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Abstract Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In this regard, lipid nanoparticles have been successfully utilized to improve mRNA delivery and protect the cargo from extracellular degradation. Encapsulation in lipid nanoparticles was an essential factor in the successful clinical application of mRNA vaccines, which conclusively demonstrated the technology's potential to yield approved medicines. In this review, we begin by describing current advances in mRNA modifications, design of novel lipids and development of lipid nanoparticle components for mRNA-based drugs. Then, we summarize key points pertaining to preclinical and clinical development of mRNA therapeutics. Finally, we cover topics related to targeted delivery systems, including endosomal escape and targeting of immune cells, tumors and organs for use with mRNA vaccines and new treatment modalities for human diseases.

The sea level in coastal areas of China reached the second highest in 2021, just after that recorded in 2022. External force and dynamic analyses based on tide gauges, satellite observations, reanalysis data and regional numerical outputs were conducted to understand these abnormally high sea levels and determine their possible causes. Results show that the coastal sea level of China had increased at an annual rate of 3.4 ± 0.3 mm during 1980–2021, with an acceleration of 0.06 ± 0.02 mm per year2. The superposition of significant oscillations of quasi-2, 3–7, quasi-9, quasi-11, quasi-19 and 20–30 years contributed to the anomalously high sea levels. The negative-phased El Niño/Southern Oscillation was correlated with the anomalously high sea level and the north‒south anti-phase pattern of the coastal sea level in 2021. Meanwhile, phase lags of 1–4 months occurred with the sea-level response. On a decadal timescale, the Pacific Decadal Oscillation (PDO) was negatively correlated with the anomalous mean sea level (MSL), and the negative-phased PDO contributed to the anomalous sea-level change in 2021. Particularly, the monthly MSL peaked in April and July, and the contribution of wind stress to the anomalously high sea level was 38.5% in the south of the Taiwan Strait in April and 30% along the coast of China in July. These results were consistent with the tide gauge and satellite data. Close agreement was also observed between the coastal sea-level fingerprint and the air and sea surface temperatures.

Abstract This study presents a pioneering investigation into the complex Holocene paleo-morphologies of the Yilan Plain, located at the southwestern edge of the Okinawa Trough. We employed a novel approach that synergized resistivity measurements with machine learning techniques to unlock valuable insights into the geological history, sedimentary patterns, and seismic activity of this dynamic region. Our methodology involved the creation of an Apparent Geological Model (AGM) through the interpolation of inverted resistivity data and the application of supervised machine learning algorithms. Classification criteria, derived from the relationship between resistivity values and sediment types found in nearby boreholes, were developed using the random forest machine-learning method. The resultant 3D resistivity model was transformed into a clay-sand-gravel model, offering a comprehensive depiction of sediment distribution within the Yilan Plain. Notably, our findings revealed distinct sedimentary patterns. Gravel-dominated regions, characterized by resistivity values above 140 Ohm-m, were identified alongside areas dominated by sand and clay sediments. The Carbon-14 dating ages in the sand sediments exhibited remarkable consistency, shedding light on the depositional history of the region. Furthermore, our research unveiled a previously unknown phenomenon of rapid subsidence in the Yilan Plain. Through meticulous analysis and correction for sea-level changes, we estimated an average subsidence rate of approximately 8.5 mm/year. This subsidence was punctuated by abrupt events around 6000–7000 years BP and 2000–3000 years BP, associated with a sudden increase. These events suggested a potential link to prehistoric seismic activity, with variable subsidence rates between episodes hinting at recurrent active seismic periods every 4000–5000 years. In conclusion, our multidisciplinary approach has provided unprecedented insights into the Holocene paleo-morphologies of the Yilan Plain. By combining resistivity measurements, machine learning, and geological analysis, we have enriched our understanding of the region's geological history, sedimentary dynamics, and seismic behavior. These findings not only contribute to the knowledge of Yilan’s past but also offer vital data for future environmental and geological studies in similarly dynamic regions.

