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Abstract Failure rate after chronic rotator cuff repair is considerably high. Moreover, diabetes mellitus is known as a compromising factor of rotator cuff tear. The effect of Polydeoxyribonucleotide (PDRN) and polynucleotide (PN) on tendon healing and fatty infiltration is unclear as tissue regeneration activator in diabetic state. Therefore, a diabetic rat model with chronic rotator cuff tear was made for mechanical, histologic and blood tests. In the animal study using a diabetic rat cuff repair model, the administration of PDRN and PN increased the load to failure of repaired cuffs and improved tendon healing and decreased fatty infiltration. Also, the plasma levels of vascular endothelial growth factor and fibroblast growth factor were elevated in PDRN and PN administrated groups. We concluded that PDRN and PN appear to boost tendon recovery and reduce the presence of fatty infiltration following cuff repair in diabetic state. Also, PN showed a later onset and a longer duration than PDRN associated with the mean plasma growth factors.

Due to the transformation of artificial intelligence (AI) tools and technologies, AI-driven drug discovery has come to the forefront. It reduces the time and expenditure. Due to these advantages, pharmaceutical industries are concentrating on AI-driven drug discovery. Several drug molecules have been discovered using AI-based techniques and tools, and several newly AI-discovered drug molecules have already entered clinical trials. In this review, we first present the data and their resources in the pharmaceutical sector for AI-driven drug discovery and illustrated some significant algorithms or techniques used for AI and ML which are used in this field. We gave an overview of the deep neural network (NN) models and compared them with artificial NNs. Then, we illustrate the recent advancement of the landscape of drug discovery using AI to deep learning, such as the identification of drug targets, prediction of their structure, estimation of drug-target interaction, estimation of drug-target binding affinity, design of de novo drug, prediction of drug toxicity, estimation of absorption, distribution, metabolism, excretion, toxicity; and estimation of drug-drug interaction. Moreover, we highlighted the success stories of AI-driven drug discovery and discussed several collaboration and the challenges in this area. The discussions in the article will enrich the pharmaceutical industry.

BackgroundMyelin oligodendrocyte glycoprotein antibody (MOG) immunoglobulin G (IgG)-associated disease (MOGAD) has clinical and pathophysiological features that are similar to but distinct from those of aquaporin-4 antibody (AQP4-IgG)-positive neuromyelitis optica spectrum disorders (AQP4-NMOSD). MOG-IgG and AQP4-IgG, mostly of the IgG1 subtype, can both activate the complement system. Therefore, we investigated whether the levels of serum complement components, regulators, and activation products differ between MOGAD and AQP4-NMOSD, and if complement analytes can be utilized to differentiate between these diseases.MethodsThe sera of patients with MOGAD (from during an attack and remission; N=19 and N=9, respectively) and AQP4-NMOSD (N=35 and N=17), and healthy controls (N=38) were analyzed for C1q-binding circulating immune complex (CIC-C1q), C1 inhibitor (C1-INH), factor H (FH), C3, iC3b, and soluble terminal complement complex (sC5b-9).ResultsIn attack samples, the levels of C1-INH, FH, and iC3b were higher in the MOGAD group than in the NMOSD group (all, p

Background: The global research community has made considerable progress in therapeutic and vaccine research during the COVID-19 pandemic. Several therapeutics have been repurposed for the treatment of COVID-19. One such compound is, favipiravir, which was approved for the treatment of influenza viruses, including drug-resistant influenza. Despite the limited information on its molecular activity, clinical trials have attempted to determine the effectiveness of favipiravir in patients with mild to moderate COVID-19. Here, we report the structural and molecular interaction landscape of the macromolecular complex of favipiravir-RTP and SARS-CoV-2 RdRp with the RNA chain. Methods: Integrative bioinformatics was used to reveal the structural and molecular interaction landscapes of two macromolecular complexes retrieved from RCSB PDB. Results: We analyzed the interactive residues, H-bonds, and interaction interfaces to evaluate the structural and molecular interaction landscapes of the two macromolecular complexes. We found seven and six H-bonds in the first and second interaction landscapes, respectively. The maximum bond length is 3.79 Å. In the hydrophobic interactions, five residues (Asp618, Asp760, Thr687, Asp623, and Val557) were associated with the first complex and two residues (Lys73 and Tyr217) were associated with the second complex. The mobilities, collective motion, and B-factor of the two macromolecular complexes were analyzed. Finally, we developed different models, including trees, clusters, and heat maps of antiviral molecules, to evaluate the therapeutic status of favipiravir as an antiviral drug. Conclusions: The results revealed the structural and molecular interaction landscape of the binding mode of favipiravir with the nsp7–nsp8–nsp12-RNA SARS-CoV-2 RdRp complex. Our findings can help future researchers in understanding the mechanism underlying viral action and guide the design of nucleotide analogs that mimic favipiravir and exhibit greater potency as antiviral drugs against SARS-CoV-2 and other infectious viruses. Thus, our work can help in preparing for future epidemics and pandemics.

Background: The 2022 outbreak of the mpox virus (previously monkeypox virus, MPXV) in non-epidemic regions has created a global issue. The emergence of MPXV was first reported in Europe, which was described as the MPXV epicenter, however, no reports are available to illustrate its outbreak patterns in Europe. Methods: The study used numerous in silico and statistical methods to analyze hMPXV1 in European countries. Here, we used different bioinformatics servers and software to evaluate the spread of hMPXV1 in European countries. For analysis, we use various advanced servers like Nextstrain, Taxonium, MpoxSpectrum, etc. Similarly, for the statistical model, we used PAST software. Results: The phylogenetic tree was depicted to illustrate the origin and evolution of hMPXV1 using vas number of genome sequences (n = 675). We found several sublineages in Europe, indicating microevolution. The scatter plot reveals the clustering patterns of the newly developed lineages in Europe. We developed statistical models for the monthly total relative frequency counts of these sublineages. The epidemiology of MPX in Europe was examined in an attempt to capture the epidemiological pattern, total cases, and deaths. Our Study noted the highest number of cases was in Spain (7500 cases) and the second-highest in France (4114 cases). The third highest number of cases was in the UK (3730 cases), which was very similar to Germany (3677 cases). Finally, we noted the mutational landscape throughout European genomes. Significant mutations were observed at the nucleotide and protein levels. We identified several unique homoplastic mutations in Europe. Conclusion: This study reveals several essential aspects of the European outbreak. It might help to eradicate the virus in Europe, assist in strategy formation to fight against the virus, and support working against the next public health emergency in Europe.

Recently, researchers have shown concern about the ChatGPT-derived answers. Here, we conducted a series of tests using ChatGPT by individual researcher at multi-country level to understand the pattern of its answer accuracy, reproducibility, answer length, plagiarism, and in-depth using two questionnaires (the first set with 15 MCQs and the second 15 KBQ). Among 15 MCQ-generated answers, 13 ± 70 were correct (Median : 82.5; Coefficient variance : 4.85), 3 ± 0.77 were incorrect (Median: 3, Coefficient variance: 25.81), and 1 to 10 were reproducible, and 11 to 15 were not. Among 15 KBQ, the length of each question (in words) is about 294.5 ± 97.60 (mean range varies from 138.7 to 438.09), and the mean similarity index (in words) is about 29.53 ± 11.40 (Coefficient variance: 38.62) for each question. The statistical models were also developed using analyzed parameters of answers. The study shows a pattern of ChatGPT-derive answers with correctness and incorrectness and urges for an error-free, next-generation LLM to avoid users’ misguidance.

