Cascade Sequence of Photooxygenation-Epoxidation for the Flow Synthesis of Epoxy Alcohols.

A photooxygenation-epoxidation cascade sequence converting alkenes to epoxy alcohols was developed and evaluated in batch and continuous-flow systems. In the batch system, the undesired interactions between the photooxygenation and epoxidation catalysts resulted in suboptimal yields, whereas the fine control of reaction parameters in the flow system allowed the allyl hydroperoxides produced through photooxygenation of alkenes to be rapidly converted to epoxy alcohols in yields of up to 93%. The developed procedure allows one to avoid an important synthetic bottleneck, works well where traditional batch synthesis fails, and can be scaled up to meet the needs of industrial production, thus presenting a valuable addition to the toolbox of practicing organic chemists.

Current advances and future prospects of in-situ desulfurization processes in oxy-fuel combustion reactors.

Oxy-fuel circulating fluidized bed combustion is known as one of the most potent fuel combustion technologies that capture ultra-low greenhouse gases and pollutant emissions. While many investigations have been conducted for carbon capturing, the associated in-situ desulfurization process using calcium-based sorbents should also be underlined. This paper critically reviews the effects of changes in the operating environment on in-situ desulfurization processes compared to conventional air combustion. A comprehensive understanding of the process, encompassing hydrodynamic, physical and chemical aspects can be a guideline for designing the oxy-fuel combustion process with effective sulfur removal, potentially eliminating the need of a flue gas desulfurization unit. Results from thermogravimetric analyzers and morphological changes of calcium-based materials were presented to offer an insight into the sulfation mechanisms involved in the oxy-fuel circulating fluidized beds. Recently findings suggested that in-situ direct desulfurization is influenced not only by the desulfurization kinetics but also by the fluidization characteristics of calcium-based materials. Therefore, a complex reaction analysis that incorporated oxy-combustion reactions, computational fluid dynamics modeling, in-situ desulfurization reaction models and particle behavior can provide a thorough understanding of desulfurization processes across the reactor. Meanwhile, machine learning as a robust tool to predict desulfurization efficiency and improve operational flexibility should be applied with consideration of environmental improvement and economic feasibility.

A lipase from Lacticaseibacillus rhamnosus IDCC 3201 with thermostability and pH resistance for use as a detergent additive.

Lipases are important biocatalysts and ubiquitous in plants, animals, and microorganisms. The high growth rates of microorganisms with low production costs have enabled the wide application of microbial lipases in detergent, food, and cosmetic industries. Herein, a novel lipase from Lacticaseibacillus rhamnosus IDCC 3201 (Lac-Rh) was isolated and its activity analyzed under a range of reaction conditions to evaluate its potential industrial application. The isolated Lac-Rh showed a molecular weight of 24 kDa and a maximum activity of 3438.5 ± 1.8 U/mg protein at 60 °C and pH 8. Additionally, Lac-Rh retained activity in alkaline conditions and in 10% v/v concentrations of organic solvents, including glycerol and acetone. Interestingly, after pre-incubation in the presence of multiple commercial detergents, Lac-Rh maintained over 80% of its activity and the stains from cotton were successfully removed under a simulated laundry  setting. Overall, the purified lipase from L. rhamnosus IDCC 3201 has potential for use as a detergent in industrial applications. KEY POINTS: • A novel lipase (Lac-Rh) was isolated from Lacticaseibacillus rhamnosus IDCC 3201 • Purified Lac-Rh exhibited its highest activity at a temperature of 60 °C and a pH of 8, respectively • Lac-Rh remains stable in commercial laundry detergent and enhances washing performance.

Prevalence of viral agents causing swine reproductive failure in Korea and the development of multiplex real-time PCR and RT-PCR assays.