Abstract Background Galactosemia is an autosomal recessive disorder resulting from an enzyme defect in the galactose metabolic pathway. The most severe manifestation of classic galactosemia is caused by galactose-1-phosphate uridylyltransferase (GALT) deficiency, and this condition can be fatal during infancy if left untreated. It also may result in long-term complications in affected individuals. Case presentation This report describes a patient whose initial clinical symptoms were jaundice and liver dysfunction. The patient’s liver and coagulation functions did not improve after multiple admissions and treatment with antibiotics, hepatoprotective and choleretic agents and blood transfusion. Genetic analysis revealed the presence of two variants in the GALT gene in the compound heterozygous state: c.377 + 2dup and c.368G > C (p.Arg123Pro). Currently, the variant locus (c.377 + 2dup) in the GALT gene has not been reported in the Human Gene Mutation Database (HGMD), while c.368G > C (p.Arg123Pro) has not been reported in the Genome Aggregation Database (GnomAD) nor the HGMD in East Asian population. We postulated that the two variants may contribute to the development of classical galactosemia. Conclusions Applications of whole-exome sequencing to detect the two variants can improve the detection and early diagnosis of classical galactosemia and, more specifically, may identify individuals who are compound heterozygous with variants in the GALT gene. Variants in the GALT gene have a potential therapeutic significance for classical galactosemia.

This study investigates the propagation of dark Alfvén solitons in low-β magnetized plasma using Hall-magnetohydrodynamic (Hall-MHD) numerical simulations. The rational solution of the nonlinear Schrödinger equation (NLSE) is presented, which is proposed as an effective tool for studying dark envelope solitons in plasma. Our results show a high degree of agreement between numerical simulations and analytical solutions derived from the NLSE via the reductive perturbation method. This agreement validates our modeling and computational approach. In addition, the simulations confirm the existence of dark Alfvén solitons in magnetized plasma. This work demonstrates the effectiveness of Hall-MHD simulations in studying complex plasma phenomena, contributing to the broader understanding of soliton propagation in plasma environments.

Abstract Background The interdisciplinary realm of medical humanities explores narratives and experiences that can enhance medical education for physicians through perspective-taking and reflective practice. However, there is a gap in comprehension regarding its appropriateness at the postgraduate level, especially when utilising art therapists as faculty. This study aims to assess the acceptability of an innovative art therapy-focused educational initiative among junior doctors during a palliative care rotation, with the goal of cultivating empathy and promoting well-being. Methods A qualitative research project was conducted at the Division of Supportive and Palliative Care (DSPC) in the National Cancer Centre Singapore (NCCS). The study involved the recruitment of junior doctors who had successfully completed a three-month palliative care rotation program, spanning from January 2020 to April 2021. In a single small-group session lasting 1.5 h, with 3 to 4 participants each time, the individuals participated in activities such as collage making, group reflection, and sharing of artistic creations. These sessions were facilitated by an accredited art therapist and a clinical psychologist, focusing on themes related to empathy and wellbeing. To assess the acceptability of the program, two individual interviews were conducted three months apart with each participant. An independent research assistant utilised a semi-structured question guide that considered affective attitude, burden, perceived effectiveness, coherence, and self-efficacy. Thematic analysis of the transcribed data was then employed to scrutinise the participants’ experiences. Results A total of 20 individual interviews were completed with 11 participants. The three themes identified were lack of pre-existing knowledge of the humanities, promotors, and barriers to program acceptability. Conclusions The participants have mixed perceptions of the program’s acceptability. While all completed the program in its entirety, the acceptability of the program is impeded by wider systemic factors such as service and manpower needs. It is vital to address these structural limitations as failing to do so risks skewing current ambivalence towards outright rejection of future endeavours to integrate humanities programs into medical education.

ObjectiveTo study the effectiveness of liver transplantation (LT) in treating mitochondrial DNA depletion syndrome (MDS) caused by the MPV17 gene variant.Case presentationA boy aged 2.8 years presented with edema of the lower limbs and abdomen, which persisted for over 10 days and was of unknown origin; this was accompanied by abnormal liver function, intractable hypoglycemia, and hyperlactatemia. During the second week of onset, he developed acute-on-chronic liver failure and was diagnosed with MDS due to homozygous variant c.293C>T in the MPV17 gene. Subsequently, he underwent LT from a cadaveric donor. At follow-up after 15 months, his liver function was found to be normal, without any symptoms. Additionally, a literature review was performed that included MDS patients with the MPV17 variant who underwent LT. The results demonstrated that the survival rates for MDS patients who underwent LT were 69.5%, 38.6%, 38.6%, and 38.6% at 1-year, 5-year, 10-year, and 20-year intervals, respectively. Sub-group analyses revealed the survival rate of MDS patients with isolated liver disease (83.33%, 5/6) was higher than that of hepatocerebral MDS patients (44.44%, 8/18). Fifteen variants were identified in the MPV17 gene, and patients with the c.293C>T (p.P98l) variant exhibited the highest survival rate.ConclusionHepatocerebral MDS patients without neurological symptoms may benefit from LT.