Since millions of cancer-related deaths and diagnoses exist yearly, malignant tumors are a primary worldwide health concern. A promising method for treating cancer is tumor immunotherapy, which focuses on neoantigens. Neoantigens are tumor-specific antigens expressed on cancer cells due to genetic changes, viral infections, or other biological processes. They serve as excellent immune system targets to identify and attack cancerous cells. Neoantigens are more immunogenic than tumor-associated antigens (TAAs) because they lack central tolerance. Successful clinical trials of neoantigen-based vaccines have raised interest in individualized tumor immunotherapy. Furthermore, neoantigens represent a significant advancement in cancer immunotherapy, offering the potential for personalized and effective tumor treatments. The identification, synthesis, and application of neoantigen-based vaccines hold promise for improving patient outcomes and revolutionizing cancer treatment approaches. This review focuses on the significance of neoantigens in cancer immunotherapy, their classification and identification, the synthesis of neoantigen vaccines, clinical trials and the principles underlying their therapeutic efficacy.

The medicine and healthcare sector has been evolving and advancing very fast. The advancement has been initiated and shaped by the applications of data-driven, robust, and efficient machine learning (ML) to deep learning (DL) technologies. ML in the medical sector is developing quickly, causing rapid progress, reshaping medicine, and improving clinician and patient experiences. ML technologies evolved into data-hungry DL approaches, which are more robust and efficient in dealing with medical data. This article reviews some critical data-driven aspects of machine intelligence in the medical field. In this direction, the article illustrated the recent progress of data-driven medical science using ML to DL in two categories: firstly, the recent development of data science in medicine with the use of ML to DL and, secondly, the chabot technologies in healthcare and medicine, particularly on ChatGPT. Here, we discuss the progress of ML, DL, and the transition requirements from ML to DL. To discuss the advancement in data science, we illustrate prospective studies of medical image data, newly evolved DL interpretation data from EMR or EHR, big data in personalized medicine, and dataset shifts in artificial intelligence (AI). Simultaneously, the article illustrated recently developed DL-enabled ChatGPT technology. Finally, we summarize the broad role of ML and DL in medicine and the significant challenges for implementing recent ML to DL technologies in healthcare. The overview of the data-driven paradigm shift in medicine using ML to DL technologies in the article will benefit researchers immensely.

Purpose: The current outbreak of monkeypox (MPX) has created colossal concerns. However, immense research gaps have been noted in our understanding of the replication process, machinery, and genomic landscape during host cell infection. To fill this gap, differentially expressed genes (DEGs) were comprehensively analyzed during viral replication in host (MK2) cells. Methods: We used a microarray GEO dataset which was divided into three groups: control, MPXV-infected MK2 cells at 3 h, and MPXV-infected MK2 cells at 7 h. Using the dataset, DEG analysis, PPI network analysis, co-expression, and pathway analysis were conducted using bioinformatics, systems biology, and statistical approaches. Results: We identified 250 DEGs and 24 top-ranked genes. During the DEG analysis, we identified eight up-regulated genes (LOC695323, TMEM107, LOC695427, HIST1H2AD, LOC705469, PMAIP1, HIST1H2BJ, and HIST1H3D) and 16 down-regulated genes (HOXA9, BAMBI, LMO4, PAX6, AJUBA, CREBRF, CD24, JADE1, SLC7A11, EID2, SOX4, B4GALT5, PPARGC1A, BUB3, SOS2, and CDK19). We also developed PPI networks and performed co-expression analyses using the top-ranked genes. Furthermore, five genes were listed for co-expression pattern analysis. Conclusions: This study will help in better understanding the replication process, machinery, and genomic landscape of the virus. This will further aid the discovery and development of therapeutics against viruses.

The release of ChatGPT has initiated new thinking about AI-based Chatbot and its application and has drawn huge public attention worldwide. Researchers and doctors have started thinking about the promise and application of AI-related large language models in medicine during the past few months. Here, the comprehensive review highlighted the overview of Chatbot and ChatGPT and their current role in medicine. Firstly, the general idea of Chatbots, their evolution, architecture, and medical use are discussed. Secondly, ChatGPT is discussed with special emphasis of its application in medicine, architecture and training methods, medical diagnosis and treatment, research ethical issues, and a comparison of ChatGPT with other NLP models are illustrated. The article also discussed the limitations and prospects of ChatGPT. In the future, these large language models and ChatGPT will have immense promise in healthcare. However, more research is needed in this direction.

Recently, passive and zero-energy construction has increased in Korea due to the government`s continuous application of budget-conscious policies for establishments. Accordingly, construction materials are being advanced, and the required performance standards for insulation materials are increasing. However, problems such as fire vulnerability and degradation of physical properties for organic and inorganic insulation materials are shown, so it is necessary to solve this problem. The objective of this research is to examine the properties of the composites by analyzing the flexural breaking load, impact resistance, density, VOCs concentration reduction rate, and fine dust concentration reduction rate of the composites manufactured based on the perlite substitution rate of the magnesia composites. The flexural breaking load test of the composites was assessed according to ‘KS F 3504’, a gypsum board standard and the impact resistance was assessed according to ‘KS F 4715’. The performance evaluation of adsorption performance of air pollutants of the VOCs and fine dust in the context of the small chamber technique suggested by Hanbat University. The results of this study are as follows: The flexural breaking load according to the perlite replacement rate tended to decrease as the perlite replacement rate increased. It is determined that the flexural breaking load is reduced by generating a large amount of pores inside due to the perlite porous structure characteristics. In the case of impact resistance, the impact resistance tended to increase as the perlite displacement rate increased. It is determined that the volume of the binder in the board is reduced, and pores inside the board are generated due to perlite, which is a porous material, thereby reducing the overall bonding force of the board. In the case of VOCs and fine dust concentrations, the VOCs and fine dust concentration reduction rates tended to increase as the perlite replacement rate increased. In the case of the perlite displace rate of 30%, the VOCs concentration decreased by 82.6%, and the fine dust concentration decreased by 87.9%. It has been established that the porous properties of perlite used to create a huge number of pores in the hardened body cause the concentration to be lowered physically through adsorption. This study's findings are thought to be fundamental information for securing the engineering properties and air pollution absorption of magnesia composites blended with perlite.

According to the National Statistical Office's 2019 Population and Housing Survey in August 2020, the number of apartments, including apartments, was about 14 million last year, accounting for 77.2% of all houses, of which 11.287 million were 80.6% of apartments. Based on this change in housing trends, researchers have developed and studied cellular light-weight concrete (CLC) that can be cured at room temperature and normal pressure with advantages such as light weight, insulation, and construction. There have been several studies in Korea, including state-run projects, but they have not been commercialized, but the biggest reason is that stability has not been secured. Therefore, to improve the reliability of CLC that can be cured at normal temperature and pressure, this study attempts to analyze the properties of CLC by incorporating CaO-CSA expansive additive. Based on the drying density of 0.55-0.65 kg/m3, cement, blast furnace slag, animal foaming additive and fiber are utilized to analyze the properties of CLC with CaO-CSA expansive and the results are as follows. By using the CaO-CSA expansive additive, it is determined that the formation of calcium hydroxide and ettringite fills the CLC between the tobermorite layers and the internal structure becomes dense. Currently, based on KS F 2701, the compression strength based on 0.6 items is more than 4.9 MPa, and the strength is about twice as strong as that of the existing CLC, and durability of the CLC are improved by incorporating CaO-CSA expansive additive.