This study aimed to investigate the prevalence of viral agents causing reproductive failure in pigs in Korea. In addition, two types of multiplex real-time PCR (mqPCR) were developed for the simultaneous detection of Aujeszky's disease virus (ADV) and porcine parvovirus (PPV) in mqPCR and encephalomyocarditis virus (EMCV) and Japanese encephalitis virus (JEV) in reverse transcription mqPCR (mRT-qPCR). A total of 150 aborted fetus samples collected from 2020 to 2022 were analyzed. Porcine reproductive and respiratory syndrome virus was the most prevalent (49/150 32.7%), followed by porcine circovirus type 2 (31/150, 20.7%), and PPV1 (7/150, 4.7%), whereas ADV, EMCV, and JEV were not detected. The newly developed mqPCR and mRT-qPCR could simultaneously detect and differentiate with high sensitivities and specificities. When applied to aborted fetuses, the newly developed mqPCR for PPV was 33.3% more sensitivities than the previously established diagnostic method. Amino acid analysis of the VP2 sequences of PPV isolates revealed considerable similarity to the highly pathogenic Kresse strain. This study successfully evaluated the prevalence of viral agents causing reproductive failure among swine in Korea, the developed mqPCR and mRT-qPCR methods could be utilized as effective and accurate diagnostic methods for the epidemiological surveillance of ADV, PPV, EMCV, and JEV.

Cholesterol profiling reveals 7ß-hydroxycholesterol as a pathologically relevant peripheral biomarker of Alzheimer's disease.

AIM: Cholesterol homeostasis is associated with Alzheimer's disease (AD). Despite the multitude of cholesterol metabolites, little is known about which metabolites are directly involved in AD pathogenesis and can serve as its potential biomarkers. METHODS: To identify "hit" metabolites, steroid profiling was conducted in mice with different age, diet, and genotype and also in humans with normal cognition, mild cognitive impairment, and AD using gas chromatography-mass spectrometry. Then, using one of the "hit" molecules (7ß-hydroxycholesterol; OHC), molecular and histopathological experiment and behavioral testing were conducted in normal mice following its intracranial stereotaxic injection to see whether this molecule drives AD pathogenesis and causes cognitive impairment. RESULTS: The serum levels of several metabolites, including 7ß-OHC, were increased by aging in the 3xTg-AD unlike normal mice. Consistently, the levels of 7ß-OHC were increased in the hairs of patients with AD and were correlated with clinical severity. We found that 7ß-OHC directly affects AD-related pathophysiology; intrahippocampal injection of 7ß-OHC induced astrocyte and microglial cell activation, increased the levels of pro-inflammatory cytokines (TNF-alpha, IL-1ß, IL-6), and enhanced amyloidogenic pathway. Mice treated with 7ß-OHC also exhibited deficits in memory and frontal/executive functions assessed by object recognition and 5-choice serial reaction time task, respectively. CONCLUSIONS: Our results suggest that 7ß-OHC could serve as a convenient, peripheral biomarker of AD. As directly involved in AD pathogenesis, 7ß-OHC assay may help actualize personalized medicine in a way to identify an at-risk subgroup as a candidate population for statin-based AD treatment.

Biosynthesis of AS2077715 and Funiculosin: Pathway Reconstitution and Identification of Enzymes that Form the All-cis Cyclopentanetetraol Moiety.

The complete biosynthetic pathways of the potent antifungals AS2077715 (1) and funiculosin (2) are reconstituted and characterized. A five-enzyme cascade, including a multifunctional flavin-dependent monooxygenease and a repurposed O-methyltransferase, is involved to perform the dearomatization, stereoselective ring contraction, and redox transformations to morph a hydroxyphenyl-containing precursor into the unusual all-cis cyclopentanetetraol moiety.

Intra-Lysosomal Peptide Assembly for the High Selectivity Index against Cancer.