Abstract Background Citrus is one of the most valuable fruits worldwide and an economic pillar industry in southern China. Nevertheless, it frequently suffers from undesirable environmental stresses during the growth cycle, which severely restricts the growth, development and yield of citrus. In plants, the growth-regulating factor (GRF) family of transcription factors (TF) is extensively distributed and plays an vital part in plant growth and development, hormone response, as well as stress adaptation. However, the systematic identification and functional analysis of GRF TFs in citrus have not been reported. Results Here, a genome-wide identification of GRF TFs was performed in Citrus sinensis, 9 members of CsGRFs were systematically identified and discovered to be scattered throughout 5 chromosomes. Subsequently, physical and chemical properties, phylogenetic relationships, structural characteristics, gene duplication events, collinearity and cis-elements of promoter were elaborately analyzed. In particular, the expression patterns of the CsGRF genes in response to multiple phytohormone and abiotic stress treatments were investigated. Predicated on this result, CsGRF04, which exhibited the most differential expression pattern under multiple phytohormone and abiotic stress treatments was screened out. Virus-induced gene silencing (VIGS) technology was utilized to obtain gene silenced plants for CsGRF04 successfully. After the three stress treatments of high salinity, low temperature and drought, the CsGRF04-VIGS lines showed significantly reduced resistance to high salinity and low temperature stresses, but extremely increased resistance to drought stress. Conclusions Taken together, our findings systematically analyzed the genomic characterization of GRF family in Citrus sinensis, and excavated a CsGRF04 with potential functions under multiple abiotic stresses. Our study lay a foundation for further study on the function of CsGRFs in abiotic stress and hormone signaling response.

Abstract Introduction Limited studies have evaluated the association between Clostridium difficile infection (CDI) and the duration of proton pump inhibitor (PPI) or histamine H2-receptor blocker (H2RA) use and provided a cutoff duration for PPI or H2RA use to mitigate a substantially increased risk of CDI. We aimed to evaluate these associations in hospitalized patients using a nationwide insurance claims database. Methods We conducted a nested case–control study to identify cases with a first ever record of CDI in a study cohort undergoing PPI or H2RA therapy from the National Health Insurance Database from 2012 to 2018. Each case was matched with one control by age, sex, and calendar year. We used conditional logistic regression to estimate the sensitivity, specificity, and area under the receiver operating characteristic curve (AUC ROC). Youden’s J statistic was used to identify the optimal cutoff duration in days for PPI or H2RA use. Results In the main analysis, the AUC ROC was 0.64 (95% CI 0.63–0.66) and optimal cutoff duration was 15 days for PPI users. The AUC ROC was 0.63 (95% CI 0.62–0.64) and optimal cutoff duration was 16 days for H2RA users. In the sensitivity analyses, the results were similar to those of the main analysis, and the optimal cutoff duration was in the range of 14–15 days. Conclusions The optimal cutoff duration for PPI and H2RA use was about 2 weeks. It is necessary to be cautious regarding the risk of CDI in patients taking PPIs or H2RAs for longer than 2 weeks.

Background: Eucommia ulmoides Oliver is a unique high-quality natural rubber tree species and rare medicinal tree species in China. The rapid characterization of E. ulmoides gene function has been severely hampered by the limitations of genetic transformation methods and breeding cycles. The polyethylene glycol (PEG)-mediated protoplast transformation system is a multifunctional and rapid tool for the analysis of functional genes in vivo, but it has not been established in E. ulmoides. Methods: In this study, a large number of highly active protoplasts were isolated from the stems of E. ulmoides seedlings by enzymatic digestion, and green fluorescent protein expression was facilitated using a PEG-mediated method. Results: Optimal enzymatic digestion occurred when the enzyme was digested for 10 h in an enzymatic solution containing 2.5% Cellulase R-10 (w/v), 0.6% Macerozyme R-10 (w/v), 2.5% pectinase (w/v), 0.5% hemicellulase (w/v), and 0.6 mol/L mannitol. The active protoplast yield under this condition was 1.13 × 106 protoplasts/g fresh weight, and the protoplast activity was as high as 94.84%. Conclusions: This study established the first protoplasm isolation and transient transformation system in hard rubber wood, which lays the foundation for subsequent functional studies of E. ulmoides genes to achieve high-throughput analysis, and provides a reference for future gene function studies of medicinal and woody plants.

[This corrects the article DOI: 10.1371/journal.pone.0296939.].