Abstract Recent efforts in designing nanomaterials to deliver potential therapeutics to the targeted site are overwhelming and palpable. Engineering nanomaterials to deliver biological molecules to exert desirable physiological changes, with minimized side effects and optimal dose, has revolutionized the next-generation therapy for several diseases. The rapid progress of nucleic acids as biopharmaceutics is going to alter the traditional pharmaceutics practices in modern medicine. However, enzymatic instability, large size, dense negative charge (hydrophilic for cell uptake), and unintentional adverse biological responses—such as prolongation of the blood coagulation and immune system activation—hamper the potential use of nucleic acids for therapeutic purposes. Moreover, the safe delivery of nucleic acids into the clinical setting is an uphill task, and several efforts are being put forward to deliver them to targeted cells. Advances in Metal-based NanoParticles (MNPs) are drawing attention due to the unique properties offered by them for drug delivery, such as large surface-area-to-volume ratio for surface modification, increased therapeutic index of drugs through site-specific delivery, increased stability, enhanced half-life of the drug in circulation, and efficient biodistribution to the desired targeted site. Here, the potential of nanoparticles delivery systems for the delivery of nucleic acids, specially MNPs, and their ability and advantages over other nano delivery systems are reviewed. Graphical Abstract

Purpose: The recent Omicron (B.1.1.529) variant poses a significant threat to global health. This variant has spread worldwide, and several sublineages have rapidly emerged. Study tried to analyze the microevolution of this variant. Methods: We studied the molecular phylogenetics, divergence, geographical distributions, frequencies, risk mutations for antibody affinity, and mutational landscape for Omicron sublineages using in silico analysis and statistical models. The risk mutation of spike for nAb affinity was analyzed and illustrated by statistical plots. Finally, the mutational properties of the spike mutations and their stability were predicted and demonstrated. Results: First, we studied the microevolutionary Omicron sublineages using molecular phylogenetics. Simultaneously, we revealed divergence events of the Omicron sublineages and observed the lowest minimum divergence of 51 in clade 21K and the highest maximum divergence of 90 in clade 21L. We have demonstrated cluster analyses, geographical distributions, frequencies of Omicron and its sublineages. Finally, we evaluated the mutational landscape of the Omicron sublineages. In this mutational study, we performed a genome-wide analysis of general mutations, mutations in the non-spike genome, and spike mutations of Omicron sublineages. The risk mutation of S-glycoprotein for nAb affinity has been analyzed for Omicron sublineages. Here, we found that some sublineages have all four significant highly destabilizing mutations. Such sublineages are BA.1 (G446S, E484A, T95I, and D614G), BA.2 (H655Y, Q493R, G493S, and D614G), BA.4 (N501Y, Y505H, N969K, and D614G), and BA.2.75 (Q454H, T547K, N764K, D614G and G446S). Finally, from the mutation stability prediction through ΔΔG, we observed that BA.1 and BA.4 had two destabilizing and two stabilizing mutations. Similarly, BA.2, BA.5, and BA.2.12.1 have one destabilizing and three stabilizing mutations. However, all four mutations in BA.2.75 are stabilizing mutations. Conclusions: Our molecular phylogenetic studies provided a deeper understanding of the microevolution of sublineages and the creation of Omicron. Similarly, this study might help scientists develop pan-coronavirus vaccines that consider their mutational properties.

Alzheimer’s disease (AD) is a deadly brain degenerative disorder that leads to brain shrinkage and dementia. AD is manifested with hyperphosphorylated tau protein levels and amyloid beta (Aβ) peptide buildup in the hippocampus and cortex regions of the brain. The nervous tissue of AD patients also contains fungal proteins and DNA which are linked to bacterial infections, suggesting that polymicrobial infections also occur in the brains of those with AD. Both immunohistochemistry and next-generation sequencing (NGS) techniques were employed to assess fungal and bacterial infections in the brain tissue of AD patients and non-AD controls, with the most prevalent fungus genera detected in AD patients being Alternaria, Botrytis, Candida, and Malassezia. Interestingly, Fusarium was the most common genus detected in the control group. Both AD patients and controls were also detectable for Proteobacteria, followed by Firmicutes, Actinobacteria, and Bacteroides for bacterial infection. At the family level, Burkholderiaceae and Staphylococcaceae exhibited higher levels in the brains of those with AD than the brains of the control group. Accordingly, there is thought to be a viscous cycle of uncontrolled neuroinflammation and neurodegeneration in the brain, caused by agents such as the herpes simplex virus type 1 (HSV1), Chlamydophilapneumonia, and Spirochetes, and the presence of apolipoprotein E4 (APOE4), which is associated with an increased proinflammatory response in the immune system. Systemic proinflammatory cytokines are produced by microorganisms such as Cytomegalovirus, Helicobacter pylori, and those related to periodontal infections. These can then cross the blood–brain barrier (BBB) and lead to the onset of dementia. Here, we reviewed the relationship between the etiology of AD and microorganisms (such as bacterial pathogens, Herpesviridae viruses, and periodontal pathogens) according to the evidence available to understand the pathogenesis of AD. These findings might guide a targeted anti-inflammatory therapeutic approach to AD.

Objective: Osteoporosis is regarded as a silent disorder affecting bone slowly, leading to an increased risk of fractures. Lately, selenium has been found to be associated with the acquisition and maintenance of bone health by affecting the bone remodeling process. However, the mechanism of action of selenium on bone is poorly understood. Here, the protective effects of sodium selenite on the differentiation process of osteoblasts as well as under oxidative stress-induced conditions were evaluated.Materials and Methods: MC3T3-E1 cells, were treated with a various doses (0, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2, 6.4 ug/ml) of sodium selenite. Cell viability and cytotoxicity were observed by MTT and LDH assay. The osteogenic activity and expression level of osteogenic markers were confirmed through ALP activity, real-time RT-PCR and sirius red staining. Role of sodium selenite and involvement of WNT signaling was assessed by Axin-2 reporter assay and western blotting.Results: It was observed that the sodium selenite could promote the ALP activity and collagen synthesis in pre-osteoblasts. Moreover, sodium selenite increased the mRNA expression levels of osteogenic transcriptional factors, such as runt-related transcription factor 2 (Runx2) and osterix (OSX). In addition, the terminal differentiation markers, such as osteocalcin (OCN), and collagen 1α (Col1α), were also increased. Treatment of sodium selenite recused the H2O2-induced inhibition of osteoblastic differentiation of pre-osteoblasts cells. Furthermore, sodium selenite restored the H2O2 repressed β-catenin stability and axin-2 reporter activity in MC3T3-E1 cells implicating involvement of WNT signaling pathway.Conclusion: It may be concluded that selenite can stimulate bone formation and rescue the oxidative repression of osteogenesis by activating WNT signaling pathway and may act as a potential therapeutic intervention for osteoporosis.

The crosstalk between androgens and Wnt signaling pathways is critical in the hair growth cycle. Therefore, natural products that target these two pathways for the inhibition of hair loss are sought after. In this study, we investigated the effect of water extracts of Mangifera indica leaves (WEML) on hair growth. WEML treatment significantly reduced the expression levels of both dickkopf-1 (DKK1) and type 2 5α-reductase (SRD5A2) involved in Wnt signal suppression activity and dihydrotestosterone (DHT) synthesis, respectively, in human follicle dermal papilla cells (HFDP). In addition, WEML treatment effectively upregulated Wnt target genes and downregulated DKK1 expression that was increased by DHT treatment. Degranulation analysis in rat basophilic leukemia mast cell line (RBL-2H3) using β-hexosaminidase release assay confirmed that WEML did not exhibit allergenic activity. Furthermore, hair growth was significantly enhanced in in vivo mice model treated with WEML. These results suggest that M. indica leave extract contains bioactive materials that can be used to treat hair loss.