Lysosomes remain powerful organelles and important targets for cancer therapy because cancer cell proliferation is greatly dependent on effective lysosomal function. Recent studies have shown that lysosomal membrane permeabilization induces cell death and is an effective way to treat cancer by bypassing the classical caspase-dependent apoptotic pathway. However, most lysosome-targeted anticancer drugs have very low selectivity for cancer cells. Here, we show intra-lysosomal self-assembly of a peptide amphiphile as a powerful technique to overcome this problem. We designed a peptide amphiphile that localizes in the cancer lysosome and undergoes cathepsin B enzyme-instructed supramolecular assembly. This localized assembly induces lysosomal swelling, membrane permeabilization, and damage to the lysosome, which eventually causes caspase-independent apoptotic death of cancer cells without conventional chemotherapeutic drugs. It has specific anticancer effects and is effective against drug-resistant cancers. Moreover, this peptide amphiphile exhibits high tumor targeting when attached to a tumor-targeting ligand and causes significant inhibition of tumor growth both in cancer and drug-resistant cancer xenograft models.

Protocatechuic Acid and Syringin from Saussurea neoserrata Nakai Attenuate Prostaglandin Production in Human Keratinocytes Exposed to Airborne Particulate Matter.

Saussurea neoserrata Nakai offers a reliable and efficient source of antioxidants that can help alleviate adverse skin reactions triggered by air pollutants. Air pollutants, such as particulate matter (PM), have the ability to infiltrate the skin and contribute to the higher occurrence of cardiovascular, cerebrovascular, and respiratory ailments. Individuals with compromised skin barriers are particularly susceptible to the impact of PM since it can be absorbed more readily through the skin. This study investigated the impact of protocatechuic acid and syringin, obtained from the n-BuOH extract of S. neoserrata Nakai, on the release of PGE2 and PGD2 induced by PM10. Additionally, it examined the gene expression of the synthesis of PGE2 and PGD2 in human keratinocytes. The findings of this research highlight the potential of utilizing safe and efficient plant-derived antioxidants in dermatological and cosmetic applications to mitigate the negative skin reactions caused by exposure to air pollution.

Systemic Delivery of a STING Agonist-Loaded Positively Charged Liposome Selectively Targets Tumor Immune Microenvironment and Suppresses Tumor Angiogenesis.

Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti-tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.

Protein-Precoated Surface of Metal-Organic Framework Nanoparticles for Targeted Delivery.

Metal-organic framework (MOF) nanoparticles have recently emerged as a promising vehicle for drug delivery with high porosity and feasibility. However, employing a MOF-based drug delivery system remains a challenge due to the difficulty in controlling interfaces of particles in a biological environment. In this paper, protein corona-blocked Zr6 -based MOF (PCN-224) nanoparticles are presented for targeted cancer therapy with high efficiency. The unmodified PCN-224 surface is precoated with glutathione transferase (GST)-fused targetable affibody (GST-Afb) proteins via simple mixing conjugations instead of chemical modifications that can induce the impairment of proteins. GST-Afb proteins are shown to stably protect the surface of PCN-224 particles in a specific orientation with GST adsorbed onto the porous surface and the GST-linked Afb posed outward, minimizing the unwanted interfacial interactions of particles with external biological proteins. The Afb-directed cell-specific targeting ability of particles and consequent induction of cell death is demonstrated both in vitro and in vivo by using two kinds of Afb, which targets the surface membrane receptor, human epidermal growth factor receptor 2 (HER2) or epidermal growth factor receptor (EGFR). This study provides insight into the way of regulating the protein-adhesive surface of MOF nanoparticles and designing a more effective MOF-hosted targeted delivery system.

In-situ desulfurization using porous Ca-based materials for the oxy-CFB process: A computational study.

Within circulating fluidized bed (CFB) processes, gas and solid behaviors are mutually affected by operating conditions. Therefore, understanding the behaviors of gas and solid materials inside CFB processes is required for designing and operating those processes. In addition, in order to minimize the environmental impact, modeling to reduce pollutants such as SOx emitted from those processes is essential, and simulation reproduction is necessary for optimization, but little is known. In this study, the gas and solid behaviors in a pilot-scale circulating fluidized bed combustor were investigated by using computational particle fluid dynamics (CPFD) numerical simulation based on the multiphase particle-in-cell (MP-PIC) method under oxy-fuel combustion conditions. In particular, the combustion and in-situ desulfurization reactions simultaneously were considered in this CPFD model. Effect of fluidization number (ULS/Umf) was investigated through the comparison of particle circulation rates with regards to the loop seal flux plane and bed height in the standpipe. In addition, the effects of parameters (temperature, Ca/S molar ratio, and particle size distribution), sensitive indicators for the desulfurization efficiency of limestone, were confirmed. Based on the cycle of the thermodynamic equilibrium curve of limestone, it is suggested that direct and indirect desulfurization occur simultaneously under different operating conditions in CFB, creating an environment in which various reactions other than desulfurization can occur. Addition of the reaction equations (i.e., porosity, diffusion) to the established simple model minimizes uncertainty in the results. Furthermore, the model can be utilized to optimize in-situ desulfurization under oxy-CFB operating conditions.