Knowledge about biological rhythms of diseases may not only help in understanding the pathophysiology of diseases but can also help health service policy makers and emergency department directors to allocate resources efficiently. Aneurysmal subarachnoid haemorrhage (SAH) has high rates of morbidity and mortality. The incidence of SAH has been attributed to patient-related factors such as characteristics of aneurysms, smoking, and hypertension. There are studies showing that the incidence of aneurysmal SAH appears to behave in periodic fashions over long time periods. However, there are inconsistencies in the literature regarding the impact of chronobiological factors such as circadian, seasonal, and lunar cycle factors on the occurrence of SAH. In this study, we focused on the analysis of a temporal pattern of SAH (infradian rhythms) with a novel approach using circular statistical methods. We aimed to see whether there is a circular pattern for the occurrence of SAH at all and if so, whether it can be related to known temporal patterns based on available literature. Our study did not support the notion that aneurysmal subarachnoid haemorrhages occur on any specific day in a cycle with specific lengths up to 365 days including specific weekdays, full moon, equinoxes, and solstices. Hence, we found no relationship between SAH incidence and timing. Study in larger populations using similar circular statistical methods is suggested.

Imagine having a knowledge graph that can extract medical health knowledge related to patient diagnosis solutions and treatments from thousands of research papers, distilled using machine learning techniques in healthcare applications. Medical doctors can quickly determine treatments and medications for urgent patients, while researchers can discover innovative treatments for existing and unknown diseases. This would be incredible! Our approach serves as an all-in-one solution, enabling users to employ a unified design methodology for creating their own knowledge graphs. Our rigorous validation process involves multiple stages of refinement, ensuring that the resulting answers are of the utmost professionalism and solidity, surpassing the capabilities of other solutions. However, building a high-quality knowledge graph from scratch, with complete triplets consisting of subject entities, relations, and object entities, is a complex and important task that requires a systematic approach. To address this, we have developed a comprehensive design flow for knowledge graph development and a high-quality entities database. We also developed knowledge distillation schemes that allow you to input a keyword (entity) and display all related entities and relations. Our proprietary methodology, multiple levels refinement (MLR), is a novel approach to constructing knowledge graphs and refining entities level-by-level. This ensures the generation of high-quality triplets and a readable knowledge graph through keyword searching. We have generated multiple knowledge graphs and developed a scheme to find the corresponding inputs and outputs of entity linking. Entities with multiple inputs and outputs are referred to as joints, and we have created a joint-version knowledge graph based on this. Additionally, we developed an interactive knowledge graph, providing a user-friendly environment for medical professionals to explore entities related to existing or unknown treatments/diseases. Finally, we have advanced knowledge distillation techniques.

Summary: Prenatal stress has been extensively documented as a contributing factor to adverse cardiac development and function in fetuses and infants. The release of glucocorticoids (GCs), identified as a significant stressor, may be a potential factor inducing cardiac hypertrophy. However, the underlying mechanism remains largely unknown. Herein, we discovered that corticosterone (CORT) overload induced cardiac hypertrophy in embryonic chicks and fetal mice in vivo, as well as enlarged cardiomyocytes in vitro. The impaired mitochondria dynamics were observed in CORT-exposed cardiomyocytes, accompanied by dysfunction in oxidative phosphorylation and ATP production. This phenomenon was found to be linked to decreased mitochondrial fusion protein mitofusin 2 (MFN2). Subsequently, we found that CORT facilitated the ubiquitin-proteasome-system-dependent degradation of MFN2 with an enhanced binding of appoptosin to MFN2, serving as the underlying cause. Collectively, our findings provide a comprehensive understanding of the mechanisms by which exposure to stress hormones induces cardiac hypertrophy in fetuses.