Complications arising from breast augmentation procedures are broadly categorized as either surgery-related or prosthesis-related. Many reports have described complications associated with breast augmentation. However, to date, periareolar post-inflammatory hyperpigmentation (PIH) after breast augmentation has not been reported. Herein, we report a case of PIH after augmentation mammoplasty using a silicone implant through the periareolar approach. A 35-year-old woman, who underwent bilateral breast augmentation using a periareolar approach, presented with bilateral periareolar tissue changes, with dark brown, irregular macules appearing 6 weeks postoperatively. Based on clinical symptoms and histological examination, the lesion was diagnosed as PIH. Topical hydroquinone and retinoic acid were applied for 8 weeks after the pigmentation appeared. After 6 months of observation, the pigmentation faded. To summarize, we report a case of pigmentation around the bilateral nipples after periareolar breast augmentation along with a literature review.

Abstract To assess the utility of machine learning (ML) algorithms in predicting clinically relevant atrial high-rate episodes (AHREs), which can be recorded by a pacemaker. We aimed to develop ML-based models to predict clinically relevant AHREs based on the clinical parameters of patients with implanted pacemakers in comparison to logistic regression (LR). We included 721 patients without known atrial fibrillation or atrial flutter from a prospective multicenter (11 tertiary hospitals) registry comprising all geographical regions of Korea from September 2017 to July 2020. Predictive models of clinically relevant AHREs were developed using the random forest (RF) algorithm, support vector machine (SVM) algorithm, and extreme gradient boosting (XGB) algorithm. Model prediction training was conducted by seven hospitals, and model performance was evaluated using data from four hospitals. During a median follow-up of 18 months, clinically relevant AHREs were noted in 104 patients (14.4%). The three ML-based models improved the discrimination of the AHREs (area under the receiver operating characteristic curve: RF: 0.742, SVM: 0.675, and XGB: 0.745 vs. LR: 0.669). The XGB model had a greater resolution in the Brier score (RF: 0.008, SVM: 0.008, and XGB: 0.021 vs. LR: 0.013) than the other models. The use of the ML-based models in patient classification was associated with improved prediction of clinically relevant AHREs after pacemaker implantation.

Abstract ChatGPT has quickly popularized since its release in November 2022. Currently, large language models (LLMs) and ChatGPT have been applied in various domains of medical science, including in cardiology, nephrology, orthopedics, ophthalmology, gastroenterology, and radiology. Researchers are exploring the potential of LLMs and ChatGPT for clinicians and surgeons in every domain. This study discusses how ChatGPT can help orthopedic clinicians and surgeons perform various medical tasks. LLMs and ChatGPT can help the patient community by providing suggestions and diagnostic guidelines. In this study, the use of LLMs and ChatGPT to enhance and expand the field of orthopedics, including orthopedic education, surgery, and research, is explored. Present LLMs have several shortcomings, which are discussed herein. However, next‐generation and future domain‐specific LLMs are expected to be more potent and transform patients’ quality of life.

The first RNA therapeutic molecule, Fomivirsen, was approved for a clinic in 1998 as an antisense oligonucleotide therapeutic. Twenty-four years later, we found that more than a dozen RNA therapeutics had received approval and entered the clinic. In this direction, the review article illustrated the journey of different classes of RNA-based therapeutics from bench to clinic. The article extensively describes a critical insight into the advancements and clinical status of nanoparticle-based delivery for various classes of RNA-based therapeutics, biopharma companies' role, and the different classes of RNA-based therapeutics. It also highlights the diverse nanoparticle formulations, including lipid-based, polymeric, and inorganic nanoparticles, emphasizing their distinct characteristics and benefits in delivering RNA-based therapeutics with precision. Additionally, the review emphasizes the significance of surface functionalization and targeting ligands in improving the delivery efficiency and site-specificity of nanoparticles for therapeutic applications. The article explores diverse classes of therapeutics, including antisense oligonucleotides, guide RNAs, siRNAs, aptamers, ribozymes, miRNAs, and mRNAs, showcasing their efficacy in clinical settings. Chemical modifications in the therapeutics' structure are also highlighted as a strategy to overcome obstacles. The success of FDA-approved RNA-based therapeutics offers hope for future clinical advancements against a range of diseases.

Advances in understanding miRNAs as endogenous posttranscriptional regulatory units have projected them as novel therapeutics for several untreatable diseases. miRNAs are endogenous non-coding small single-stranded RNA molecules (20–24 nucleotides) with specific gene regulatory functions like repression of mRNA translation by degrading mRNAs. Emerging evidence suggests the role of miRNAs in various stages of bone growth and development. Undoubtedly, due to their critical role in bone remodeling, miRNAs might be projected as a novel approach to treating bone-related diseases. However, the instability associated with miRNAs in their complex environment, such as degradation by nucleases, is a concern. Thus, recent attention is being paid to maintaining the miRNAs' safety and efficacy in the cells. Various efficient delivery systems and chemical modifications of miRNAs are being developed to make them a potential therapeutic option for bone diseases. Here, we have tried to recapitulate the recent advances in the role of miRNAs in bone disease, along with the potential delivery systems for their efficient delivery to the cells.

Recently, several emerging variants of SARS-CoV-2 have originated from the Wuhan strain and spread throughout the globe within one and a half years. One mutation, D614G, is very prominent in all VOI and VOC in SARS-CoV-2. This mutation might help to increase the viral fitness in all emerging variants where the mutation is present. With the help of this mutation (D614G), the SARS-CoV-2 variants have gained viral fitness to enhance viral replication and increase transmission. This paper attempts to answer the question of whether the mutation (D614G) occurs due to positive selection or not.

Circular RNAs (circRNAs), an emerging family member of RNAs, have gained importance in research due to their new functional roles in cellular physiology and disease progression. circRNAs are usually available in a wide range of cells and have shown tissue-specific expression as well as developmental specific expression. circRNAs are characterized by structural stability, conservation, and high abundance in the cell. In this review, we discuss the different models of biogenesis. The properties of circRNAs such as localization, structure and conserved pattern, stability, and expression specificity are also been illustrated. Furthermore, we discuss the biological functions of circRNAs such as microRNA (miRNA) sponging, cell cycle regulation, cell-to-cell communication, transcription regulation, translational regulation, disease diagnosis, and therapeutic potential. Finally, we discuss the recent research progress and future perspective of circRNAs. This review provides an understanding of potential diagnostic markers and the therapeutic potential of circRNAs, which are emerging daily.

Cases of foreign body ingestion are encountered relatively often in clinical settings; however, serious complications are rare. In such cases, mediastinal abscess due to esophageal perforation can become a life-threatening complication. We encountered two cases of severe complications due to an esophageal fish bone foreign body. The first case was a 40-year-old male with an intramural esophageal abscess due to a fish bone after eating fish five days before visiting the hospital. The patient underwent surgical treatment, but the esophageal abscess did not improve; so, the abscess was drained through endoscopic mucosal dissection, and the abscess improved. In the second case, a 64-year-old male, who had eaten fish three days before visiting the hospital, had esophageal perforation by a fish bone, and abscess formation in the mediastinum and the lesser sac in the abdominal cavity were observed. Although surgical treatment was performed, the intra-abdominal abscess formation was not controlled; so, percutaneous drainage (PCD) was inserted, and the abscess improved. Both patients were discharged without any complications. Here, we report two cases that were improved through surgical treatments and additional treatments such as endoscopic dissection and PCD.