Systematic review and meta-analysis of randomization controlled and nonrandomized controlled studies on nurse-led nonpharmacological interventions to improve cognition in people with dementia.

AIMS AND OBJECTIVES: To evaluate nurse-led nonpharmacological interventions for improving cognition in people with dementia. BACKGROUND: Starting in 2006, donepezil was administered worldwide to improve cognition; however, its side effects limited its therapeutic value for long-term use, prompting a need for nonpharmacological interventions to improve cognition. Nurse-led nonpharmacological interventions are especially important because they are effective in terms of resources and costs, reduce patient latency and improve patient safety and satisfaction. METHODS: A systematic review was identified by searching 10 electronic databases. The search period was between 1 January 2007, and 30 September 2021. Languages were limited to English and Korean. The inclusion criteria were studies of nurse-led interventions that evaluated cognition using validated instruments. The exclusion criteria were qualitative research, scale development studies, abstracts and grey literature. Quality appraisal of research was conducted using the Risk of Bias in Nonrandomized Studies of Interventions for quasi-experimental studies and the Risk of Bias 2.0 for randomised controlled studies. This study was conducted in accordance with PRISMA reporting guideline (Appendix S1). The search protocol was registered in the PROSPERO (CRD 42021229358). RESULTS: A total of 24 studies were included in the systematic review, and 15 studies were included in the meta-analysis. Meta-analysis included 8 RCT and 7 quasi-experimental studies. The studies (11 quasi-experimental studies and 9 randomised controlled studies) demonstrated low to moderate quality of evidence for improving the cognition of people with dementia. The meta-analysis showed that nurse-led single nonpharmacological interventions more effectively improved cognition than complex interventions in people with dementia. CONCLUSION: Nurse-led nonpharmacological interventions were effective for improving cognition in people with dementia. RELEVANCE TO CLINICAL PRACTICE: Nurses are qualified professionals with expertise in providing nonpharmacological interventions to improve cognition in people with dementia. Nurse-led nonpharmacological interventions for this purpose should be developed in future research.

Targeting the Sequences of Circulating Tumor DNA of Cholangiocarcinomas and Its Applications and Limitations in Clinical Practice.

Cholangiocarcinoma is a malignant epithelial tumor arising from bile ducts that is frequently fatal. Diagnosis is difficult due to tumor location in the biliary tract. Earlier diagnosis requires less invasive methods of identifying effective biomarkers for cholangiocarcinoma. The present study investigated the genomic profiles of cell-free DNA (cfDNA) and DNA from corresponding primary cholangiocarcinomas using a targeted sequencing panel. Somatic mutations in primary tumor DNA and circulating tumor DNA (ctDNA) were compared and clinical applications of ctDNA validated in patients with cholangiocarcinoma. A comparison of primary tumor DNA and ctDNA identified somatic mutations in patients with early cholangiocarcinomas that showed clinical feasibility for early screening. The predictive value of single-nucleotide variants (SNVs) of preoperative plasma cfDNA positive for somatic mutations of the primary tumor was 42%. The sensitivity and specificity of postoperative plasma SNVs in detecting clinical recurrence were 44% and 45%, respectively. Targetable fibroblast growth factor receptor 2 (FGFR2) and Kirsten rat sarcoma virus (KRAS) mutations were detected in 5% of ctDNA samples from patients with cholangiocarcinoma. These findings showed that genomic profiling of cfDNA was useful in clinical evaluation, although ctDNA had limited ability to detect mutations in cholangiocarcinoma patients. Serial monitoring of ctDNA is important clinically and in assessing real-time molecular aberrations in cholangiocarcinoma patients.