Sialyltransferase-catalyzed membrane protein and lipid glycosylation plays a vital role as one of the most abundant post-translational modifications and diversification reactions in eukaryotes. However, aberrant sialylation has been associated with cancer malignancy and metastasis. Sialyltransferases thus represent emerging targets for the development of small molecule cancer drugs. Herein, we report the inhibitory effects of a recently discovered lithocholic acid derivative FCW393 on sialyltransferase catalytic activity, integrin sialyation, cancer-associated signal transduction, MDA-MB-231 and B16F10 cell migration and invasion, and in in vivo studies, on tumor growth, metastasis, and angiogenesis. FCW393 showed effective and selective inhibition of the sialyltransferases ST6GAL1 (IC50 = 7.8 μM) and ST3GAL3 (IC50 = 9.45 μM) relative to ST3GAL1 (IC50 > 400 μM) and ST8SIA4 (IC50 > 100 μM). FCW393 reduced integrin sialylation in breast cancer and melanoma cells dose-dependently and downregulated proteins associated with the integrin-regulated FAK/paxillin and GEF/Rho/ROCK pathways, and with the VEGF-regulated Akt/NFκB/HIF-1α pathway. FCW393 inhibited cell migration (IC50 = 2.6 μM) and invasion in in vitro experiments, and in in vivo studies of tumor-bearing mice, FCW393 reduced tumor size, angiogenesis, and metastatic potential. Based on its demonstrated selectivity, cell permeability, relatively low cytotoxicity (IC50 = 55 μM), and high efficacy, FCW393 shows promising potential as a small molecule experimental tool compound and a lead for further development of a novel cancer therapeutic.

Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In this regard, lipid nanoparticles have been successfully utilized to improve mRNA delivery and protect the cargo from extracellular degradation. Encapsulation in lipid nanoparticles was an essential factor in the successful clinical application of mRNA vaccines, which conclusively demonstrated the technology's potential to yield approved medicines. In this review, we begin by describing current advances in mRNA modifications, design of novel lipids and development of lipid nanoparticle components for mRNA-based drugs. Then, we summarize key points pertaining to preclinical and clinical development of mRNA therapeutics. Finally, we cover topics related to targeted delivery systems, including endosomal escape and targeting of immune cells, tumors and organs for use with mRNA vaccines and new treatment modalities for human diseases. [ABSTRACT FROM AUTHOR]

Simple Summary: The Colorado potato beetle, Leptinotarsa decemlineata, poses a significant threat to potato crops worldwide, causing substantial agricultural damage. To better understand how these pests develop and potentially find ways to control them, we studied a group of genes called Knickkopf (Knk) genes in the larvae of the beetle. These genes are crucial for forming and maintaining the insect's outer shell, known as the cuticle, which protects them from the environment. We identified four LdKnk-family genes in the beetle and analyzed when and where these genes are expressed during the insect's growth stages. By using RNA interference (RNAi) to silence these genes, we observed that larvae became weaker, with damaged cuticles and higher death rates. These findings indicate that LdKnk-family genes are vital for the beetle's survival and development. Targeting LdKnk-family genes could provide a new strategy for pest control, potentially weakening the beetles' defenses and making them more susceptible to environmental factors and insecticides, ultimately helping to protect potato crops. The Colorado potato beetle (Leptinotarsa decemlineata) is a major pest of potato crops. While Knickkopf (Knk) genes are essential for insect cuticle formation, their roles in pests like L. decemlineata remain unclear. This study aims to identify and characterize Knk genes in L. decemlineata and explore their functions in larval development and cuticle integrity. We used genomic and transcriptomic databases to identify LdKnk-family genes, validated through RT-PCR and RACE. Gene expression was analyzed at various developmental stages and tissues using qRT-PCR. RNA interference (RNAi) and Transmission electron microscopy (TEM) were applied to determine the functional roles of these genes. Four LdKnk-family genes were identified. Spatio-temporal expression analysis indicated significant gene expression during larval molting and pupal stages, especially in the epidermis. RNAi experiments showed that silencing LdKnk and LdKnk3-5′ led to reduced larval weight, cuticle thinning, and increased mortality, while LdKnk3-FL knockdown caused abnormal cuticle thickening and molting disruptions. LdKnk2 knockdown increased epicuticle and endocuticle thickness without visible phenotypic changes. The study highlights the essential roles of LdKnk-family genes in maintaining cuticle structure and integrity, suggesting their potential as targets for RNAi-based pest control. [ABSTRACT FROM AUTHOR]

This study investigates the propagation of dark Alfvén solitons in low-β magnetized plasma using Hall-magnetohydrodynamic (Hall-MHD) numerical simulations. The rational solution of the nonlinear Schr o ̈ dinger equation (NLSE) is presented, which is proposed as an effective tool for studying dark envelope solitons in plasma. Our results show a high degree of agreement between numerical simulations and analytical solutions derived from the NLSE via the reductive perturbation method. This agreement validates our modeling and computational approach. In addition, the simulations confirm the existence of dark Alfvén solitons in magnetized plasma. This work demonstrates the effectiveness of Hall-MHD simulations in studying complex plasma phenomena, contributing to the broader understanding of soliton propagation in plasma environments. [ABSTRACT FROM AUTHOR]