Abstract We describe a novel algorithm for information recovery from DNA sequences by using a digital filter. This work proposes a three-part algorithm to decide the k-mer or q-gram word density. Employing a finite impulse response digital filter, one can calculate the sequence's k-mer or q-gram word density. Further principal component analysis is used on word density distribution to analyze the dissimilarity between sequences. A dissimilarity matrix is thus formed and shows the appearance of cluster formation. This cluster formation is constructed based on the alignment-free sequence method. Furthermore, the clusters are used to build phylogenetic relations. The cluster algorithm is in good agreement with alignment-based algorithms. The present algorithm is simple and requires less time for computation than other currently available algorithms. We tested the algorithm using beta hemoglobin coding sequences (HBB) of 10 different species and 18 primate mitochondria genome (mtDNA) sequences.

The rapid spread of the SARS-CoV-2 virus and its variants has created a catastrophic impact worldwide. Several variants have emerged, including B.1.351 (Beta), B.1.1.28/triple mutant (P.1), B.1.1.7 (Alpha), and B.1.429 (Epsilon). We performed comparative and comprehensive antigenicity mapping of the total S-glycoprotein using the Wuhan strain and the other variants and identified 9-mer, 15-mer, and 20-mer CTL epitopes through in silico analysis. The study found that 9-mer CTL epitope regions in the B.1.1.7 variant had the highest antigenicity and an average of the three epitope types. Cluster analysis of the 9-mer CTL epitopes depicted one significant cluster at the 70% level with two nodes (KGFNCYFPL and EGFNCYFPL). The phage-displayed peptides showed mimic 9-mer CTL epitopes with three clusters. CD spectra analysis showed the same band pattern of S-glycoprotein of Wuhan strain and all variants other than B.1.429. The developed 3D model of the superantigen (SAg)-like regions found an interaction pattern with the human TCR, indicating that the SAg-like component might interact with the TCR beta chain. The present study identified another partial SAg-like region (ANQFNSAIGKI) from the S-glycoprotein. Future research should examine the molecular mechanism of antigen processing for CD8+ T cells, especially all the variants’ antigens of S-glycoprotein.

Background: miRNAs, a class of small endogenous RNAs, are one of the essential biopharmaceuticals which are in commercial spans as next-generation medicine in recent times. Aim of the Review: A snapshot of the current scenario regarding the miRNAs as biopharmaceuticals have been discussed. Key Scientific Concepts of Review: In this work, biopharmaceutical companies working with miRNAs and the current status of preclinical/clinical trials about miRNA therapeutics have been reviewed. Finally, recent updates on the absorption, distribution, metabolism, and excretion (ADME), as well as a delivery system of miRNAs, have been illustrated.

Objective: Rspondins (RSPOs) are regarded as the significant modulators of WNT signaling pathway and they are expressed dynamically during developmental stages. Since in osteoarthritis (OA) both cartilage and subchondral bone suffer damages and WNT signaling pathway has a crucial role in their maintenance, the objective of the study was to analyze expression profile of RSPO family and its receptors [leucine-rich repeat-containing G-protein coupled receptors (LGRs)] in OA tissue samples as well as in differentiating chondrocytes and osteoblasts. Material and Methods: In this experimental study, human early and advanced stage of OA tissue samples were analyzed for the morphological changes of articular cartilage by hematoxylin and eosin (H&E) staining, safranin-O staining and lubricin immunostaining. RSPOs and LGRs expression were confirmed by immunohistochemistry. Human primary chondrocytes and human osteoblast cell line, SaOS-2, were cultured in differentiation medium till day 14 and they were analyzed in terms of expression of RSPOs, LGRs and specific marker for chondrogenesis and osteogenesis by western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results: Advanced stage OA tissue samples showed increased expression of RSPO1 and LGR6 in a region close to subchondral bone. While RSPO2 and LGR5 expression were seen overlapping in the deep region of articular cartilage. Differentiating chondrocytes demonstrated elevated expression of RSPO2 and LGR5 from day 7 to day 14, whereas, osteoblasts undergoing differentiation showed enhanced expression of RSPO1 and LGR6 from day 2 to day 14. Under tumor necrosis factor alpha (TNFα) stimulatory conditions, RSPO2 and RSPO1 recovered the suppressed expression of inflammatory, chondrogenic and osteogenic markers, respectively. A recovery in the stability of β-catenin was also noticed in both cases. Conclusions: Spatial expression of RSPOs during progression of OA might be dynamically controlled by cartilage and subchondral bone. Interplay amid chondrocytes and osteoblasts, via RSPOs, might provide probable mechanisms for treating inflammatory pathogenic conditions like OA.

Background To determine the prevalence of rotator cuff diseases in a population older than 40 years in or nearby Chuncheon city, Republic of Korea. Methods Sixty shoulders of 30 people older than 40 years who participated in a health lecture were examined for free by an orthopedic surgeon. Visual analog scale of pain and American Shoulder and Elbow Surgeons scores were assigned, and routine physical examination was performed. Ultrasonography was performed on the shoulder. Results On ultrasonographic examination, there were one shoulder with full thickness rotator cuff tear, 20 of 60 (33%) with partial thickness rotator cuff tear, five of 60 (8%) with calcific tendinitis, one of 60 (2%) with tear of the long head of the biceps, and five of 60 (8%) with tendinitis of the long head of the biceps. Participants older than 60 years showed significantly high proportions of lesion of the long head of the biceps and rotator cuff diseases (P=0.019 and P=0.015, respectively). Participants who performed physical labor had high proportions of rotator cuff tear and rotator cuff disease (P=0.001 and P

Inflammation is closely related with the progression of cancer and is an indispensable component that orchestrates the tumor microenvironment. Studies suggest that different mediator and cellular effectors, including cytokines (interleukins, tumor necrosis factor-α [TNF-α], transforming growth factor-β [TGF-β], and granulocyte macrophage colony-stimulating factor [GM-CSF]), chemokines, as well as some transcription factors (nuclear factor κB [NF-κB], signal transducer and activator of transcription 3 [STAT3], hypoxia-inducible factor-1α [HIF1α]), play a crucial role during cancer-related inflammation (CRI). MicroRNAs (miRNAs) are the key components of cellular physiology. They play notable roles during posttranscriptional gene regulation and, thus, might have a potential role in controlling the inflammatory cascade during cancer progression. Taking into consideration the role identified for miRNAs in relation to inflammatory cytokines, we have tried to review their participation in neoplastic progression. Additionally, the involvement of miRNAs with some important transcription factors (NF-κB, STAT3, HIF1α) and proteins (cyclooxygenase-2 [COX-2], inducible nitric oxide synthase [iNOS]) closely associated with inflammation during cancer has also been discussed. A clear insight into the responsibility of miRNAs in cytokine signaling and inflammation related to CRI could project them as new therapeutic molecules, which could lead to improved treatment of CRI in the near future.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus (CoV), has recently emerged as a significant pathogen for humans and the cause for the recent outbreak of the 2019 novel coronavirus disease (COVID-19) throughout the globe. For developing any preventive measure, an understanding of the zoonotic pattern for this virus is a necessity. We should have a clear knowledge of its reservoir host, its distribution pattern and spreading routes. Information about zoonotic reservoirs and its transmission among them can help to understand the COVID-19 outbreaks. In this article, we discuss about the bats as the zoonotic reservoir of several CoV strains, co-existence of bats and CoV/viruses, the sequence similarity of SARS-CoV-2 with bat SARS-like CoV, the probable source of the origin of SARS-CoV-2 strain and COVID-19 outbreak, intermediate host of CoVs and SARS-CoV-2, human to human transmission and the possibility to maintain the zoonotic barriers. Our knowledge about the zoonotic reservoir of SARS-CoV-2 and its transmission ability may help develop the preventive measures and control for the future outbreak of CoV.