Changes in sleep profile on exposure to sodium chloride and artificially carbonated springs: a pilot study.

[Purpose] Herein, we aimed to investigate the effects of bathing in a sodium chloride spring and an artificially carbonated spring on core body temperature and electroencephalograms, to assess whether the springs facilitate sleep. [Participants and Methods] This randomized, controlled, crossover study evaluated the effects of a sodium chloride spring, an artificially carbonated spring, a plain hot bath, and no bath on sleep. The subjective evaluations and recording of temperature were performed before/after bathing at 40 °C for 15 min at 22:00 h, before nocturnal sleep (0:00-7:00 h), and after the participants (n=8) woke up in the morning. [Results] Bathing significantly increased the core body temperature, with significant subsequent declines observed until bedtime. Participants in the sodium chloride spring group had the highest average core body temperature, while participants in the no-bath group had the lowest average core body temperature before bedtime (23:00-0:00 h). During bedtime (1:00-2:00 h), the participants in the no bath group had the highest average core body temperature, while participants in the artificially carbonated spring group had the lowest average core body temperature. The amount of delta power/min in the first sleep cycle significantly increased in the bathing groups, with the highest value during bedtime being recorded in the artificially carbonated spring group, followed by the sodium chloride spring, plain hot bath, and no-bath groups. These sleep changes were associated with significant declines in the elevated core body temperature. Increased heat dissipation and decreased core body temperature were observed in the artificially carbonated spring and sodium chloride spring groups, which increased the delta power during the first sleep cycle compared with that observed in the plain hot bath group, followed by the no-bath group. [Conclusion] An artificially carbonated spring would be the most appropriate given each circumstance because it did not cause fatigue, as observed with the sodium chloride spring.

MLM-based typographical error correction of unstructured medical texts for named entity recognition.

BACKGROUND: Unstructured text in medical records, such as Electronic Health Records, contain an enormous amount of valuable information for research; however, it is difficult to extract and structure important information because of frequent typographical errors. Therefore, improving the quality of data with errors for text analysis is an essential task. To date, few prior studies have been conducted addressing this. Here, we propose a new methodology for extracting important information from unstructured medical texts by overcoming the typographical problem in surgical pathology records related to lung cancer. METHODS: We propose a typo correction model that considers context, based on the Masked Language Model, to solve the problem of typographical errors in real-world medical data. In addition, a word dictionary was used for the typo correction model based on PubMed abstracts. After refining the data through typo correction, fine tuning was performed on pre-trained BERT model. Next, deep learning-based Named Entity Recognition (NER) was performed. By solving the quality problem of medical data, we sought to improve the accuracy of information extraction in unstructured text data. RESULTS: We compared the performance of the proposed typo correction model based on contextual information with an existing SymSpell model. We confirmed that our proposed model outperformed the existing model in a typographical correction task. The F1-score of the model improved by approximately 5% and 9% when compared with the model without contextual information in the NCBI-disease and surgical pathology record datasets, respectively. In addition, the F1-score of NER after typo correction increased by 2% in the NCBI-disease dataset. There was a significant performance difference of approximately 25% between the before and after typo correction in the Surgical pathology record dataset. This confirmed that typos influenced the information extraction of the unstructured text. CONCLUSION: We verified that typographical errors in unstructured text negatively affect the performance of natural language processing tasks. The proposed method of a typo correction model outperformed the existing SymSpell model. This study shows that the proposed model is robust and can be applied in real-world environments by focusing on the typos that cause difficulties in analyzing unstructured medical text.

Stimuli-Responsive Adaptive Nanotoxin to Directly Penetrate the Cellular Membrane by Molecular Folding and Unfolding.

