICR and BALB/C mice. Systemic validation revealed that wild-type mice are less responsive to AO-mediated exon skipping than mdx mice. Our study provides evidence for the first time that wild-type mice can be appropriate models for assessing DMD AO exon-skipping efficiency with similar sensitivity to that of mdx mice and this finding can further accelerate the development of effective DMD AOs.

Antisense oligonucleotide (AO)-mediated exon-skipping therapy is one of the most promising therapeutic strategies for Duchenne Muscular Dystrophy (DMD) and several AO chemistries have been rigorously investigated. In this report, we focused on the effect of 2'-O-methoxyethyl oligonucleotides (MOE) on exon skipping in cultured mdx myoblasts and mice. Efficient dose-dependent skipping of targeted exon 23 was achieved in myoblasts with MOE AOs of different lengths and backbone chemistries. Furthermore, we established that 25-mer MOE phosphorothioate (PS) AOs provided the greatest exon-skipping efficacy. When compared with 2'O methyl phosphorothioate (2'OmePS) AOs, 25-mer MOE (PS) AOs also showed higher exon-skipping activity in vitro and in mdx mice after intramuscular injections. Characterization of uptake in vitro corroborated with exon-skipping results, suggesting that increased uptake of 25-mer MOE PS AOs might partly contribute to the difference in exon-skipping activity observed in vitro and in mdx mice. Our findings demonstrate the substantial potential for MOE PS AOs as an alternative option for the treatment of DMD.