The infective SARS-CoV-2 is more prone to immune escape. Presently, the significant variants of SARS-CoV-2 are emerging in due course of time with substantial mutations, having the immune escape property. Simultaneously, the vaccination drive against this virus is in progress worldwide. However, vaccine evasion has been noted by some of the newly emerging variants. Our review provides an overview of the emerging variants’ immune escape and vaccine escape ability. We have illustrated a broad view related to viral evolution, variants, and immune escape ability. Subsequently, different immune escape approaches of SARS-CoV-2 have been discussed. Different innate immune escape strategies adopted by the SARS-CoV-2 has been discussed like, IFN-I production dysregulation, cytokines related immune escape, immune escape associated with dendritic cell function and macrophages, natural killer cells and neutrophils related immune escape, PRRs associated immune evasion, and NLRP3 inflammasome associated immune evasion. Simultaneously we have discussed the significant mutations related to emerging variants and immune escape, such as mutations in the RBD region (N439K, L452R, E484K, N501Y, K444R) and other parts (D614G, P681R) of the S-glycoprotein. Mutations in other locations such as NSP1, NSP3, NSP6, ORF3, and ORF8 have also been discussed. Finally, we have illustrated the emerging variants’ partial vaccine (BioNTech/Pfizer mRNA/Oxford-AstraZeneca/BBIBP-CorV/ZF2001/Moderna mRNA/Johnson & Johnson vaccine) escape ability. This review will help gain in-depth knowledge related to immune escape, antibody escape, and partial vaccine escape ability of the virus and assist in controlling the current pandemic and prepare for the next.

Interspinous spacer devices used in interspinous fixation surgery remove soft tissues in the lumbar spine, such as ligaments and muscles and may cause degenerative diseases in adjacent segments its stiffness is higher than that of the lumbar spine. Therefore, this study aimed to structurally and kinematically optimize a lumbar interspinous fixation device (LIFD) using a full lumbar finite element model that allows for minimally invasive surgery, after which the normal behavior of the lumbar spine is not affected. The proposed healthy and degenerative lumbar spine models reflect the physiological characteristics of the lumbar spine in the human body. The optimum number of spring turns and spring wire diameter in the LIFD were selected as 3 mm and 2 turns, respectively-from a dynamic range of motion (ROM) perspective rather than a structural maximum stress perspective-by applying a 7.5 N∙m extension moment and 500 N follower load to the LIFD-inserted lumbar spine model. As the spring wire diameter in the LIFD increased, the maximum stress generated in the LIFD increased, and the ROM decreased. Further, as the number of spring turns decreased, both the maximum stress and ROM of the LIFD increased. When the optimized LIFD was inserted into a degenerative lumbar spine model with a degenerative disc, the facet joint force of the L3-L4 lumbar segment was reduced by 56%-98% in extension, lateral bending, and axial rotation. These results suggest that the optimized device can strengthen the stability of the lumbar spine that has undergone interspinous fixation surgery and reduce the risk of degenerative diseases at the adjacent lumbar segments.

Skeletal disabilities are a prominent burden on the present population with an increasing life span. Advances in osteopathy have provided various medical support for bone-related diseases, including pharmacological and prosthesis interventions. However, therapeutics and post-surgery complications are often reported due to side effects associated with modern-day therapies. Thus, therapies utilizing natural means with fewer toxic or other side effects are the key to acceptable interventions. Flavonoids constitute a class of bioactive compounds found in dietary supplements, and their pharmacological attributes have been well appreciated. Recently, flavonoids’ role is gaining renowned interest for its effect on bone remodeling. A wide range of flavonoids has been found to play a pivotal role in the major bone signaling pathways, such as wingless-related integration site (Wnt)/β-catenin, bone morphogenetic protein (BMP)/transforming growth factor (TGF)-β, mitogen-activated protein kinase (MAPK), etc. However, the reduced bioavailability and the absorption of flavonoids are the major limitations inhibiting their use against bone-related complications. Recent utilization of nanotechnological approaches and other delivery methods (biomaterial scaffolds, micelles) to target and control release can enhance the absorption and bioavailability of flavonoids. Thus, we have tried to recapitulate the understanding of the role of flavonoids in regulating signaling mechanisms affecting bone remodeling and various delivery methods utilized to enhance their therapeutical potential in treating bone loss.

The COVID-19 pandemic has created an urgent situation throughout the globe. Therefore, it is necessary to identify the differentially expressed genes (DEGs) in COVID-19 patients to understand disease pathogenesis and the genetic factor(s) responsible for inter-individual variability. The DEGs will help understand the disease’s potential underlying molecular mechanisms and genetic characteristics, including the regulatory genes associated with immune response elements and protective immunity. This study aimed to determine the DEGs in mild and severe COVID-19 patients versus healthy controls. The Agilent-085982 Arraystar human lncRNA V5 microarray GEO dataset (GSE164805 dataset) was used for this study. We used statistical tools to identify the DEGs. Our 15 human samples dataset was divided into three groups: mild, severe COVID-19 patients and healthy control volunteers. We compared our result with three other published gene expression studies of COVID-19 patients. Along with significant DEGs, we developed an interactome map, a protein-protein interaction (PPI) pattern, a cluster analysis of the PPI network, and pathway enrichment analysis. We also performed the same analyses with the top-ranked genes from the three other COVID-19 gene expression studies. We also identified differentially expressed lncRNA genes and constructed protein-coding DEG-lncRNA co-expression networks. We attempted to identify the regulatory genes related to immune response elements and protective immunity. We prioritized the most significant 29 protein-coding DEGs. Our analyses showed that several DEGs were involved in forming interactome maps, PPI networks, and cluster formation, similar to the results obtained using data from the protein-coding genes from other investigations. Interestingly we found six lncRNAs (TALAM1, DLEU2, and UICLM CASC18, SNHG20, and GNAS) involved in the protein-coding DEG-lncRNA network; which might be served as potential biomarkers for COVID-19 patients. We also identified three regulatory genes from our study and 44 regulatory genes from the other investigations related to immune response elements and protective immunity. We were able to map the regulatory genes associated with immune elements and identify the virogenomic responses involved in protective immunity against SARS-CoV-2 infection during COVID-19 development.

Mechanically robust and chemically stable polyphenylene sulfide (PPS) membrane of efficient porous architecture as well as high porosity has been prepared from a PPS/SiO2 composite including homogeneous distribution of SiO2 nanoparticles, and its applicability as a separator in lithium-ion battery (LIB) was extensively examined in terms of sustainability of electrochemical behaviors. To improve distribution of SiO2 nanoparticles for the incompatible PPS/SiO2 mixture, prerequisite for the efficient porous architecture, interface modulation by plasma-assisted mechanochemical (MP) treatment has been performed, and the MP-treated PPS/SiO2 composite exhibited perfectly homogeneous distribution of SiO2 nanoparticles, finally resulting in porous PPS membrane including a large number of pores with nearly monodisperse pore diameter after removal of SiO2 phase. Alongside the well-developed porous architecture, the porous PPS membrane also deployed notably improved wetting to electrolyte imparted by the MP-based interface modulation, which gave rise to the complete suppression of disastrous build-up and intrusion of lithium dendrite on a separator as well as the electrochemical performances superior to those of the existing PP separator such as the highly sustainable cyclic charging/discharging behavior. Furthermore, it was notable that the PPS membrane exhibited outstanding mechanical stability especially at high temperature even after a large number of pores were developed inside, which has been generic from the nature of PPS. Conclusively, it could be stated that the porous PPS separator is a promising candidate fulfilling the performance requirements for the high-performance LIB.