Biological nanomachines, including proteins and nucleic acids whose function is activated by conformational changes, are involved in every biological process, in which their dynamic and responsive behaviors are controlled by supramolecular recognition. The development of artificial nanomachines that mimic the biological functions for potential application as therapeutics is emerging; however, it is still limited to the lower hierarchical level of the molecular components. In this work, we report a synthetic machinery nanostructure in which actuatable molecular components are integrated into a hierarchical nanomaterial in response to external stimuli to regulate biological functions. Two nanometers core-sized gold nanoparticles are covered with ligand layers as actuatable components, whose folding/unfolding motional response to the cellular environment enables the direct penetration of the nanoparticles across the cellular membrane to disrupt intracellular organelles. Furthermore, the pH-responsive conformational movements of the molecular components can induce the apoptosis of cancer cells. This strategy based on the mechanical motion of molecular components on a hierarchical nanocluster would be useful to design biomimetic nanotoxins.

Soluble CCR2 gene therapy controls joint inflammation, cartilage damage, and the progression of osteoarthritis by targeting MCP-1 in a monosodium iodoacetate (MIA)-induced OA rat model.

BACKGROUND: Osteoarthritis (OA) is the most common type of degenerative arthritis and affects the entire joint, causing pain, joint inflammation, and cartilage damage. Various risk factors are implicated in causing OA, and in recent years, a lot of research and interest have been directed toward chronic low-grade inflammation in OA. Monocyte chemoattractant protein-1 (MCP-1; also called CCL2) acts through C-C chemokine receptor type 2 (CCR2) in monocytes and is a chemotactic factor of monocytes that plays an important role in the initiation of inflammation. The targeting of CCL2-CCR2 is being studied as part of various topics including the treatment of OA. METHODS: In this study, we evaluated the potential therapeutic effects the sCCR2 E3 gene may exert on OA. The effects of sCCR2 E3 were investigated in animal experiments consisting of intra-articular injection of sCCR2 E3 in a monosodium iodoacetate (MIA)-induced OA rat model. The effects after intra-articular injection of sCCR2 E3 (fusion protein encoding 20 amino acids of the E3 domain of the CCL2 receptor) in a monosodium iodoacetate-induced OA rat model were compared to those in rats treated with empty vector (mock treatment) and full-length sCCR2. RESULTS: Pain improved with expression of the sCCR2 gene. Improved bone resorption upon sCCR2 E3 gene activation was confirmed via bone analyses using micro-computed tomography. Histologic analyses showed that the sCCR2 E3 gene exerted protective effects against cartilage damage and anti-inflammatory effects on joints and the intestine. CONCLUSIONS: These results show that sCCR2 E3 therapy is effective in reducing pain severity, inhibiting cartilage destruction, and suppressing intestinal damage and inflammation. Thus, sCCR2 E3 may be a potential therapy for OA.

Dynamic multimodal holograms of conjugated organogels via dithering mask lithography.

Polymeric materials have been used to realize optical systems that, through periodic variations of their structural or optical properties, interact with light-generating holographic signals. Complex holographic systems can also be dynamically controlled through exposure to external stimuli, yet they usually contain only a single type of holographic mode. Here, we report a conjugated organogel that reversibly displays three modes of holograms in a single architecture. Using dithering mask lithography, we realized two-dimensional patterns with varying cross-linking densities on a conjugated polydiacetylene. In protic solvents, the organogel contracts anisotropically to develop optical and structural heterogeneities along the third dimension, displaying holograms in the form of three-dimensional full parallax signals, both in fluorescence and bright-field microscopy imaging. In aprotic solvents, these heterogeneities diminish as organogels expand, recovering the two-dimensional periodicity to display a third hologram mode based on iridescent structural colours. Our study presents a next-generation hologram manufacturing method for multilevel encryption technologies.

Efficacy and safety of switching from reference adalimumab to CT-P17 (100 mg/ml): 52-week randomized, double-blind study in rheumatoid arthritis.