SARS-CoV-2 has spread across the globe in no time. In the beginning, people suffered due to the absence of efficacious drugs required to treat severely ill patients. Nevertheless, still, there are no established therapeutic molecules against the SARS-CoV-2. Therefore, repurposing of the drugs started against SARS-CoV-2, due to which several drugs were approved for the treatment of COVID-19 patients. This paper reviewed the treatment regime for COVID-19 through drug repurposing from December 8, 2019 (the day when WHO recognized COVID-19 as a pandemic) until today. We have reviewed all the clinical trials from RECOVERY trials, ACTT-1 and ACTT-2 study group, and other major clinical trial platforms published in highly reputed journals such as NEJM, Lancet, etc. In addition to single-molecule therapy, several combination therapies were also evaluated to understand the treatment of COVID-19 from these significant clinical trials. To date, several lessons have been learned on the therapeutic outcomes for COVID-19. The paper also outlines the experiences gained during the repurposing of therapeutic molecules (hydroxychloroquine, ritonavir/ lopinavir, favipiravir, remdesivir, ivermectin, dexamethasone, camostatmesylate, and heparin), immunotherapeutic molecules (tocilizumab, mavrilimumab, baricitinib, and interferons), combination therapy, and convalescent plasma therapy to treat COVID-19 patients. We summarized that anti-viral therapeutic (remdesivir) and immunotherapeutic (tocilizumab, dexamethasone, and baricitinib) therapy showed some beneficial outcomes. Until March 2021, 4952 clinical trials have been registered in ClinicalTrials.gov toward the drug and vaccine development for COVID-19. More than 100 countries have participated in contributing to these clinical trials. Other than the registered clinical trials (medium to large-size), several small-size clinical trials have also been conducted from time to time to evaluate the treatment of COVID-19. Four molecules showed beneficial therapeutic to treat COVID-19 patients. The short-term repurposing of the existing drug may provide a successful outcome for COVID-19 patients. Therefore, more clinical trials can be initiated using potential anti-viral molecules by evaluating in different phases of clinical trials.

Carbon fiber-reinforced polymers (CFRPs) show excellent mechanical strength and lightweight. However, conventional CFRPs require high loading of carbon fibers (CFs) to improve their mechanical properties due to poor polymer–CF interfacial adhesion. We propose a dry and ecofriendly method to fabricate high-performance CFRPs by improving interfacial adhesion. The plasma-assisted mechanochemistry (PMC) process can create physical and chemical linkages between polymers and carbon fillers via application of a mechanical force and plasma treatment. We use carbon nanotubes as bridge materials to increase the effective interfacial area and promote mechanical interlocking. The PMC-treated CFRPs exhibit reduced C-factor and increased degree of entanglement, indicating efficient stress transfer the polymer to the filler. Additionally, the PMC process can provide the significantly improved mechanical properties of CFRPs even at low CF loading. Notably, the PMC-treated CFRPs showed continuously increasing tensile strength, Young's modulus, and elongation at break with increasing CF content up to 30 wt%, which has not been observed previously for CFRPs. As a result, the tensile strength, Young's modulus, and elongation at break of the PMC-treated composites with a CF content of 30 wt% increased by 47.1%, 43.0%, and 91.7%, respectively, compared to those of the conventional composites. We believe that this simple approach opens a new route to the fabrication of high-performance CFRPs exhibiting extraordinary mechanical properties.

ABSTRACT The recent emergence of multiple variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant concern for public health worldwide. New variants have been classified either as variants of concern (VOCs) or variants of interest (VOIs) by the CDC (USA) and WHO. The VOCs include lineages such as B.1.1.7 (20I/501Y.V1 variant), P.1 (20J/501Y.V3 variant), B.1.351 (20H/501Y.V2 variant), and B.1.617.2. In contrast, the VOI category includes B.1.525, B.1.526, P.2, and B.1.427/B.1.429. The WHO provided the alert for last two variants (P.2 and B.1.427/B.1.429) and labeled them for further monitoring. As per the WHO, these variants can be reclassified due to their status at a particular time. At the same time, the CDC (USA) has marked these two variants as VOIs up through today. This article analyzes the evolutionary patterns of all these emerging variants, as well as their geographical distributions and transmission patterns, including the circulating frequency, entropy diversity, and mutational event diversity throughout the genomes of all SARS-CoV-2 lineages. The transmission pattern was observed highest in the B.1.1.7 lineage. Our frequency evaluation found that this lineage achieved 100% frequency in early October 2020. We also critically evaluated the above emerging variants mutational landscape and significant spike protein mutations (E484K, K417T/N, N501Y, and D614G) impacting public health. Finally, the effectiveness of vaccines against newly SARS-CoV-2 variants was also analyzed. IMPORTANCE Irrespective of the aggressive vaccination drive, the newly emerging multiple SARS-CoV-2 variants are causing havoc in several countries. As per the CDC (USA) and WHO, the VOCs include the B.1.1.7, P.1, B.1.351, and B.1.617.2 lineages, while the VOIs include the B.1.525, B.1.526, P.2, and B.1.427/B.1.429 lineages. This study analyzed the evolutionary patterns, geographical distributions and transmission patterns, circulating frequency, entropy diversity, and mutational event diversity throughout the genome of significant SARS-CoV-2 lineages. A higher transmission pattern was observed for the B.1.1.7 variant. The study also evaluated the mutational landscape and important spike protein mutations (E484K, K417T/N, N501Y, and D614G) of all of the above variants. Finally, a survey was performed on the efficacy of vaccines against these variants from the previously published literature. The results presented in this article will help design future countrywide pandemic planning strategies for the emerging variants, next-generation vaccine development using alternative wild-type antigens and significant viral antigens, and immediate planning for ongoing vaccination programs worldwide.

Recently, mRNA vaccines have become a significant type of therapeutic and have created new fields in the biopharmaceutical industry. mRNA vaccines are promising next-generation vaccines that have introduced a new age in vaccinology. The recent approval of two COVID-19 mRNA vaccines (mRNA-1273 and BNT162b2) has accelerated mRNA vaccine technology and boosted the pharmaceutical and biotechnology industry. These mRNA vaccines will help to tackle COVID-19 pandemic through immunization, offering considerable hope for future mRNA vaccines. Human trials with data both from mRNA cancer vaccines and mRNA infectious disease vaccines have provided encouraging results, inspiring the pharmaceutical and biotechnology industries to focus on this area of research. In this article, we discuss current mRNA vaccines broadly in two parts. In the first part, mRNA vaccines in general and COVID-19 mRNA vaccines are discussed. We presented the mRNA vaccine structure in general, the different delivery systems, the immune response, and the recent clinical trials for mRNA vaccines (both for cancer mRNA vaccines and different infectious diseases mRNA vaccines). In the second part, different COVID-19 mRNA vaccines are explained. Finally, we illustrated a snapshot of the different leading mRNA vaccine developers, challenges, and future prospects of mRNA vaccines.

Engineered biomaterials are envisioned to replace, augment, or interact with living tissues for improving the functional deformities associated with end-stage joint pathologies. Unfortunately, wear debris from implant interfaces is the major factor leading to periprosthetic osteolysis. Fibroblast-like synoviocytes (FLSs) populate the intimal lining of the synovium and are in direct contact with wear debris. This study aimed to elucidate the effect of Ti particles as wear debris on human FLSs and the mechanism by which they might participate in the bone remodeling process during periprosthetic osteolysis. FLSs were isolated from synovial tissue from patients, and the condition medium (CM) was collected after treating FLSs with sterilized Ti particles. The effect of CM was analyzed for the induction of osteoclastogenesis or any effect on osteogenesis and signaling pathways. The results demonstrated that Ti particles could induce activation of the NFκB signaling pathway and induction of COX-2 and inflammatory cytokines in FLSs. The amount of Rankl in the conditioned medium collected from Ti particle–stimulated FLSs (Ti CM) showed the ability to stimulate osteoclast formation. The Ti CM also suppressed the osteogenic initial and terminal differentiation markers for osteoprogenitors, such as alkaline phosphate activity, matrix mineralization, collagen synthesis, and expression levels of Osterix, Runx2, collagen 1α, and bone sialoprotein. Inhibition of the WNT and BMP signaling pathways was observed in osteoprogenitors after the treatment with the Ti CM. In the presence of the Ti CM, exogenous stimulation by WNT and BMP signaling pathways failed to stimulate osteogenic activity in osteoprogenitors. Induced expression of sclerostin (SOST: an antagonist of WNT and BMP signaling) in Ti particle–treated FLSs and secretion of SOST in the Ti CM were detected. Neutralization of SOST in the Ti CM partially restored the suppressed WNT and BMP signaling activity as well as the osteogenic activity in osteoprogenitors. Our results reveal that wear debris–stimulated FLSs might affect bone loss by not only stimulating osteoclastogenesis but also suppressing the bone-forming ability of osteoprogenitors. In the clinical setting, targeting FLSs for the secretion of antagonists like SOST might be a novel therapeutic approach for preventing bone loss during inflammatory osteolysis.

Abstract Background Extracellular vesicles (EVs) play important roles in intercellular communication by delivering RNA, lipid, and proteins to neighboring or distant cells. Identification and classification of EVs secreted from diverse cell types are essential for understanding their signaling properties. Methods In this study, EVs from the culture media were isolated by ultracentrifugation and analyzed by electron microscopy (EM) and nanoparticle tracking analyses. Conditioned media (CM) from HEK293 cells culture grown either in serum-free (SF) or 10% fetal bovine serum (FBS) containing media were centrifuged at 100,000×g to separate the SNΔ supernatant and the P100 pellet in which exosomes are enriched. Then, the SNΔ fraction was centrifuged at 200,000×g to yield the P200 pellet fraction containing novel EVs smaller than exosomes. The exosomal markers in the EV subgroups were examined by western blotting and immune-EM, and the functional analyses of EVs were conducted on HEK293 and THP-1 cell culture. Results We identified a new group of EVs in the P200 fraction that was smaller than exosomes in size. Typical exosome markers such as Hsp70, TSG101, and CD63 were found in both P100 exosomes and the P200 vesicles, but CD81 was highly enriched in exosomes but not in the P200 vesicles. Furthermore, chemicals that inhibit the major exosome production pathway did not decrease the level of P200 vesicles. Therefore, these small EVs indeed belong to a distinguished group of EVs. Exosomes and the P200 vesicles were found in CM of human cell lines as well as FBS. Addition of the exosomes and the P200 vesicles to human cell cultures enhanced exosome production and cell proliferation, respectively. Conclusions Our study identifies a novel population of EVs present in the P200 fraction. This EV population is distinguished from exosomes in size, protein contents, and biogenesis pathway. Furthermore, exosomes promote their own production whereas the P200 vesicles support cell proliferation. In sum, we report a new group of EVs that are distinct physically, biologically and functionally from exosomes.

Ebola virus disease (EVD) is associated with haemorrhagic fever in humans and nonhuman primates, with a high rate of fatality (up to 90%). Some outbreaks in human history have proven the lethality of EVD. The recent epidemic of 2014 and 2015 in West Africa was the deadliest of all time (11 284 deaths). To understand the transmission dynamics, we have reviewed the epidemiology of EVD to date. The absence of any licensed vaccines or approved drugs against Ebola virus (EBOV) further highlights the severity and crisis level of EVD. Some organizations (public and private) are making considerable efforts to develop novel therapeutic approaches or vaccines to contain the outbreak of EBOV shortly. Here, we summarized the various potential drugs and vaccines (undergoing multiple phases of clinical trials) that have arisen as an alternative against EBOV, and we highlighted the numerous issues and limitations hindering this process. Alternatively, an increasing focus on strengthening the medical and civic health structure could provide speedy benefits in containing the spread of EVD, as well as offer a resilient foundation for the deployment of novel drugs and vaccines to the affected countries, once such drugs and vaccines become available.

Biomaterials are used as implants for bone and dental disabilities. However, wear particles from the implants cause osteolysis following total joint arthroplasty (TJA). Ceramic implants are considered safe and elicit a minimal response to cause periprosthetic osteolysis. However, few reports have highlighted the adverse effect of ceramic particles such as alumina (Al2O3) on various cell types. Hence, we aimed to investigate the effect of Al2O3 particles on osteoprogenitors. A comparative treatment of Al2O3, Ti, and UHMWPE particles to osteoprogenitors at a similar concentration of 200 μg/mL showed that only Al2O3 particles were able to suppress the early and late differentiation markers of osteoprogenitors, including collagen synthesis, alkaline phosphatase (ALP) activity and mRNA expression of Runx2, OSX, Col1α, and OCN. Al2O3 particles even induced inflammation and activated the NFkB signaling pathway in osteoprogenitors. Moreover, bone-forming signals such as the WNT/β-catenin signaling pathway were inhibited by the Al2O3 particles. Al2O3 particles were found to induce the mRNA expression of WNT/β-catenin signaling antagonists such as DKK2, WIF, and sFRP1 several times in osteoprogenitors. Taken together, this study highlights a mechanistic view of the effect of Al2O3 particles on osteoprogenitors and suggests therapeutic targets such as NFĸB and WNT signaling pathways for ceramic particle-induced osteolysis.

Lacquer sap has received much attention as a traditional natural resin because it is a renewable and eco-friendly biopolymer resource unlike artificial coating materials. However, strict drying conditions and long drying times of lacquer sap should be modified to expand its applications. This study presents the first attempt to investigate the effect of different amplitudes of ultrasonic waves on the lacquer sap composed of water-in-oil (W/O) emulsion droplets and the mechanical properties of the resultant film by solvent evaporation. Acoustically induced cavitation via batch ultrasonication facilitates the generation of submicron-sized W/O emulsion. The drying time of sonicated lacquer sap was noticeably shortened as the amplitude of acoustic power increased. Interestingly, the transparency of the film cast from lacquer sap consisting of the smallest emulsion droplets increased significantly, weakening the degree of colour change from caramel-like yellow to dark brown as polymerisation progressed. These are attributed to the effective and frequent contact of laccase enzyme with urushiol at the increased interfacial area of nano-emulsified W/O droplets pulverised by ultrasonic waves. The quinone radical-generation in the interface layer and its transfer to the urushiol oil phase through water-insoluble glycoprotein emulsifier are greatly promoted, resulting in highly cross-linked, dense three-dimensional polymer networks, which also increased the lacquer film hardness after drying. As the emulsion droplet size decreased, the mutual interaction between the catechol moiety of urushiol and the substrates increased, resulting in improved adhesion. The nano-emulsification of the lacquer sap by ultrasonic waves can be used in a simple, effective, and eco-friendly way to shorten the drying time and improve the film characteristics of natural resins. This approach could pave the way for its wide range of applications in industrial fields, taking into account green and sustainable chemistry.