OBJECTIVE: To compare the safety and efficacy of switching from reference adalimumab to adalimumab biosimilar CT-P17 with continuing reference adalimumab/CT-P17 in active RA. METHODS: This double-blind, phase III study randomized (1:1) subjects with active RA to receive 40 mg (100 mg/ml) CT-P17 or European Union-sourced reference adalimumab subcutaneously every 2 weeks (Q2W) until week (W) 24 [treatment period (TP) 1]. Thereafter, subjects receiving reference adalimumab were randomized (1:1) to continue reference adalimumab or switch to CT-P17 from W26 (both Q2W until W48; TP2). Subjects receiving CT-P17 in TP1 continued CT-P17. W0-W24 results were previously reported; we present W26-W52 findings. End points were efficacy (including joint damage progression), pharmacokinetics, safety and immunogenicity. RESULTS: Of 607 subjects who initiated TP2 treatment, 303 continued CT-P17, 153 continued reference adalimumab and 151 switched to CT-P17. Efficacy improvements up to W24 were maintained during TP2; efficacy was comparable among groups. At W52, 20% improvement in ACR response rates were 80.5% (continued CT-P17), 77.8% (continued reference adalimumab) and 82.2% (switched to CT-P17). Joint damage progression was minimal. Mean trough serum adalimumab concentrations were similar among groups. CT-P17 and reference adalimumab safety profiles were numerically similar and switching did not affect immunogenicity. At W52, 28.4% (continued CT-P17), 27.0% (continued reference adalimumab) and 28.3% (switched to CT-P17) of subjects were anti-drug antibody-positive. CONCLUSION: Efficacy, pharmacokinetics, safety and immunogenicity of CT-P17 and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to CT-P17. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT03789292.

Whole-genome sequencing and genetic characteristics of representative porcine reproductive and respiratory syndrome virus (PRRSV) isolates in Korea.

BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is a macrophage-tropic arterivirus with extremely high genetic and pathogenic heterogeneity that causes significant economic losses in the swine industry worldwide. PRRSV can be divided into two species [PRRSV1 (European) and PRRSV2 (North American)] and is usually diagnosed and genetically differentiated into several lineages based on the ORF5 gene, which constitutes only 5% of the whole genome. This study was conducted to achieve nonselective amplification and whole-genome sequencing (WGS) based on a simplified sequence-independent, single-primer amplification (SISPA) technique with next-generation sequencing (NGS), and to genetically characterize Korean PRRSV field isolates at the whole genome level. METHODS: The SISPA-NGS method coupled with a bioinformatics pipeline was utilized to retrieve full length PRRSV genomes of 19 representative Korean PRRSV strains by de novo assembly. Phylogenetic analysis, analysis of the insertion and deletion (INDEL) pattern of nonstructural protein 2 (NSP2), and recombination analysis were conducted. RESULTS: Nineteen complete PRRSV genomes were obtained with a high depth of coverage by the SISPA-NGS method. Korean PRRSV1 belonged to the Korean-specific subtype 1A and vaccine-related subtype 1C lineages, showing no evidence of recombination and divergent genetic heterogeneity with conserved NSP2 deletion patterns. Among Korean PRRSV2 isolates, modified live vaccine (MLV)-related lineage 5 viruses, lineage 1 viruses, and nation-specific Korean lineages (KOR A, B and C) could be identified. The NSP2 deletion pattern of the Korean lineages was consistent with that of the MN-184 strain (lineage 1), which indicates the common ancestor and independent evolution of Korean lineages. Multiple recombination signals were detected from Korean-lineage strains isolated in the 2010s, suggesting natural interlineage recombination between circulating KOR C and MLV strains. Interestingly, the Korean strain GGYC45 was identified as a recombinant KOR C and MLV strain harboring the KOR B ORF5 gene and might be the ancestor of currently circulating KOR B strains. Additionally, two novel lineage 1 recombinants of NADC30-like and NADC34-like viruses were detected. CONCLUSION: Genome-wide analysis of Korean PRRSV isolates retrieved by the SISPA-NGS method and de novo assembly, revealed complex evolution and recombination in the field. Therefore, continuous surveillance of PRRSV at the whole genome level should be conducted, and new vaccine strategies for more efficient control of the virus are needed.